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Size effects of latex nanomaterials on lung inflammation in mice
Abstract
Effects of nano-sized materials (nanomaterials) on sensitive population have not been well elucidated. This study examined the effects of pulmonary exposure to (latex) nanomaterials on lung inflammation related to lipopolysaccharide (LPS) or allergen in mice, especially in terms of their size-dependency. In protocol 1, ICR male mice were divided into 8 experimental groups that intratracheally received a single exposure to vehicle, latex nanomaterials (250 μg/animal) with three sizes (25, 50, and 100 nm), LPS (75 μg/animal), or LPS plus latex nanomaterials. In protocol 2, ICR male mice were divided into 8 experimental groups that intratracheally received repeated exposure to vehicle, latex nanomaterials (100 μg/animal), allergen (ovalbumin: OVA; 1 μg/animal), or allergen plus latex nanomaterials. In protocol 1, latex nanomaterials with all sizes exacerbated lung inflammation elicited by LPS, showing an overall trend of amplified lung expressions of proinflammatory cytokines. Furthermore, LPS plus nanomaterials, especially with size less than 50 nm, significantly elevated circulatory levels of fibrinogen, macrophage chemoattractant protein-1, and keratinocyte-derived chemoattractant, and von Willebrand factor as compared with LPS alone. The enhancement tended overall to be greater with the smaller nanomaterials than with the larger ones. In protocol 2, latex nanomaterials with all sizes did not significantly enhance the pathophysiology of allergic asthma, characterized by eosinophilic lung inflammation and Igs production, although latex nanomaterials with less than 50 nm significantly induced/enhanced neutrophilic lung inflammation. These results suggest that latex nanomaterials differentially affect two types of (innate and adaptive immunity-dominant) lung inflammation.
... For example, when a dose of 1.25 mg/kg was administered to rats by oral gavage, NPs of 50 nm demonstrated the highest extent of translocation and most varied range of biodistribution, whereas micronsized particles of 3 μm were only retained at low concentrations and not found outside the digestive system [161]. More recently, this size-dependent effect has been confirmed on numerous occasions, including observations of low translocation of micron-sized plastics following oral gavage in mice [162], transport of nanosized PS (20,40,100,200, and 500 nm) across the placenta and deposition within foetal organs following intravenous exposure to pregnant mice [163], and higher levels of toxicity and pulmonary inflammation associated with smaller nano-sized PS following intratracheal instillation of both rats [164] and mice [165]. Although these studies provide an indication that NPs may offer a wider distribution following exposure, and with it potentially greater toxicity, this is not to say that these larger (micro-sized) particles pose no hazard. ...
... The addition of LPS to the surface of normally innocuous nanomaterials such as gold, has been shown to elicit strong responses in vitro [119], or even act synergistically in the stimulation of proinflammatory responses [217]. It is highly likely that if found under the same conditions, NMPs would induce similar responses to those of the innocuous particles mentioned above, and is certainly a scenario which requires attention, as demonstrated by Inoue et al. [165]. Using a mouse model, with exposure via intratracheal instillation, Inoue et al. [165] were able to discern the effect of combined exposures of latex nanoparticles with either LPS or the allergen ovalbumin (OVA). ...
... It is highly likely that if found under the same conditions, NMPs would induce similar responses to those of the innocuous particles mentioned above, and is certainly a scenario which requires attention, as demonstrated by Inoue et al. [165]. Using a mouse model, with exposure via intratracheal instillation, Inoue et al. [165] were able to discern the effect of combined exposures of latex nanoparticles with either LPS or the allergen ovalbumin (OVA). It was shown that latex nanomaterials in co-exposure with LPS significantly intensified lung inflammation compared to that elicited by either latex alone or LPS alone, and this was shown for various sizes (25,50, and 100 nm) of latex nanoparticles. ...
Human exposure to nano- and microplastics (NMPs) has raised major societal concerns, yet no framework to assess the risks of NMPs for human health exists. A substantial proportion of plastic produced worldwide is not properly
disposed and persists in the environment for decades while degrading. Plastic degradation generates a size continuum of fragments, including nano- and microplastic particles, with numerous associated environmental
pollutants and plastic additives, and microbial communities colonising their surfaces. The ubiquitous presence of NMPs, their availability for uptake by organisms and their potential to act as vectors for toxicants and pathogens
render risk assessment a priority on the political agenda at the global level. We provide a new, fully integrated risk
assessment framework tailored to the specificities of NMPs, enabling an assessment of current and future human health risks from NMPs. The framework consists of four novel paradigms to the traditional risk assessment
methodology. These paradigms deal with techniques in NMP analysis, gaps in empirical data, theoretical and modelling approaches and stakeholder engagement. Within the proposed framework, we propose how we can use
research experiences gained so far to carry out the different steps of the assessment process, and we define priorities for further research.
Keywords: Microplastics, nanoplastics, risk assessment, human health, hazard identification, exposure assessment, hazard characterization, stakeholder engagement, food, air
... Among various physicochemical features, particle size of metallic NPs has shown greater relevance with immunotoxicity [38][39][40][47][48][49][50][51][52]. Coradeghini et al. [38] have evaluated size-dependent immunotoxicity of different sizes (5 and 15 nm) of citrate-capped Au-NPs by using the mouse fibroblasts. ...
... Owing to their higher internalization, they provoke more severe immunotoxicity compared to bigger size particles [47]. Similarly, Inoue et al. [49] evaluated the immunotoxic potential of metallic NPs at three different sizes (such as 25, 50, and 100 nm). Results showed that ultra-fine particles (25 nm) induced highest immune reaction and inflammation compared with larger size particles. ...
... Results showed that ultra-fine particles (25 nm) induced highest immune reaction and inflammation compared with larger size particles. Since the particle size and the relative surface area are directly proportional to each other, the smaller the size, the higher the surface area and thus the higher dissolution of toxic ions, leading to greater ROS generation [49]. ...
Owing to their specialized characteristic features, nanomaterials have been dynamically employed in various fields including the medical and health sciences. However, unwanted biological interactions of nanomaterials with biomolecules, cells, tissues, organs, or body systems is critically important and not fully understood, yet. Therefore, the aim of the present review is to critically analyse the available evidence and comprehend the journey of nanomaterials in the body after their exposure through different routes (i.e., oral, inhalation, percutaneous or intravenous). Analysis of the literature revealed that upon interaction with biological tissues, nanomaterials induce oxidative stress via generation of super-reactive free radical species, leading to genotoxicity, mitochondrial damage, lysosomal dysfunction, and ultimately cell necrosis or apoptosis. The nanotoxicity induced by nanomaterials is very much dependent on their physicochemical features (i.e., size, surface chemistry, and morphology), dosage regimen, route of exposure, and immunogenicity. Through careful design of nanomaterials exhibiting optimum physicochemical characteristics and successive assessment of nanotoxicity through validated experimentation, unwanted biological concerns can be avoided.
... The significantly greater level of OVA-specific serum IgE and IgG1, airway eosinophil inflammation, mucous cell metaplasia, and Th2 and Th17 cytokine gene and protein expression were observed from the SNP/OVA-mice compared to those from OVA-mice or SNP/saline-mice, and these results indicate that airway exposure to engineered SNP during the sensitization of mice to OVA enhances allergic airway disease with a dose-dependent fashion upon secondary OVA challenge. Besides silica nanoparticles, the adverse adjuvant effect of other nanomaterials, such as carbon black nanoparticles (CNP, (73)), single-walled carbon nanotubes (SWCNT, (74)), silver nanoparticles (AgNP, (75)) and latex nanoparticles (LNP, (76)) have also been studied in literatures. CNP (14 and 56 nm, (73)) was used and intratracheally administrated with bacterial endotoxin (lipopolysaccharide, LPS) in ICR male mice and the results indicate that CNP can aggravate the LPS-related lung inflammation with 14-nm CNP having more severe inflammation than 56-nm CNP. ...
... More recently, the adverse asthmatic effect of AgNP (33 nm) was reported by Cheng and coworkers using proteomic approach in allergen OVA-AgNP sensitized female BALB/c mice model (75). The protein profiles of bronchoalveolar lavage fluid (BALF) and plasma suggested that metabolic, cellular, and immune system processes were associated with pulmonary exposure to AgNPs, and significant allergy responses were observed after AgNP exposure in both control and allergic mice as determined by greater level of OVA-specific Ig E. The size effect of adjuvant activity of spherical LNP (25, 50 and 100 nm, carboxylated particle surface) on lung inflammation in mice induced by LPS or OVA allergen was studied by Inoue and coworkers (76). Surprisingly, LNP with all sizes in mice model sensitized by OVA-LNP did not enhance significant allergic asthma. ...
Nanoparticles have growing applications in industry, consumer products, biology and medicine. One of those applications involves the interaction between nanoparticles and immune components. The nanoparticles can act as antigen carriers to deliver and release antigens to specific targets, and enhance the immune response against a variety of antigens as adjuvants. The adjuvant effects of nanoparticle size, shape, surface charge, linkage method on the immunological response are also discussed. In contrast, as-prepared nanomaterials and ambient particulate matter (PM) from air pollution exhibit adverse adjuvant effect in vitro and in vivo, and recent advances to address their potential risk on human health are also included in this review.
... In a similar investigation, 14-nm carbon black nanoparticles significantly aggravated lung inflammation and pulmonary edema, whereas larger nanoparticles (56 nm) did not [70]. In another study, small latex nanoparticles (less than 50 nm) amplified the lung inflammation elicited by LPS in ICR mice compared with large nanoparticles [109]. ...
... After concomitant intratracheal instillation of OVA and carbon nanoparticles in mice, IL-5 expression, activation of Th2-like lymphocytes, and eosinophilic inflammation were observed [108]. An enhancement of neutrophilic rather than eosinophilic lung inflammation by latex nanoparticles in OVA-sensitized mice has been reported [109]. Simultaneous intranasal exposure to OVA and TiO 2 nanoparticles (14 and 29 nm) to mice amplifies the effects of OVA in inducing cell immunity as manifested by the increased number of lung-draining peribronchial lymph node cells and the production of OVA-specific Th2 cytokines (interleukin (IL)-4 (IL-4), IL-5, IL-10, and IL-13) [110]. ...
Due to the increasing applications of nanomaterials and nanotechnology, potential danger of nanoparticle exposure has become a critical issue. However, recent nanotoxicity studies have mainly focused on the health risks to healthy adult population. The nanotoxicity effects on susceptible populations (such as pregnant, neonate, diseased, and aged populations) have been overlooked. Due to the alterations in physiological structures and functions in susceptible populations, they often suffer more damage from the same exposure. Thus, it is urgent to understand the effects of nanoparticle exposure on these populations. In order to fill this gap, the potential effects of nanoparticles to pregnant females, neonate, diseased, and aged population, as well as the possible underlying mechanisms are reviewed in this article. Investigations show that responses from susceptible population to nanoparticle exposure are often more severe. Reduced protection mechanism, compromised immunity, and impaired self-repair ability in these susceptible populations may contribute to the aggravated toxicity effects. This review will help minimize adverse effects of nanoparticles to susceptible population in future nanotechnology applications.
... Note that the physical and chemical properties of all materials change as their size decreases to the nanometer scale [2]. Compared with the bulk size of the same material, nano-sized particles exhibit different optical, electrical, and magnetic properties [3]. Their properties depend on certain properties such as particle size, distribution, morphology [4], and high surface/volume ratio [5]. ...
In this work, the one-step synthesis of multicomponent polymer nanocomposites containing zinc oxide and cuprous oxide nanoparticles based on chitosan and polyvinyl alcohol was investigated using underwater pulsed discharge plasma. Direct initiation of electrical discharge between metal electrodes in a polymer solution enables reagent-free obtaining of metal oxide nanoparticles with an average diameter of about 30 nm. Transmission electron microscopy observations showed °that metal oxide nanoparticles uniformly dispersed in polymer matrix. It has been established that a partial destruction of chitosan occurs with the formation of glucosamine, N-acetylglucosamine, and delta-mannitol under the action of the discharge. The polymer film containing 0.35% Cu2O and 3.41% ZnO nanoparticles demonstrated the highest antimicrobial activity Escherichia coli, Staphylococcus albicans, and Bacillus subtilis.
... The biodistribution and toxicity of microspheres are believed to be related to particle size [2,11,12,13], dose [14], rigidity [11,15,16], and shape [13,17,18]. Studies have shown that regardless of the type of microspheres (non-biodegradable or biodegradable), a particle size of 7-12 µm is the best for passive lung-targeting [2,19]. ...
Background: In the treatment of lung diseases, drug showed low bioavailability and efficacy by conventional administration methods. Passive lung-targeting microspheres provide a method to deliver drugs from the vascular side, there is still a paucity of systematic studies on the biocompatibility of biodegradable-polymer microspheres.
Results: We used poly (lactic acid-glycolic acid) (PLGA) microspheres with different particle sizes (3, 10, 25, and 40 mm) as a model. The optimal lung-targeting particle size of the PLGA microspheres is 10 mm and the corresponding range of maximum tolerated dose is 125-150 mg/kg. We hypothesized that the decrease of blood oxygen saturation under treatment of microspheres was caused by pulmonary embolism. We found varying degrees of blood circulation loss of lungs by micro computed tomography test, which indicated severe pulmonary embolism subsequent to intravenous injection of microspheres with a particle size >25 mm. Furthermore, we found lung injury and microspheres leaked from the blood vessels into the alveoli by H&E staining. This process was likely induced by increased secretion of matrix metalloproteinases (MMPs), which destroyed the alveolar-capillary barrier and trigger an inflammatory cascade. Finally, we found that optimal particle size and dose conditions did not affect normal physiological activities after the microspheres degraded. The upregulation of vascular endothelial growth factor (VEGF) and platelet endothelial cell adhesion molecule-1 (PECAM-1 or CD31) induced vessel recanalization and reestablishment, which promoted the progress of lung repair.
Conclusions: Collectively, our results highlight the importance of accurately designing the optimal size and dose of microspheres for passive lung-targeting delivery.
... Materials manufactured at the nano-scale, have properties that differ from their "bulk sized" equivalents, often due to their large surface area to volume ratio. Although in one study larger intratracheally instilled nanoparticles particles were found to be more toxic in mice (Grassian et al., 2007), inhalation studies in other rodents and in vitro studies have in general indicated that smaller NPs generate greater inflammatory responses than larger ones (Brown et al., 2001;Inoue et al., 2009;Singh et al., 2004). Though size and surface area are related, size may however not be an accurate dose pattern. ...
The novel characteristics specific to nanomaterials have led to many new applications. The property of NMs is unique as they differ significantly from their microcrystalline counterpart. These properties offer great opportunities for the development of new industrial applications increasing their worldwide distribution. Widescale commercial exploitation also enhances the likelihood of their environmental and human exposure. In this regard, nanotoxicology and nano-risk have been attracting the increasing attention of toxicologists and regulatory scientists, particularly in relation to the unique properties of NPs that may render them potentially more dangerous than their micro-sized counterpart and may cause unexpected adverse health effects to exposed people However, there are also concerns arising on the potential health and environmental impacts of such nanomaterials. There are several pathways that includes air, water and land borne pathways leading to exposure of such nanomaterials to living systems. Therefore, it is articulated that prerequisite of nanotoxicological assessment is the need of the hour. This review provides international status on studies relating to nanotoxicological assessment and factors of nano-bio interactions within biological systems.
... Nanotechnology is known as the formulation, utilization and synthesis of materials at a scale up to 100 nm in diameter (2). The nanosize of particles change their physical and chemical properties and thus will lead to show various optical, magnetic and electric properties (3). The reason for the nanoparticles differ in their properties from conventional materials is the size, shape, distribution and surface / volume ratio of nanoparticles (4). ...
Abstract. The efficiency of copper oxide nanoparticles synthesized from aqueous extract of
cordia myxa L. on some breast cancer lines AMJ-13,MCF-7, and HBL-100 as normal cell
lines was studied. Different concentration of copper oxide nanoparticles (25 ,50,75,100)
μg/ml at different times (24,48 and72) h were selected. The results showed that the effect of
nanoparticles depend on the concentration. As the concentration of nanoparticles increase the
percent of inhibition increase. It was found that concentration of copper oxide nanoparticles
at 100 μg / ml gave the highest inhibitory rate of cell growth MCF-7 (71.1%) after 24 hours,
while the percent of inhibition for AMJ-13 was (69.6)%. When the exposure time was
increased to48 h, the rate of inhibition at 100 mg/ml was 80% for MCF-7 while 73% for
AMJ13 . By increasing the duration of the exposure to 72 hours, the rate of inhibition at
l00μg/ml were (85.2 and 78.2)for MCF-7 and AMJ13 respectively .No significant inhibition
was found for HBL-100 at different concentration and different times. These results was
indicated that copper oxide nanoparticles synthesized from the aqueous extract of cordia
myxa L. had a toxic effect on growth of some breast cancer cell lines.
... Nanotechnology is known as the formulation, utilization and synthesis of materials at a scale up to 100 nm in diameter (2). The nanosize of particles change their physical and chemical properties and thus will lead to show various optical, magnetic and electric properties (3). The reason for the nanoparticles differ in their properties from conventional materials is the size, shape, distribution and surface / volume ratio of nanoparticles (4). ...
Abstract. The efficiency of copper oxide nanoparticles synthesized from aqueous extract of
cordia myxa L. on some breast cancer lines AMJ-13,MCF-7, and HBL-100 as normal cell
lines was studied. Different concentration of copper oxide nanoparticles (25 ,50,75,100)
μg/ml at different times (24,48 and72) h were selected. The results showed that the effect of
nanoparticles depend on the concentration. As the concentration of nanoparticles increase the
percent of inhibition increase. It was found that concentration of copper oxide nanoparticles
at 100 μg / ml gave the highest inhibitory rate of cell growth MCF-7 (71.1%) after 24 hours,
while the percent of inhibition for AMJ-13 was (69.6)%. When the exposure time was
increased to48 h, the rate of inhibition at 100 mg/ml was 80% for MCF-7 while 73% for
AMJ13 . By increasing the duration of the exposure to 72 hours, the rate of inhibition at
l00μg/ml were (85.2 and 78.2)for MCF-7 and AMJ13 respectively .No significant inhibition
was found for HBL-100 at different concentration and different times. These results was
indicated that copper oxide nanoparticles synthesized from the aqueous extract of cordia
myxa L. had a toxic effect on growth of some breast cancer cell lines.
... Effect of pH: Green synthesis of copper oxide nanoparticles using aqueous extract of Cordia myxa L. leaves was examined over a broad pH range (3)(4)(5)(6)(7)(8)(9)(10)(11). Variations in pH were highly affected the SPR of CuONPs. ...
Copper oxide nanoparticles )CuONPs) were green synthesized using leaf extract of cordiamyxa L as reducing and capping agent. The synthesized nanoparticles were characterized byUV –visible spectrophotometer ,FTIR,X-ray diffraction,scanning electron microscope, and atomic force microscope.The prepared copper oxide nanoparticles showed surface Plasmon resonance centered at 400 nm. The optimized condition for the synthesis of copper nanoparticles revealed that,aqueous extract : copper sulfate ratio was 1:3, pH was 9andcopper sulfate concentration was 40 mM.FTIR results showed that stabilization and formationof CuONPs were due to phenolic groups and amines in plant extract. The XRD pattern showed that the particles are monoclinic in nature.The crystalline morphology and size of the nanoparticles were determined by SEM.Presence of elemental copper was revealed by EDX analysis.Size range wasfrom20 nm to 106.81nm was determined by atomic force microscope.
... Furthermore, various characteristics, including size of particles, composition, surface area and surface chemistry, coagulation and aggregation state, vapor pressure, and lipid and water solubility, also influenced particle properties [8,10]. The toxicity is also affected by the size of nanoparticles [11][12][13]. However, the relationship between biological effects and particle size of Ag-NPs is still unclear. ...
Silver nanoparticles (Ag-NPs) have wide applications in the medical field; however, the toxicological effects are still poorly studied. The study was aimed to determine the effects of 15.78 nm spherical and amine-coated Ag-NPs on hematology and histology of gills and liver tissues in 28 days treated Labeo rohita (L. rohita). It was found that Ag-NPs induced alterations in the hematological parameters in a dose dependent manner. The Ag-NPs also induced histological alterations in a dose-dependent manner. In gill tissues, it induced fusion of secondary lamellae, separation of gill epithelium, fusion and necrosis of lamellar cells, hyperplasia, deformed cartilaginous skeleton, separation and lifting of epithelium, and curling of lamellae in a dose dependent manner. In the liver, Ag-NPs produced abnormalities in hepatic tissues by reducing the size of hepatocytes and nuclei, and stimulated the production of necrotic and apoptotic bodies. It was concluded that Ag-NPs are toxic to aquatic organisms and induce hematotoxicity and histopathological conditions in exposed fish.
... Several studies have demonstrated that size significantly determines nanoparticle biological effects (5)(6)(7)(78)(79)(80)(81)(82)(83). The smaller the size, the higher the relative surface area, and therefore the higher the dissolution of toxic ions and reactive oxygen species (ROS) production (71). ...
When nanoparticles enter the body, their interactions with cells are almost unavoidable. Unintended nanoparticle interaction with immune cells may elicit a molecular response that can have toxic effects and lead to greater susceptibility to infectious diseases, autoimmune disorders, and cancer development. As evidenced by several studies, nanoparticle interactions with biological systems can stimulate inflammatory or allergic reactions and activate the complement system. Nanoparticles can also stimulate immune response by acting as adjuvants or as haptens. Immunosuppressive effects have also been reported. This article gives a brief review of in vitro and in vivo research evidencing stimulatory or suppressive effects of nanoparticles on the immune system of mammals. In order to ensure safe use of nanosized particles, future research should focus on how their physical and chemical properties influence their behaviour in the biological environment, as they not only greatly affect nanoparticle-immune system interactions but can also interfere with experimental assays.
... No information [57] PEGylated gold nanoparticles Endotoxin contamination: a key element in the interpretation of nanosafety studies Review toxin could promote the adverse effects of engineered nanoparticles on lung functions both in vitro and in vivo [48][49][50][51][52]. Titanium particles, which deliberately contaminated with endotoxin, triggered inflammation in macrophages by inducing the production of inflammatory cytokines. ...
The study of toxicity and potential risks of engineered nanoparticles is of particular importance in nanomedicine. Endotoxin, a common contaminant of bacterial origin, has biological effects that can mask the true biological effects of nanoparticles, if its presence is overlooked. In this review, we report the features of nanoparticle contamination by endotoxin, and the different biological effects of endotoxin-contaminated nanoparticles. We will describe different methods for endotoxin detection applied to nanoparticles, and discuss their pros and cons. Eventually, we describe various methods for eliminating endotoxin contamination in nanoparticles. Although there is no universal technique for efficiently removing endotoxin from nanoparticles, specific solutions can be found case by case, which can allow us to perform nanosafety studies in biologically relevant conditions.
... Several studies have demonstrated that size significantly determines nanoparticle biological effects (5)(6)(7)(78)(79)(80)(81)(82)(83). The smaller the size, the higher the relative surface area, and therefore the higher the dissolution of toxic ions and reactive oxygen species (ROS) production (71). ...
When nanoparticles enter the body, their interactions with cells are almost unavoidable. Unintended nanoparticle interaction with immune cells may elicit a molecular response that can have toxic effects and lead to greater susceptibility to infectious diseases, autoimmune disorders, and cancer development. As evidenced by several studies, nanoparticle interactions with biological systems can stimulate inflammatory or allergic reactions and activate the complement system. Nanoparticles can also stimulate immune response by acting as adjuvants or as haptens. Immunosuppressive effects have also been reported. This article gives a brief review of in vitro and in vivo research evidencing stimulatory or suppressive effects of nanoparticles on the immune system of mammals. In order to ensure safe use of nanosized particles, future research should focus on how their physical and chemical properties influence their behaviour in the biological environment, as they not only greatly affect nanoparticle-immune system interactions but can also interfere with experimental assays.
... These data show stronger stimulation of the immune system by 14 nm carbon black particles than by 95 nm particles (Shwe et al. 2005). Polystyrene latex particles of 25 and 50 nm had a stronger effect than 100 nm particles (Inoue et al. 2009), while 50 and 200 nm gold NPs caused similarly little inflammation (Gosens et al. 2010). These data suggest stronger immune stimulation by smaller than by larger particles. ...
Adverse effect of nanoparticles may include impairment of phagocyte function. To identify the effect of nanoparticle size on uptake, cytotoxicity, chemotaxis, cytokine secretion, phagocytosis, oxidative burst, nitric oxide production and myeloperoxidase release, leukocytes isolated from human peripheral blood, monocytes and macrophages were studied. Carboxyl polystyrene (CPS) particles in sizes between 20 and 1,000 nm served as model particles. Twenty nanometers CPS particles were taken up passively, while larger CPS particles entered cells actively and passively. Twenty nanometers CPS were cytotoxic to all phagocytes, ≥500 nm CPS particles only to macrophages. Twenty nanometers CPS particles stimulated IL-8 secretion in human monocytes and induced oxidative burst in monocytes. Five hundred nanometers and 1,000 nm CPS particles stimulated IL-6 and IL-8 secretion in monocytes and macrophages, chemotaxis towards a chemotactic stimulus of monocytes and phagocytosis of bacteria by macrophages and provoked an oxidative burst of granulocytes. At very high concentrations, CPS particles of 20 and 500 nm stimulated myeloperoxidase release of granulocytes and nitric oxide generation in macrophages. Cytotoxic effect could contribute to some of the observed effects. In the absence of cytotoxicity, 500 and 1,000 nm CPS particles appear to influence phagocyte function to a greater extent than particles in other sizes.
... The mechanism behind the exaggeration of endotoxin-induced PCA by dendrimers remains unknown. Understanding this phenomenon is important, because exaggeration of other endotoxin-mediated inflammatory reactions has been reported for several types of nanomaterials [22][23][24]. It is also important to the nanomedicine field, because endotoxin contamination is very common in engineered nanomaterials, and amino groups are often used for drug, ligand and imaging agent conjugation to nanoparticle surfaces. ...
Nanoparticle interactions with the blood coagulation system can be beneficial or adverse depending on the intended use of a nanomaterial. Nanoparticles can be engineered to be procoagulant or to carry coagulation-initiating factors to treat certain disorders. Likewise, they can be designed to be anticoagulant or to carry anticoagulant drugs to intervene in other pathological conditions in which coagulation is a concern. An overview of the coagulation system was given and a discussion of a desirable interface between this system and engineered nanomaterials was assessed in part I, which was published in the May 2013 issue of Nanomedicine. Unwanted pro- and anti-coagulant properties of nanoparticles represent significant concerns in the field of nanomedicine, and often hamper the development and transition into the clinic of many promising engineered nanocarriers. This part will focus on the undesirable effects of engineered nanomaterials on the blood coagulation system. We will discuss the relationship between the physicochemical properties of nanoparticles (e.g., size, charge and hydrophobicity) that determine their negative effects on the blood coagulation system in order to understand how manipulation of these properties can help to overcome unwanted side effects.
... Although low chimerism inherent in these experimental approaches may lead to some underestimation of slow microglia turnover from the periphery [39], a more likely explanation of our findings is that particles exert stimulatory effects on myeloid cell trafficking [36]. Both latex particles and aluminum hydroxide agglomerates promote inflammation [40,41] and non-specific immune stimulation can increase monocyte transendothelial migration by up to 20-fold in in vitro models of the BBB [42]. Consistently, i.m. injection of rCCL2 strongly increased particle incorporation into intact brain while CCL2-deficient mice had decreased neurodelivery. ...
Long-term biodistribution of nanomaterials used in medicine is largely unknown. This is the case for alum, the most widely used vaccine adjuvant, which is a nanocrystalline compound spontaneously forming micron/submicron-sized agglomerates. Although generally well tolerated, alum is occasionally detected within monocyte-lineage cells long after immunization in presumably susceptible individuals with systemic/neurologic manifestations or autoimmune (inflammatory) syndrome induced by adjuvants (ASIA).
On the grounds of preliminary investigations in 252 patients with alum-associated ASIA showing both a selective increase of circulating CCL2, the major monocyte chemoattractant, and a variation in the CCL2 gene, we designed mouse experiments to assess biodistribution of vaccine-derived aluminum and of alum-particle fluorescent surrogates injected in muscle. Aluminum was detected in tissues by Morin stain and particle induced X-ray emission) (PIXE) Both 500 nm fluorescent latex beads and vaccine alum agglomerates-sized nanohybrids (Al-Rho) were used.
Intramuscular injection of alum-containing vaccine was associated with the appearance of aluminum deposits in distant organs, such as spleen and brain where they were still detected one year after injection. Both fluorescent materials injected into muscle translocated to draining lymph nodes (DLNs) and thereafter were detected associated with phagocytes in blood and spleen. Particles linearly accumulated in the brain up to the six-month endpoint; they were first found in perivascular CD11b+ cells and then in microglia and other neural cells. DLN ablation dramatically reduced the biodistribution. Cerebral translocation was not observed after direct intravenous injection, but significantly increased in mice with chronically altered blood-brain-barrier. Loss/gain-of-function experiments consistently implicated CCL2 in systemic diffusion of Al-Rho particles captured by monocyte-lineage cells and in their subsequent neurodelivery. Stereotactic particle injection pointed out brain retention as a factor of progressive particle accumulation.
Nanomaterials can be transported by monocyte-lineage cells to DLNs, blood and spleen, and, similarly to HIV, may use CCL2-dependent mechanisms to penetrate the brain. This occurs at a very low rate in normal conditions explaining good overall tolerance of alum despite its strong neurotoxic potential. However, continuously escalating doses of this poorly biodegradable adjuvant in the population may become insidiously unsafe, especially in the case of overimmunization or immature/altered blood brain barrier or high constitutive CCL-2 production.
... Some studies have demonstrated that ultrafine particle exposure to the respiratory tract can induce pulmonary inflammation [9,10,[25][26][27]. Latex nanomaterials instilled intratracheally enhanced neutrophilic lung inflammation with pulmonary vascular permeability related to LPS resulting from the activation of innate immune responses [28]. The present study was performed to assess pulmonary immune responses and toxicity in response to nasal administration of nano-TiO 2 and found that 38 genes (4.49% of 847 genes) involved in immune and inflammatory responses were significantly changed as shown by the microarray data (Table S1). ...
The pulmonary damage induced by nanosized titanium dioxide (nano-TiO(2)) is of great concern, but the mechanism of how this damage may be incurred has yet to be elucidated. Here, we examined how multiple genes may be affected by nano-TiO(2) exposure to contribute to the observed damage. The results suggest that long-term exposure to nano-TiO(2) led to significant increases in inflammatory cells, and levels of lactate dehydrogenase, alkaline phosphate, and total protein, and promoted production of reactive oxygen species and peroxidation of lipid, protein and DNA in mouse lung tissue. We also observed nano-TiO(2) deposition in lung tissue via light and confocal Raman microscopy, which in turn led to severe pulmonary inflammation and pneumonocytic apoptosis in mice. Specifically, microarray analysis showed significant alterations in the expression of 847 genes in the nano-TiO(2)-exposed lung tissues. Of 521 genes with known functions, 361 were up-regulated and 160 down-regulated, which were associated with the immune/inflammatory responses, apoptosis, oxidative stress, the cell cycle, stress responses, cell proliferation, the cytoskeleton, signal transduction, and metabolic processes. Therefore, the application of nano-TiO(2) should be carried out cautiously, especially in humans.
... In addition, typical granulomatous reactions are observed after pulmonary exposures to CNTs [39][40][41]. Furthermore functional disturbances could be observed after NP exposure including airway hyper-reactivity (AHR) to non-specific stimuli, tissue injury leading to disturbance in respiratory functions [42][43][44][45] and effects on existing pulmonary inflammation [46]. These disturbances are generally studied in pathologic animal models, like asthma etc. Translocation could be increased by lung injury and thus the presence of cadmium NPs in the liver, after inhalation of high doses, has been attributed to their pulmonary toxicity [47]. ...
Nanotechnology is a promising tool for the development of innovative treatment strategies allowing to overcome obstacles encountered by classical drug delivery. This has led to the development of nanomedicine. Indeed, nano-delivery systems (NDS) may allow the controlled release of therapeutics, protection of drugs against degradation, targeted drug delivery and facilitated transport across barriers. All these advantages of NDS are particularly interesting for treatments of the lung which is a challenging organ in respect to drug delivery. However, for the development of nanomaterials aimed to transport therapeutics, there is also a need to assess the potential health hazards of these new materials, especially as a variety of nanoparticles have been shown to induce toxicity related to their nanometer size leading to the new field of nanotoxicology. We will address both aspects of NDS, specifically in respect to lung treatments: their potential benefits and the possible adverse health effects of these materials.
... However, it has been largely unclear how exposure to these nanomaterials affects human health, especially the airway tissues. Inoue et al. (2005 Inoue et al. ( , 2009a Inoue et al. ( , 2009b) and others (Alessandrini, 2006; de Haar, 2008) have extensively studied the effects of nanoparticles on allergen-induced asthmatic responses in mice, reporting that relatively small diameters of particles induced enhancement of allergic airway inflammation. For example, nanoparticles with a diameter of 14 nm produced more prominent allergic airway inflammation, characterized by infiltration of eosinophils and neutrophils, by an increase in epithelial goblet cell number, and by increases in levels of cytokines and chemokines in the lung than those with a diameter of 56 nm. ...
... These results suggest that nanomaterials exacerbate lung inflammation related to LPS with systemic inflammation and coagulatory disturbance and that the exacerbation is more prominent with smaller nanomaterials than with larger ones [36]. Additionally, we demonstrated that latex nanoparticles [37] and carbon nanotubes [38] have similar effects on the lung pathophysiology. ...
Although the adverse health effects of nanoparticles/materials have been proposed and are being clarified, their facilitating effects on preexisting pathological conditions have not been fully established. We provide insights into the environmental immunotoxicity of nanoparticles as an aggravating factor in hypersusceptible subjects, especially those with respiratory disorders, using our in vivo models. We first examined the effects of nanoparticles/materials on lung inflammation induced by bacterial endotoxin (lipopolysaccharide) as a test model against innate immunity, and demonstrated that nanoparticles instilled through both an intratracheal tube and an inhalation system can exacerbate lung inflammation. Secondly, we examined the effects of nanoparticles/materials on allergic pathophysiology, and showed that repetitive pulmonary exposure to nanoparticles has aggravating effects on allergic airway inflammation, including adjuvant effects on Th2-milieu. Taken together, nanoparticle exposure may synergistically facilitate pathological inflammatory conditions in the lung via both innate and adaptive immunological abnormalities.
... These results suggest that engineered nanoparticles also exacerbate lung inflammation related to LPS and accompanying systemic inflammation, and the exacerbation is more prominent with smaller nanoparticles than with larger particles[44]. Additionally, we demonstrated that latex nanoparticles[45] and carbon nanotubes[46] have similar aggravating potential on the lung pathophysiology. Our next study was conducted to determine whether inhaled exposure to diesel engine–derived nanoparticles also exacerbates the model. ...
Although the adverse health effects of nanoparticles have been proposed and are being clarified, their aggravating effects on pre-existing pathological conditions have not been fully investigated. In this review, we provide insights into the immunotoxicity of both airborne and engineered nanoparticles as an exacerbating factor on hypersusceptible subjects, especially those with immune-mediated pulmonary inflammation, using our in vivo experimental model. First, we exhibit the effects of nanoparticles on pulmonary inflammation induced by bacterial endotoxin (lipopolysaccharide: LPS) as a disease model in innate immunity, and demonstrate that nanoparticles instilled through both an intratracheal tube and an inhalation system can exacerbate the lung inflammation. Second, we introduce the effects of nanoparticles on allergic pulmonary inflammation as a disease model in adaptive immunity, and show that repetitive pulmonary exposure to nanoparticles has aggravating effects on allergic inflammation, including adjuvant effects on Th2-milieu. Third, we show that very small nanoparticle exposure exacerbates emphysematous pulmonary inflammation, which is concomitant with enhanced lung expression of proinflammatory molecules (including those that are innate immunity related). Taken together, nanoparticle exposure may synergistically facilitate pathological pulmonary inflammation via both innate and adaptive immunological impairment.
... These results suggest that nanomaterials exacerbate lung inflammation related to LPS with systemic inflammation and coagulatory impairment, and the exacerbation is more prominent with smaller nanomaterials than that with larger ones ( [35] and unpublished data). Additionally, we demonstrated that latex nanoparticles [36] and carbon nanotubes [37] have similar adverse effects on the lung pathophysiology. ...
Although the adverse health effects of nanoparticles/materials have been proposed and are being clarified, their facilitating effects on preexisting pathological conditions have not been fully examined. In this paper, we provide insights into the immunotoxicity of nanoparticles/materials as an aggravating factor in hypersusceptible subjects, especially those with immune-related respiratory disorders using our in vivo experimental model. We first exhibit the effects of nanoparticles/materials on lung inflammation induced by bacterial endotoxin (lipopolysaccharide: LPS) in vivo as a disease model in innate immunity, and demonstrated that nanoparticles instilled through both an intratracheal tube and an inhalation system can exacerbate the lung inflammation. Secondly, we introduce the effects of nanoparticles/materials on allergic asthma in vivo as a disease model in adaptive immunity, and showed that repetitive pulmonary exposure to nanoparticles has aggravating effects on allergic airway inflammation, including adjuvant effects on Th2-milieu. Taken together, nanoparticle exposure may synergistically facilitate pathological inflammatory conditions in the lung via both innate and adaptive immunological abnormalities.
... Size, and therefore surface area, have been implicated as key factors influencing the toxicity of nanoparticles� Inhalation studies in rodents and in vitro studies have in general indicated that smaller nanoparticles generate greater inflammatory responses than larger particles (Brown et al�, 2001;Inoue et al�, 2009;Singh et al�, 2004)� Although size and surface area are related, size may, however, not be an accurate dose metric� Instillation studies in mouse and rat models have shown that although smaller-sized nanoparticles cause a greater inflammatory response than larger-sized particles on a mass basis, the level of inflammatory response was dependent on the total surface area of particles instilled (Brown et al�, 2001;Oberdörster, 2000;Stoeger et al�, 2006;Yamamoto et al�, 2006)� In vitro studies with mammalian cells have also shown that the size of a particle, and therefore likely its surface area, may play a role in mediating response, demonstrating that smaller-sized particles are more toxic (Karlsson et al�, 2009;Renwick et al�, 2004;Tamura et al�, 2004) than larger-sized particles and there is a size-dependent generation of ROS (Cagle et al�, 1999;)� In non-mammalian systems, particle size has been indicated to affect its relative toxicity� The size of a number of different nanoparticle types, including TiO 2 and polystyrene, has been shown to affect their toxicity to bacteria and mammalian cell lines (Mayer et al�, 2009;Singh et al�, 2004;Verran et al�, 2007), although other factors such as ability to generate free radicals (Verran et al�, 2007), particle surface charge (Mayer et al�, 2009), and particle-cell interaction (Singh et al�, 2004) have been shown to be involved also� In exposure studies with fish, association of particles in the tissues was found to depend on both the size of the nanoparticle and the tissue examined� In rainbow trout, 10-nm silver particles were found to associate more readily with gill tissue, whereas particles of 600-1600 nm were more readily taken up into the liver (Scown et al�, 2009)� Size may also potentially be a factor in determining particle transport in biological systems� Kreyling et al� showed smaller-sized iridium nanoparticles were more readily transported from the lung epithelium to extrapulmonary organs compared with larger nanoparticles (Kreyling et al�, 2002); however, another study showed there was no size-related difference in the transport of TiO 2 particles in a tracheal explants (Churg et al�, 1998)� ...
Nanotechnology is a rapidly growing industry of global economic importance, exploiting the novel characteristics of materials manufactured at the nanoscale. The properties of engineered nanoparticles (ENPs) that make them useful in a wide range of industrial applications, however, have led to concerns regarding their potential impact on human and environmental health. The aquatic environment is particularly at risk of exposure to ENPs, as it acts as a sink for most environmental contaminants. This paper critically evaluates what is currently known about sources and discharge of ENPs to the aquatic environment and how the physicochemical characteristics of ENPs affect their fate and behaviour and thus availability for uptake into aquatic organisms, and assesses reported toxicological effects. Having reviewed the ecotoxicological information, the conclusion is that whilst there are data indicating some nanoparticles have the potential to induce harm in exposed aquatic organisms, there is insufficient evidence for harm, for known/modelled environmental concentrations for almost all ENPs considered. This conclusion, however, must be balanced by the fact that there are significant gaps in our understanding on the fate and behaviour of ENPs in the aquatic environment. Greater confidence in the assessments on ENP impacts in aquatic systems to enable effective comparisons across studies urgently requires more standardised approaches for ENP hazard identification, and critically, more thorough characterisations on the exposed particles. There is also an urgent need for the advancement of tools and techniques that can accurately quantify and visualise uptake of nanoparticles into biological tissues.
Introduction: Nanotechnology as a key technology in the 21st century refers to the science of manipulating molecules and atoms in size range of 1 to 100 nanometers. Given the importance of investment in research and development, promoting knowledge and attitude of students can have a positive effect on expanding the scope and use of these emerging technologies.
Methods: In this descriptive analytical study, the knowledge and attitudes of 130 students towards the benefits and risks of nanotechnology were investigated through a questionnaire. The participants were studying occupational and environmental health engineering in Hamadan, Ilam, and Semnan Universities of Medical Sciences.
Results: The mean score of students' knowledge was 16.08 ± 1.61. A significant difference was observed between the mean scores of knowledge in undergraduate and graduate students (P= 0.001). However, no significant deference was observed in the mean score of knowledge between women and men, different age groups, and the year of entrance to university. Using linear regression equation and by considering knowledge level as a dependent variable, it was indicated that age and educational level were significantly related to the state of knowledge.
Conclusion: The results showed that most students did not have an acceptable level of knowledge about nanotechnology. Considering the benefits and risks of this technology, students have a positive attitude to develop use of nanotechnology in Iran.
Due to their small size, nanoparticles have brought a new era for researchers. They are utilized in different areas, including the food industry, pharmaceuticals, and medicals, for their outstanding properties. Many medicines are also used to treat patients with various diseases. Many researchers are continuing their research to find more applications of these materials. This paper reviews how nanoparticles synthesized from plants can help the immune response. Different nanoparticles have been initially studied with their source of origin, properties, and applications in the immune response. Then, how various nanoparticles work on the immune response has been briefly discussed. Different applications of nanoparticles on immune response with different perceptions have also been considered. The results of the applications of these particles have been debated as well. In the end, these particles’ potential challenges and future opportunities for immune response have been reviewed. This review paper will work as a guide for nanoparticle researchers in immunity.
Nanotechnology application in the food industry creates more opportunities for enhancing food quality, safety, bioavailability, and ultimately in healthier products. In addition to the novelty which nanotechnology brings, the safety of nano-foods is a vital matter for both public and food organizations concerned with potential toxicity (adverse effects), which requires a lot of attention as well as investigations in this field. Therefore, this chapter first discusses the toxicokinetics and toxicodynamics of nano-food in the human body. In particular, it summarizes how nanoparticles change under such human body influences as absorption, highlighting the toxicity effects of nano-food in the format of toxic characteristics (e.g., size, shape) and mechanisms (e.g., genotoxicity, protein corona). Second, toxicity assessment of nanomaterials has been briefly reviewed, figuring nano-food safety assessment tools like electron microscopy besides explaining some nanotoxicology evaluating criteria, and the need to enhance both nanoparticles evaluation and the guidelines to improve nano-food safety. Third, this chapter focuses on the public concerns and acceptance factors such as the market-encouragement circle in the nano-food field. Proper regulatory frameworks by food regulatory organizations could also have a high impact on nano-food safety. Many studies enhance the level of nano-food safety. Nevertheless, due to the critical emphasis on the fields of nano-food exposure, toxicity routes and safety regulations and considering the rising demand for novel-food highlights, more experiments need to be conducted.
Nanotoxicity has become the topic of great concern in nanoscience and nanotechnology because of the increasing toxic effects of nanomaterials on living organisms. The toxic patterns of chemotherapeutic drugs, nanomedicines, and nanocarrier are closely associated. Long term exposure of nanocarrier composed of several bioactive (protein and peptide drugs) and chemotherapeutic drugs (anticancerous agents) leads to toxicity, selective induction of cytotoxicity in normal cells and organ. Important factors that contribute directly and significantly to the toxicity of nanoparticles (NPs) constitute particle size, shape and surface area. Apart from size and shape, the structure of the NPs also contributes to nanotoxicity. The review focused on the basic perceptions and mechanisms of nanomaterial-based drug delivery and nanotoxicity is introduced along with a detailed classification of drug delivery approaches i.e., carbon nanotubes, Quantum dots, fullernes and NPs and nanotoxicity models, supported by the most contemporary investigation studies with distinctive emphasis on the communicates between nanotoxicity and nanomedicines research, which is emphasized in order to discover future prospects for developing progressive therapeutic methods. In this framework, the present silhouette focused to assemble and present recent advances, outcomes, and interlinks between nanomaterial-based drug delivery and nanotoxicity disciplines in order to provide inclusive supervision for future nanotechnology-based medicinal research. Reactive oxygen stress with subsequent DNA damage is the major reason for nanotoxicity which can be overcome using green nanoscience uses of antioxidants and surface modification. The silhouette is established with future forecasts on the use of nanocarrier for manipulating the behavior living organism.
Nanotoxicology is a branch of toxicology that is related to potential effects of nanoparticles of diameter less than 100 nm. Due to relatively small size, they are reported to enter through biological tissue barriers and cellular membranes leading to toxic effects. Release of nanoparticles on the target surface also induces high level of toxicity in target cells. The nanoparticles are usually cationic and are easily attracted to the anionic biological membrane, resulting in the destruction of the membrane and interaction with proteins, DNA, and enzymes of the host cell. The carcinogenicity of some multiwall carbon nanotubes and nanoparticles are also reported in recent researches. Various concerns about the usage of nanoparticles including systemic translocation, direct effects on the central nervous system, intestinal tract involvement, biocompatibility, deposition, and clearing are reported till date. In this book chapter, we will review the potent role of nanomaterials to confer their toxicity at cellular and subcellular levels. Efforts have been made to summarize the new aspects of interactions with other toxicants either by reducing or enhancing health risks and the potent negative effects associated with nanomaterial pollution.
Asthma is a chronic respiratory disease known for its high susceptibility to environmental exposure. Inadvertent inhalation of engineered or incidental nanomaterials is a concern for human health, particularly for those with underlying disease susceptibility. In this review we provide a comprehensive analysis of those studies focussed on safety assessment of different nanomaterials and their unique characteristics on asthma and allergic airway disease. These include in vivo and in vitro approaches as well as human and population studies. The weight of evidence presented supports a modifying role for nanomaterial exposure on established asthma as well as the development of the condition. Due to the variability in modelling approaches, nanomaterial characterisation and endpoints used for assessment in these studies, there is insufficient information for how one may assign relative hazard potential to individual nanoscale properties. New developments including the adoption of standardised models and focussed in vitro and in silico approaches have the potential to more reliably identify properties of concern through comparative analysis across robust and select testing systems. Importantly, key to refinement and choice of the most appropriate testing systems is a more complete understanding of how these materials may influence disease at the cellular and molecular level. Detailed mechanistic insight also brings with it opportunities to build important population and exposure susceptibilities into models. Ultimately, such approaches have the potential to more clearly extrapolate relevant toxicological information, which can be used to improve nanomaterial safety assessment for human disease susceptibility.
Electronic supplementary material
The online version of this article (10.1186/s12989-017-0228-y) contains supplementary material, which is available to authorized users.
This book provides a comprehensive overview of the cascade of events activated in the body following the implant of biomaterials and devices. It is one of the first books to shed light on the role of the host immune response on therapeutic efficacy, and reviews the state-of-the-art for both basic science and medical applications. The text examines advantages and disadvantages of the use of synthetic versus natural biomaterials. Particular emphasis is placed on the role of biomimicry in the development of smart strategies able to modulate infiltrating immune cells, thus reducing side effects (such as acute and chronic inflammation, fibrosis and/or implant rejection) and improving the therapeutic outcome (healing, tissue restoration). Current cutting-edge approaches in tissue engineering, regenerative medicine, and nanomedicine offer the latest insights into the role immunomodulation in improving tolerance during tissue transplant in the treatment of orthopaedic, pancreatic, and hepatic diseases. "Immune Response to Implanted Materials and Devices" is intended for an audience of graduate students and professional researchers in both academia and industry interested in the development of smart strategies, which are able to exploit the self-healing properties of the body and achieve functional tissue restoration.
Nanotechnology has a potential to transform healthcare by improving the quality of drugs and medical devices. The benefits of using nanomaterials in medical devices include improving device durability, decreasing bacterial adhesion and biofilm formation, and providing slow and controlled release of device-associated drugs. Using nanoparticles as implantable materials and components of medical devices also poses some safety concerns and regulatory challenges. This chapter reviews hematological and immunological toxicities relevant to the nanomaterials used in medical devices. Regulatory challenges, translational considerations, and literature case studies pertinent to the immunological safety of nanotechnology-based devices are also discussed.
Asthma is a chronic respiratory disease characterized by airway inflammation,
bronchoconstriction, airway hyperresponsiveness and recurring attacks of impaired
breathing. Vasoactive intestinal peptide (VIP) has been proposed as a novel antiasthma
drug due to its effects on airway smooth muscle relaxation, bronchodilation and
vasodilation along with its immunomodulatory and anti-inflammatory properties. In the
current study, we investigated the therapeutic effects of VIP when conjugated with α-
alumina nanoparticle (α-AN) to prevent enzymatic degradation of VIP in the respiratory
tract. VIP was conjugated with α-AN. Balb/c mice were sensitized and challenges with
ovalbumin (OVA) or PBS and were divided in four groups; VIP-treated, α-AN-treated, α-
AN-VIP-treated and beclomethasone-treated as a positive control group. Specific and
total IgE level, airway hyperresponsiveness (AHR), bronchial cytokine expression and
lung histology were measured. α-AN-VIP significantly reduced the number of
eosinophils (Eos), serum IgE level, Th2 cytokines and AHR. These effects of α-AN-VIP
were more pronounced than that seen with beclomethasone or VIP alone (P<0.05). The
current data indicate that α-AN-VIP can be considered as an effective nano-drug for the
treatment of asthma
Allergy is an adaptive immune response against antigens that are not pathogens but can derive from a wide range of sources including house dust, animal hair, insect stings, and plant pollen. The response is characterized by mechanisms that are observed during the defense against parasites, so allergy against harmless substances is often considered as an erroneous antiparasite response. For nanoparticles, it has to be determined whether they can influence either the sensitization against an allergen or the reaction occurring during reexposure. In addition, the issue of allergens as cargo has to be addressed: what happens if nanoparticles have allergens attached when they enter the body? The fact that allergens attached to nanoparticles behave differently is the basis for numerous attempts at development of novel antiallergic therapies, but allergen/nanoparticle complexes as a possible risk factor for sensitive persons will require more attention in the future.
This chapter reviews the main techniques currently used to size nanoparticles (NPs) in environmental matrices, which are classified according to the physical principle on which they are based (microscopy, light scattering, and light spectroscopy, among others). Hyphenated techniques based on chromatography or electrophoresis, size-separation of colloidal suspensions, are also reviewed. The inherent characteristics, advantages, and limitations are presented and discussed. To size each kind of sample, the user should adopt a specific strategy depending on the matrix, the type of nanomaterials, and the desired additional information. A transmission electron microscopy + nanoparticle tracking analysis combination is proposed as a robust and balanced combination that may be sufficient to acquire the size distribution population of most of the NP suspensions and to obtain morphological, quantitative, and Z-potential parameters.
Invertebrates lack an adaptive immunity; however, they are endowed with a potent and complex innate immune system similar to that of vertebrates. In most invertebrates, free circulating cells (hemocytes) are responsible for cell-mediated immunity; when activated, different hemocyte types are capable of phagocytosis, reactive oxygen species and NO production, release of hydrolytic enzymes and antimicrobial peptides. Conservation of the general mechanisms of innate immunity from invertebrates to mammals is useful for the evaluation of the environmental impact of nanoparticles. The mechanisms of innate immunity in two model representatives of aquatic (bivalves) and terrestrial (earthworms) environments are summarized, and data supporting the view that cell-mediated immunity can represent the primary target of nanoparticles in invertebrates are presented. The evaluation of immune parameters in invertebrate models may represent a powerful tool for the rapid screening of the immunomodulatory effects of nanoparticles and may provide a basis for designing environmentally safer nanomaterials.
Different types of nanomaterials possess excellent physical and chemical properties. Nanoparticles (NPs) have been implicated for use in drug and gene delivery. Several in vitro and in vivo studies suggest the cytotoxic and proinflammatory potential of NPs. Further, parenteral administration of NPs results in their accumulation in several tissues. The possible mechanism of toxicity appears to be production of free radicals, mitogen activated protein kinase (MAPK) activation and translocation of transcription factors from cytoplasm to nucleus. This leads to induction of apoptosis, growth arrest, and cell death. Further, factors like nuclear factor-κB (NF-κB) lead to production of proinflammatory cytokines. The present review focuses on the cytotoxicity, biodistribution, and mechanism of NPs toxicity with special emphasis on carbon nanotubes (CNTs) toxicity.
Nanoparticles (NPs) present in the environment and in consumer products can cause immunotoxic effects. The immune system is very complex, and in vivo studies are the gold standard for evaluation. Due to the increased amount of NPs that are being developed, cellular screening assays to decrease the amount of NPs that have to be tested in vivo are highly needed. Effects on the unspecific immune system, such as effects on phagocytes, might be suitable for screening for immunotoxicity because these cells mediate unspecific and specific immune responses. They are present at epithelial barriers, in the blood, and in almost all organs. This review summarizes the effects of carbon, metal, and metal oxide NPs used in consumer and medical applications (gold, silver, titanium dioxide, silica dioxide, zinc oxide, and carbon nanotubes) and polystyrene NPs on the immune system. Effects in animal exposures through different routes are compared to the effects on isolated phagocytes. In addition, general problems in the testing of NPs, such as unknown exposure doses, as well as interference with assays are mentioned. NPs appear to induce a specific immunotoxic pattern consisting of the induction of inflammation in normal animals and aggravation of pathologies in disease models. The evaluation of particle action on several phagocyte functions in vitro may provide an indication on the potency of the particles to induce immunotoxicity in vivo. In combination with information on realistic exposure levels, in vitro studies on phagocytes may provide useful information on the health risks of NPs.
The facilitating effects of multiwalled carbon nanotubes (MWCNT) on allergic asthma have not been sufficiently examined, although MWCNT appear to significantly increase the risk of health problems from occupational or environmental exposure. In this study, we examined whether sensitization by the combination of MWCNT with ovalbumin (OVA) promotes allergic asthmatic responses. BALB/c mice administered vehicle, MWCNT, OVA, or MWCNT+OVA through an intranasal route were challenged with OVA intratracheally four times. In the MWCNT+OVA group, the fourth challenge caused not only early- but also late-phase increases in airway resistance, although these responses were not observed in the vehicle, MWCNT, or OVA group; furthermore, the extents of the early and late responses were comparable to those in mice systemically sensitized with OVA+alum. Sensitization with MWCNT and OVA promoted airway inflammation and goblet cell hyperplasia in the lung compared with the vehicle, MWCNT or OVA group. In addition, adjuvant activity for OVA-specific immunoglobulin E (IgE), IgG1, and IgG2a production in serum and increased levels of interleukin-4 (IL-4), IL-5, IL-13, and IL-17 in the lung tissue were observed. In conclusion, these results suggest that exposure to MWCNT and antigen can induce a biphasic increase in airway resistance, airway inflammation, goblet cell hyperplasia, and the production of antigen-specific antibodies. This study highlights the risk of exposure to a combination of MWCNT with antigen.
Increasing utilizations of nanomaterials in the industrial as well as consumer products augment the possibilities of environmental and occupational human exposures. Because of this fact, nanoparticles (NPs) have become potential candidates for the risk assessment. Among the possible exposure routes, inhalation represents the most important route of non-intentional exposure to NPs. There are increasing evidences that NPs exhibit ability to cross biological barriers getting access to the bloodstream and secondary target organs where they could accumulate and induce pathological consequences. The surface area and reactivity of particles increase many fold relative to particle mass as particle size is reduced. Together with chemical composition, they constitute important determinants of NPs toxicity. They contribute in the production of reactive oxygen species (ROS) leading to the toxicological outcomes induced by NPs. In this study, we present a systemic overview of the current knowledge on the exposure, secondary organ translocation and potential health effects of the NPs. Moreover, potential mechanisms of NP-induced cellular effects and role of physico-chemical characteristics are elaborated. The potentially deleterious effects of NPs require further studies in order to build on our mechanistic understanding of the toxicological events in which they can be implicated.
Manufactured nanomaterials are in more than 1000 consumer products that contain some nanotechnology-based material on the market today. In the last five years there has been much effort put toward understanding the health effects associated with nanoparticle exposure. Toxicity assessment plays a significant role in this effort since human exposure can occur during production processes, handling, as well as their use and application. Although, though there is a large body of literature on “ultrafine particles” from a pulmonary exposure assessment, one should proceed with caution to expand this information to nanomaterials as we are still just at the beginning stages of their toxicity assessment. In this chapter, we consider the respiratory system as the main route of exposure to nanoparticles and we focus our attention mainly on metal-based nanomaterials and in vivo models used to evaluate them. We also discuss available data for other materials, since similar material properties whether size, shape, or chemical composition could lead to comparable toxicities and this will help in the development of screening strategies for nanomaterials that are very much warranted at this time.
Keywords:
metal nanoparticles;
metal oxide nanoparticles toxicity;
inhalation;
instillation;
mouse model;
sub-acute exposure
Using survey data, public awareness of and attitudes toward nanotechnology are examined in Iran (N=759). Iran is a developing country with a national nanotechnology action plan for a ten year period starting from 2003
and has been active in the field of research and development of nanotechnology meanwhile. First, the results show that majority
of people are still not familiar with nanotechnology and perceived risks posed by this technology are not considered to be
a lot and most people feel its benefits outweigh the risks. The emotions toward this technology are of a hopeful and positive
nature and this technology is looked upon favorably in Iran. In particular, our results reveals that although the level of
trust is high specially in scientists to communicate the risks with the public, there are a great number who just have some
trust not quite a lot of it. Knowing that it is a hard and time-consuming effort to manage a nation’s view on nanotechnology,
extensive research as well as collaboration with other countries is needed to effectively communicate the risks in time.
KeywordsNanotechnology–Risk perception–Iranian public risk perception–Risk communication
To the Editors:
We read with great interest a recent experimental ( in vivo ) study by Hussain et al. 1 and would like to comment on that article. First of all, we were very interested in the overall results that a single airway exposure to relatively low dose (16 μg·mouse−1) of nanoparticles facilitates allergic airway inflammation. We have previously examined several types of nanoparticles/nanomaterials on ovalbumin-induced airway inflammation 2–5. However, the doses were higher (25–100 μg·mouse−1 administered weekly a total of seven times) and provoked a more moderate increase in the number of inflammatory leukocytes into bronchoalveolar spaces in the absence of allergen than that in the present study by Hussain et al. …
As a nanotechnology has been actively applied to the overall areas of scientific fields, it is necessary to understand the characteristic features, physical behaviors and the potential effects of exposure to nanomaterials and their toxicity. In this article we review the immunological influences induced by several nanomaterials and emphasize establishment of the animal models to estimate the impact of these nanomaterials on development of immunological diseases.
The aim of this study was to investigate the modulation of an asthmatic response by titanium dioxide (TiO₂) or gold (Au) nanoparticles (NPs) in a murine model of diisocyanate-induced asthma. On days 1 and 8, BALB/c mice received 0.3% toluene diisocyanate (TDI) or the vehicle acetone-olive oil (AOO) on the dorsum of both ears (20 μL). On day 14, the mice were oropharyngeally dosed with 40 μL of a NP suspension (0.4 mg·mL⁻¹ (∼0.8 mg·kg⁻¹) TiO₂ or Au). 1 day later (day 15), the mice received an oropharyngeal challenge with 0.01% TDI (20 μL). On day 16, airway hyperreactivity (AHR), bronchoalveolar lavage (BAL) cell and cytokine analysis, lung histology, and total serum immunoglobulin E were assessed. NP exposure in sensitised mice led to a two- (TiO₂) or three-fold (Au) increase in AHR, and a three- (TiO₂) or five-fold (Au) increase in BAL total cell counts, mainly comprising neutrophils and macrophages. The NPs taken up by BAL macrophages were identified by energy dispersive X-ray spectroscopy. Histological analysis revealed increased oedema, epithelial damage and inflammation. In conclusion, these results show that a low, intrapulmonary doses of TiO₂ or Au NPs can aggravate pulmonary inflammation and AHR in a mouse model of diisocyanate-induced asthma.
Recent studies have reported associations between particulate air pollution and daily mortality rates. Population-based, cross-sectional studies of metropolitan areas in the United States have also found associations between particulate air pollution and annual mortality rates, but these studies have been criticized, in part because they did not directly control for cigarette smoking and other health risks.
In this prospective cohort study, we estimated the effects of air pollution on mortality, while controlling for individual risk factors. Survival analysis, including Cox proportional-hazards regression modeling, was conducted with data from a 14-to-16-year mortality follow-up of 8111 adults in six U.S. cities.
Mortality rates were most strongly associated with cigarette smoking. After adjusting for smoking and other risk factors, we observed statistically significant and robust associations between air pollution and mortality. The adjusted mortality-rate ratio for the most polluted of the cities as compared with the least polluted was 1.26 (95 percent confidence interval, 1.08 to 1.47). Air pollution was positively associated with death from lung cancer and cardiopulmonary disease but not with death from other causes considered together. Mortality was most strongly associated with air pollution with fine particulates, including sulfates.
Although the effects of other, unmeasured risk factors cannot be excluded with certainty, these results suggest that fine-particulate air pollution, or a more complex pollution mixture associated with fine particulate matter, contributes to excess mortality in certain U.S. cities.
IL-18 expression and functional activity has been identified in several autoimmune and infectious diseases. To clarify the potential role of IL-18 during early innate immune responses, we have explored the capacity of IL-18 to activate neutrophils. Human peripheral blood-derived neutrophils constitutively expressed IL-18R (alpha and beta) commensurate with the capacity to rapidly respond to IL-18. IL-18 induced cytokine and chemokine release from neutrophils that was protein synthesis dependent, up-regulated CD11b expression, induced granule release, and enhanced the respiratory burst following exposure to fMLP, but had no effect upon the rate of neutrophil apoptosis. The capacity to release cytokine and chemokine was significantly enhanced in neutrophils derived from rheumatoid arthritis synovial fluid, indicating differential responsiveness to IL-18 dependent upon prior neutrophil activation in vivo. Finally, IL-18 administration promoted neutrophil accumulation in vivo, whereas IL-18 neutralization suppressed the severity of footpad inflammation following carrageenan injection. The latter was accompanied by reduction in tissue myeloperoxidase expression and suppressed local TNF-alpha production. Together, these data define a novel role for IL-18 in activating neutrophils and thereby promoting early innate immune responses.
Particle research has been historically closely connected to industrial activities or materials, such as coal, asbestos, man-made mineral fibers, and more recently ambient particulate matter (PM). It is the purpose of this review to combine insights and developments in particle toxicology with the historical context of exposure and organizations sponsoring such research in Europe. In supporting research on particle-induced respiratory effects and mechanisms, research programs of the European Community on Steel and Coal (ECSC) have played a tremendous role. Current particle research in Europe is dominated by PM, and funded by the World Health Organization (WHO), European Union Framework programs, and the Health Effects Institute (HEI). Differences between historical and current research in particle toxicology include the exposure concentrations, particle size, target populations, endpoints, and length of exposure. Inhaled particle effects are no longer confined to the lung, since particles are suggested to translocate to the blood while lung inflammation invokes systemic responses. Finally, the particle size and concentrations have both been reduced about 100-fold from 2-5 mg/m3 to 20-50 mg/m3 and from 1-2 microm to 20-100 nm (ultrafine) as domestic fuel burning has decreased and vehicle sources have increased and attention has moved from coal mining industry to general environment. There is, however, a further occupational link to nanotechnology, which continuously produces new materials in the ultrafine range. Although inhalation exposure is considered to be minimal in this technology, some particles are produced to be used for carrier purpose in medical applications. Based on our current knowledge of particle toxicology, it is highly desirable that toxicology and technology are linked in this extremely rapid developing area, to learn more about potential risks and also to develop knowledge on the role of surface and size in particle toxicity.
Diesel exhaust particles (DEP) synergistically aggravate acute lung injury related to lipopolysaccharide (LPS) in mice, but the components in DEP responsible for this have not been identified. A study was undertaken to examine the effects of the organic chemicals (DEP-OC) and residual carbonaceous nuclei (washed DEP) derived from DEP on LPS related lung injury.
ICR mice were divided into experimental groups and vehicle, LPS, washed DEP, DEP-OC, washed DEP+LPS, and DEP-OC+LPS were administered intratracheally. The cellular profile of the bronchoalveolar lavage (BAL) fluid, pulmonary oedema, lung histology, and expression of proinflammatory molecules and Toll-like receptors in the lung were evaluated.
Both DEP-OC and washed DEP enhanced the infiltration of neutrophils into BAL fluid in the presence of LPS. Washed DEP combined with LPS synergistically exacerbated pulmonary oedema and induced alveolar haemorrhage, which was concomitant with the enhanced lung expression of interleukin-1beta, macrophage inflammatory protein-1alpha, macrophage chemoattractant protein-1, and keratinocyte chemoattractant, whereas DEP-OC combined with LPS did not. Gene expression of Toll-like receptors 2 and 4 was increased by combined treatment with washed DEP and LPS. The enhancement effects of washed DEP on LPS related changes were comparable to those of whole DEP.
These results suggest that the residual carbonaceous nuclei of DEP rather than the extracted organic chemicals predominantly contribute to the aggravation of LPS related lung injury. This may be mediated through the expression of proinflammatory cytokines, chemokines, and Toll-like receptors.
The aim of this study was to evaluate the acute lung toxicity of intratracheally instilled single-wall carbon nanotubes (SWCNT) in rats. The lungs of rats were instilled either with 1 or 5 mg/kg of the following control or particle types: (1) SWCNT, (2) quartz particles (positive control), (3) carbonyl iron particles (negative control), (4) phosphate-buffered saline (PBS) + 1% Tween 80, or (5) graphite particles (lung tissue studies only). Following exposures, the lungs of PBS and particle-exposed rats were assessed using bronchoalveolar lavage (BAL) fluid biomarkers and cell proliferation methods, and by histopathological evaluation of lung tissue at 24 h, 1 week, 1 month, and 3 months postinstillation. Exposures to high-dose (5 mg/kg) SWCNT produced mortality in ~15% of the SWCNT-instilled rats within 24 h postinstillation. This mortality resulted from mechanical blockage of the upper airways by the instillate and was not due to inherent pulmonary toxicity of the instilled SWCNT particulate. Exposures to quartz particles produced significant increases versus controls in pulmonary inflammation, cytotoxicity, and lung cell parenchymal cell proliferation indices. Exposures to SWCNT produced transient inflammatory and cell injury effects. Results from the lung histopathology component of the study indicated that pulmonary exposures to quartz particles (5 mg/kg) produced dose-dependent inflammatory responses, concomitant with foamy alveolar macrophage accumulation and lung tissue thickening at the sites of normal particle deposition. Pulmonary exposures to carbonyl iron or graphite particles produced no significant adverse effects. Pulmonary exposures to SWCNT in rats produced a non-dose-dependent series of multifocal granulomas, which were evidence of a foreign tissue body reaction and were nonuniform in distribution and not progressive beyond 1 month postexposure (pe). The observation of SWCNT-induced multifocal granulomas is inconsistent with the following: (1) lack of lung toxicity by assessing lavage parameters, (2) lack of lung toxicity by measuring cell proliferation parameters, (3) an apparent lack of a dose response relationship, (4) nonuniform distribution of lesions, (5) the paradigm of dust-related lung toxicity effects, (6) possible regression of effects over time. In addition, the results of two recent exposure assessment studies indicate very low aerosol SWCNT exposures at the workplace. Thus, the physiological relevance of these findings should ultimately be determined by conducting an inhalation toxicity study.
A characteristic feature of all inflammatory disorders is the excessive recruitment of leukocytes to the site of inflammation. The loss of control in trafficking these cells contributes to inflammatory diseases. Leukocyte recruitment is a well-orchestrated process that includes several protein families including the large cytokine subfamily of chemotactic cytokines, the chemokines. Chemokines and their receptors are involved in the pathogenesis of several diseases. Acute lung injury that clinically manifests as acute respiratory distress syndrome (ARDS) is caused by an uncontrolled systemic inflammatory response resulting from clinical events including major surgery, trauma, multiple transfusions, severe burns, pancreatitis, and sepsis. Systemic inflammatory response syndrome involves activation of alveolar macrophages and sequestered neutrophils in the lung. The clinical hallmarks of ARDS are severe hypoxemia, diffuse bilateral pulmonary infiltrates, and normal intracardiac filling pressures. The magnitude and duration of the inflammatory process may ultimately determine the outcome in patients with ARDS. Recent evidence shows that activated leukocytes and chemokines play a key role in the pathogenesis of ARDS. The expanding number of antagonists of chemokine receptors for inflammatory disorders may hold promise for new medicines to combat ARDS.
Single-walled carbon nanotubes (SWCNT) are new materials of emerging technological importance. As SWCNT are introduced into the life cycle of commercial products, their effects on human health and environment should be addressed. We demonstrated that pharyngeal aspiration of SWCNT elicited unusual pulmonary effects in C57BL/6 mice that combined a robust but acute inflammation with early onset yet progressive fibrosis and granulomas. A dose-dependent increase in the protein, LDH, and gamma-glutamyl transferase activities in bronchoalveolar lavage were found along with accumulation of 4-hydroxynonenal (oxidative biomarker) and depletion of glutathione in lungs. An early neutrophils accumulation (day 1), followed by lymphocyte (day 3) and macrophage (day 7) influx, was accompanied by early elevation of proinflammatory cytokines (TNF-alpha, IL-1beta; day 1) followed by fibrogenic transforming growth factor (TGF)-beta1 (peaked on day 7). A rapid progressive fibrosis found in mice exhibited two distinct morphologies: 1) SWCNT-induced granulomas mainly associated with hypertrophied epithelial cells surrounding SWCNT aggregates and 2) diffuse interstitial fibrosis and alveolar wall thickening likely associated with dispersed SWCNT. In vitro exposure of murine RAW 264.7 macrophages to SWCNT triggered TGF-beta1 production similarly to zymosan but generated less TNF-alpha and IL-1beta. SWCNT did not cause superoxide or NO.production, active SWCNT engulfment, or apoptosis in RAW 264.7 macrophages. Functional respiratory deficiencies and decreased bacterial clearance (Listeria monocytogenes) were found in mice treated with SWCNT. Equal doses of ultrafine carbon black particles or fine crystalline silica (SiO2) did not induce granulomas or alveolar wall thickening and caused a significantly weaker pulmonary inflammation and damage.
Although humans have been exposed to airborne nanosized particles (NSPs; < 100 nm) throughout their evolutionary stages, such exposure has increased dramatically over the last century due to anthropogenic sources. The rapidly developing field of nanotechnology is likely to become yet another source through inhalation, ingestion, skin uptake, and injection of engineered nanomaterials. Information about safety and potential hazards is urgently needed. Results of older biokinetic studies with NSPs and newer epidemiologic and toxicologic studies with airborne ultrafine particles can be viewed as the basis for the expanding field of nanotoxicology, which can be defined as safety evaluation of engineered nanostructures and nanodevices. Collectively, some emerging concepts of nanotoxicology can be identified from the results of these studies. When inhaled, specific sizes of NSPs are efficiently deposited by diffusional mechanisms in all regions of the respiratory tract. The small size facilitates uptake into cells and transcytosis across epithelial and endothelial cells into the blood and lymph circulation to reach potentially sensitive target sites such as bone marrow, lymph nodes, spleen, and heart. Access to the central nervous system and ganglia via translocation along axons and dendrites of neurons has also been observed. NSPs penetrating the skin distribute via uptake into lymphatic channels. Endocytosis and biokinetics are largely dependent on NSP surface chemistry (coating) and in vivo surface modifications. The greater surface area per mass compared with larger-sized particles of the same chemistry renders NSPs more active biologically. This activity includes a potential for inflammatory and pro-oxidant, but also antioxidant, activity, which can explain early findings showing mixed results in terms of toxicity of NSPs to environmentally relevant species. Evidence of mitochondrial distribution and oxidative stress response after NSP endocytosis points to a need for basic research on their interactions with subcellular structures. Additional considerations for assessing safety of engineered NSPs include careful selections of appropriate and relevant doses/concentrations, the likelihood of increased effects in a compromised organism, and also the benefits of possible desirable effects. An interdisciplinary team approach (e.g., toxicology, materials science, medicine, molecular biology, and bioinformatics, to name a few) is mandatory for nanotoxicology research to arrive at an appropriate risk assessment.
Particulate matter (PM) can exacerbate allergic airway diseases. Although health effects of PM with a diameter of less than 100 nm have been focused, few studies have elucidated the correlation between the sizes of particles and aggravation of allergic diseases. We investigated the effects of nano particles with a diameter of 14 nm or 56 nm on antigen-related airway inflammation.
ICR mice were divided into six experimental groups. Vehicle, two sizes of carbon nano particles, ovalbumin (OVA), and OVA + nano particles were administered intratracheally. Cellular profile of bronchoalveolar lavage (BAL) fluid, lung histology, expression of cytokines, chemokines, and 8-hydroxy-2'-deoxyguanosine (8-OHdG), and immunoglobulin production were studied.
Nano particles with a diameter of 14 nm or 56 nm aggravated antigen-related airway inflammation characterized by infiltration of eosinophils, neutrophils, and mononuclear cells, and by an increase in the number of goblet cells in the bronchial epithelium. Nano particles with antigen increased protein levels of interleukin (IL)-5, IL-6, and IL-13, eotaxin, macrophage chemoattractant protein (MCP)-1, and regulated on activation and normal T cells expressed and secreted (RANTES) in the lung as compared with antigen alone. The formation of 8-OHdG, a proper marker of oxidative stress, was moderately induced by nano particles or antigen alone, and was markedly enhanced by antigen plus nano particles as compared with nano particles or antigen alone. The aggravation was more prominent with 14 nm of nano particles than with 56 nm of particles in overall trend. Particles with a diameter of 14 nm exhibited adjuvant activity for total IgE and antigen-specific IgG1 and IgE.
Nano particles can aggravate antigen-related airway inflammation and immunoglobulin production, which is more prominent with smaller particles. The enhancement may be mediated, at least partly, by the increased local expression of IL-5 and eotaxin, and also by the modulated expression of IL-13, RANTES, MCP-1, and IL-6.
As a growing applied science, nanotechnology has considerable global socioeconomic value, and the benefits afforded by nanoscale materials and processes are expected to have significant impacts on almost all industries and all areas of society. A diverse array of engineered nanoscale products and processes have emerged [e.g., carbon nanotubes, fullerene derivatives, and quantum dots (QDs)], with widespread applications in fields such as medicine, plastics, energy, electronics, and aerospace. With the nanotechnology economy estimated to be valued at dollar 1 trillion by 2012, the prevalence of these materials in society will be increasing, as will the likelihood of exposures. Importantly, the vastness and novelty of the nanotechnology frontier leave many areas unexplored, or underexplored, such as the potential adverse human health effects resulting from exposure to novel nanomaterials. It is within this context that the need for understanding the potentially harmful side effects of these materials becomes clear. The reviewed literature suggests several key points: Not all QDs are alike; engineered QDs cannot be considered a uniform group of substances. QD absorption, distribution, metabolism, excretion, and toxicity depend on multiple factors derived from both inherent physicochemical properties and environmental conditions; QD size, charge, concentration, outer coating bioactivity (capping material and functional groups), and oxidative, photolytic, and mechanical stability have each been implicated as determining factors in QD toxicity. Although they offer potentially invaluable societal benefits such as drug targeting and in vivo biomedical imaging, QDs may also pose risks to human health and the environment under certain conditions. Key words: environment, human health, nanomaterials, nanosized particles, nanotechnology, nanotoxicology, quantum dots, toxicology.
Nanomaterials are engineered structures with at least one dimension of 100 nanometers or less. These materials are increasingly
being used for commercial purposes such as fillers, opacifiers, catalysts, semiconductors, cosmetics, microelectronics, and
drug carriers. Materials in this size range may approach the length scale at which some specific physical or chemical interactions
with their environment can occur. As a result, their properties differ substantially from those bulk materials of the same
composition, allowing them to perform exceptional feats of conductivity, reactivity, and optical sensitivity. Possible undesirable
results of these capabilities are harmful interactions with biological systems and the environment, with the potential to
generate toxicity. The establishment of principles and test procedures to ensure safe manufacture and use of nanomaterials
in the marketplace is urgently required and achievable.
Pulmonary toxicology studies in rats demonstrate that nanoparticles administered to the lung are more toxic than larger, fine-sized particles of similar chemistry at identical mass concentrations. The aim of this study was to evaluate the acute lung toxicity in rats of intratracheally instilled pigment-grade TiO2 particles (rutile-type particle size = approximately 300 nm) versus nanoscale TiO2 rods (anatase = 200 nm x 35 nm) or nanoscale TiO2 dots (anatase = approximately 10 nm) compared with a positive control particle type, quartz. Groups of rats were instilled with doses of 1 or 5 mg/kg of the various particle types in phosphate-buffered saline (PBS). Subsequently, the lungs of PBS- and particle-exposed rats were assessed using bronchoalveolar lavage fluid biomarkers, cell proliferation methods, and by the histopathological evaluation of lung tissue at 24 h, 1 week, 1 month, and 3 months postinstillation exposure. Exposures to nanoscale TiO2 rods or nanoscale TiO2 dots produced transient inflammatory and cell injury effects at 24 h postexposure (pe) and were not different from the pulmonary effects of larger sized TiO2 particle exposures. In contrast, pulmonary exposures to quartz particles in rats produced a dose-dependent lung inflammatory response characterized by neutrophils and foamy lipid-containing alveolar macrophage accumulation as well as evidence of early lung tissue thickening consistent with the development of pulmonary fibrosis. The results described herein provide the first example of nanoscale particle types which are not more cytotoxic or inflammogenic to the lung compared to larger sized particles of similar composition. Furthermore, these findings run counter to the postulation that surface area is a major factor associated with the pulmonary toxicity of nanoscale particle types.
Although adverse health effects of particulate matter with a diameter of < 100 nm (nanoparticles) have been proposed, molecular and/or experimental evidence for their facilitation of lung inflammation in vivo is not fully defined.
In the present study we investigated the effects of nanoparticles on lung inflammation related to bacterial endotoxin [lipopolysaccharide (LPS) ] in mice.
We intratracheally administered vehicle, two sizes (14 nm, 56 nm) of carbon black nanoparticles (4 mg/kg) , LPS (2.5 mg/kg) , or LPS plus nanoparticles and evaluated parameters for lung inflammation and coagulation. Nanoparticles alone induced slight lung inflammation and significant pulmonary edema compared with vehicle. Fourteen-nanometer nanoparticles intensively aggravated LPS-elicited lung inflammation and pulmonary edema that was concomitant with the enhanced lung expression of interleukin-1beta (IL-1beta) , macrophage inflammatory protein-1alpha (MIP-1alpha) , macrophage chemoattractant protein-1, MIP-2, and keratinocyte chemoattractant in overall trend, whereas 56-nm nanoparticles did not show apparent effects. Immunoreactivity for 8-hydroxyguanosine, a marker for oxidative stress, was more intense in the lungs from the LPS + 14-nm nanoparticle group than in those from the LPS group. Circulatory fibrinogen levels were higher in the LPS + plus 14-nm nanoparticle group than in the LPS group.
Taken together, evidence indicates that nanoparticles can aggravate lung inflammation related to bacterial endotoxin, which is more prominent with smaller particles. The enhancement may be mediated, at least partly, via the increased local expression of proinflammatory cytokines and via the oxidative stress. Furthermore, nanoparticles can promote coagulatory disturbance accompanied by lung inflammation.
Titanium dioxide nanoparticles (nanoTiO2) have been widely used as a photocatalyst in air and water cleaning. However, these nanoparticles inhalation can induce pulmonary toxicity and its mechanism is not fully understood. In this study we investigated the pulmonary toxicity of nanoTiO2 and its molecular pathogenesis. The adult male ICR mice were exposed to intratracheal single dose of 0.1 or 0.5 mg nanoTiO2 (19-21 nm) and lung tissues were collected at 3rd day, 1st wk, and 2nd wk for morphometric, microarray gene expression, and pathway analyses. NanoTiO2 can induce pulmonary emphysema, macrophages accumulation, extensive disruption of alveolar septa, type II pneumocyte hyperplasia, and epithelial cell apoptosis. NanoTiO2 induced differential expression of hundreds of genes include activation of pathways involved in cell cycle, apoptosis, chemokines, and complement cascades. In particular, nanoTiO2 up-regulates placenta growth factor (PlGF) and other chemokines (CXCL1, CXCL5, and CCL3) expressions that may cause pulmonary emphysema and alveolar epithelial cell apoptosis. Cultured human THP-1 cell-derived macrophages treated with nanoTiO2 in vitro also resulted in up-regulations of PlGF, CXCL1, CXCL5, and CCL3. These results indicated that nanoTiO2 can induce severe pulmonary emphysema, which may be caused by activation of PlGF and related inflammatory pathways.
Pulmonary toxicology studies in rats demonstrate that nanoparticles are more toxic than fine-sized particles of similar chemistry. This study, however, provides evidence to contradict this theory. The aims of the study were (1) to compare the toxicity of synthetic 50 nm nanoquartz I particles versus (mined) Min-U-Sil quartz ( approximately 500 nm); the toxicity of synthetic 12 nm nanoquartz II particles versus (mined) Min-U-Sil ( approximately 500 nm) versus (synthetic) fine-quartz particles (300 nm); and (2) to evaluate the surface activities among the samples as they relate to toxicity. Well-characterized samples were tested for surface activity and hemolytic potential. In addition, groups of rats were instilled with either doses of 1 or 5 mg/kg of carbonyl iron (CI) or various alpha-quartz particle types in phosphate-buffered saline solution and subsequently assessed using bronchoalveolar lavage fluid biomarkers, cell proliferation, and histopathological evaluation of lung tissue at 24 h, 1 week, 1 month, and 3 months postexposure. Exposures to the various alpha-quartz particles produced differential degrees of pulmonary inflammation and cytotoxicity, which were not always consistent with particle size but correlated with surface activity, particularly hemolytic potential. Lung tissue evaluations of three of the quartz samples demonstrated "typical" quartz-related effects--dose-dependent lung inflammatory macrophage accumulation responses concomitant with early development of pulmonary fibrosis. The various alpha-quartz-related effects were similar qualitatively but with different potencies. The range of particle-related toxicities and histopathological effects in descending order were nanoscale quartz II = Min-U-Sil quartz > fine quartz > nanoscale quartz I > CI particles. The results demonstrate that the pulmonary toxicities of alpha-quartz particles appear to correlate better with surface activity than particle size and surface area.
Patients with refractory asthma have persistent symptoms despite maximal treatment with inhaled corticosteroids and long-acting bronchodilators. The availability of add-on therapies is limited, and effective add-on therapies that target noneosinophilic airway inflammation are needed. Macrolide antibiotics, such as clarithromycin, have in vitro efficacy against IL-8 and neutrophils, key inflammatory mediators in noneosinophilic asthma.
To determine the efficacy of clarithromycin in patients with severe refractory asthma and specifically in a subgroup of patients with noneosinophilic asthma.
Subjects with severe refractory asthma (n = 45) were randomized to receive clarithromycin (500 mg twice daily) or placebo for 8 weeks.
The primary outcome for this study was sputum IL-8 concentration. Other inflammatory outcomes assessed included sputum neutrophil numbers and concentrations of neutrophil elastase and matrix metalloproteinase (MMP)-9. Clinical outcomes were also assessed, including lung function, airway hyperresponsiveness to hypertonic saline, asthma control, quality of life, and symptoms. Clarithromycin therapy significantly reduced airway concentrations of IL-8 and neutrophil numbers and improved quality-of-life scores compared with placebo. Reductions in neutrophil elastase and MMP-9 concentrations were also observed. These reductions in inflammation were most marked in those with refractory noneosinophilic asthma.
Clarithromycin therapy can modulate IL-8 levels and neutrophil accumulation and activation in the airways of patients with refractory asthma. Macrolide therapy may be an important additional therapy that could be used to reduce noneosinophilic airway inflammation, particularly neutrophilic inflammation, in asthma. Clinical trial registered with the Australian Clinical Trials Registry www.actr.org.au (No. 12605000318684).
Interleukin (IL)-18 was originally regarded to induce T helper cell (Th)1-related cytokines. In general, factors favoring interferon (IFN)-gamma production are believed to abolish allergic diseases. Thus, we tested the role of IL-18 in regulation of bronchial asthma. To avoid a background response of host-derived T cells, we administered memory type Th1 or Th2 cells into unsensitized mice and examined their role in induction of bronchial asthma. Administration of antigen (Ag) induced both airway inflammation and airway hyperresponsiveness (AHR) in mice receiving memory Th2 cells. In contrast, the same treatment induced only airway inflammation but not AHR in mice receiving memory Th1 cells. However, these mice developed striking AHR when they were coadministered with IL-18. Furthermore, mice having received IFN-gamma-expressing Th1 cells sorted from polarized Th1 cells developed severe airway inflammation and AHR after intranasal administration of Ag and IL-18. Thus, Th1 cells become harmful when they are stimulated with Ag and IL-18. Newly polarized Th1 cells and IFN-gamma-expressing Th1 cells, both of which express IL-18 receptor alpha chain strongly, produce IFN-gamma, IL-9, IL-13, granulocyte/macrophage colony-stimulating factor, tumor necrosis factor alpha, regulated on activation, normal T cell expressed and secreted, and macrophage inflammatory protein 1alpha upon stimulation with Ag, IL-2, and IL-18 in vitro. Thus, Ag and IL-18 stimulate memory Th1 cells to induce severe airway inflammation and AHR in the naive host.
Study objectives:
To identify the characteristics of airway inflammation in persistent asthma and to examine the role of neutrophilic inflammation in noneosinophilic persistent asthma.
Methods:
Nonsmoking adults (n = 56) with persistent asthma and healthy control subjects (n = 8) underwent hypertonic saline solution challenge and sputum induction. Selected sputum portions were dispersed with dithiothreitol and assayed for total cell count, cellular differential, supernatant eosinophil cationic protein (ECP), myeloperoxidase, and interleukin (IL)-8.
Results:
We identified two distinct inflammatory patterns. Typical eosinophilic inflammation occurred in 41% of subjects, whereas the remainder exhibited noneosinophilic asthma (59%). Both neutrophil percentage and absolute neutrophil counts were increased in subjects with noneosinophilic asthma (64%, 283 × 106/mL) compared to eosinophilic asthma (14%, 41 × 106/mL) and control subjects (34%, 49 × 106/mL; p = 0.0001). Myeloperoxidase was elevated in both noneosinophilic (280 ng/mL) and eosinophilic groups (254 ng/mL) compared with control subjects (82 ng/mL; p = 0.002). Sputum IL-8 levels were highest in subjects with noneosinophilic asthma (45 ng/mL) compared to eosinophilic asthma (9.6 ng/mL) and control subjects (3.5 ng/mL; p = 0.0001). Neutrophils correlated with IL-8 levels (r = 0.72). ECP was highest in subjects with eosinophilic asthma (2,685 ng/mL) compared with noneosinophilic asthma (1,081 ng/mL) and control subjects (110 ng/mL; p = 0.0001).
Conclusion:
Induced-sputum analysis in persistent asthma identifies two different inflammatory patterns. The most common pattern is noneosinophilic, associated with a neutrophil influx and activation, which may be mediated by IL-8 secretion. There is heterogeneity of airway inflammation in persistent asthma, which indicates differing mechanisms and may impact on treatment responses.
Histopathological examination and cytological analyses in bronchial alveolar lavage fluids (BALF) were performed to clarify the acute toxicity of diesel exhaust particles (DEP) introduced into the lung of ICR mice by intratracheal instillation. Activated charcoal (Norit) was intratracheally administered as a control for non-oedemagenic carbon particles. After administration of two doses (0.4 mg or 0.8 mg per mouse) of DEP, lung water contents increased with instillation dose and with time and increased 1.9 and 2.7-fold, respectively, compared to control animals 24 h after the administration of DEP. In contrast, the instillation of Norit had no effect on the increase in water contents. An inflammatory response in lungs was observed by an increase of inflammatory cells in BALF from mice instilled with DEP. The degree of increase in neutrophils of BALF from mice treated with DEP was much greater than in mice treated with Norit. An intense color of MB-pigment, which showed the extent and degree of endothelial cell injury, was found up to 4 h after administration of DEP. Histopathologically, the disruption of capillary endothelial cells, the detachment from their basement membrane and necrosis, disruption and desquamation of type I pneumocytes were observed, 6 h after the injection of DEP, by electron microscopy. An influx of neutrophils into alveoli, intra-alveolar hemorrhage, perivascular oedema and bronchiolar cell hypertrophy were detected between 18 and 24 h after DEP administration. However, the magnitude of these appearances was greater in mice treated with 0.8 mg of DEP than in mice treated with 0.4 mg. The administration of Norit caused an increase of alveolar macrophages and slight infiltration of neutrophils into the alveolar air spaces and alveolar septa in the animals and had no effects on the bronchioles. These results may suggest that damage of capillary endothelial cells and type I pneumocytes are the earliest changes of lung toxicities by DEP and these cell injuries lead to alveolar oedema and the subsequent inflammatory response.
Systemic exposure to LPS initiates a complex sequence of events resulting in organ-specific leukocyte recruitment and end-organ injury. We hypothesized that macrophage inflammatory protein-1 alpha (MIP-1 alpha), a C-C chemokine with leukocyte chemotactic and activating properties, may play an important role in lung inflammatory cell recruitment, subsequent lung injury, and mortality in endotoxemia. CD-1 mice were challenged with LPS (200 micrograms), resulting in a maximal 3.5-fold increase in neutrophils (polymorphonuclear leukocytes (PMNs)) at 6 h post-LPS, and a 2.6-fold increase in numbers of macrophages (M phi) within lung minces at 24 h. A time-dependent increase in MIP-1 alpha mRNA and protein was detected in lung after LPS treatment, with immunolocalization of MIP-1 alpha to blood and lung M phi, and the subendothelium. The pretreatment of mice with rabbit anti-MIP-1 alpha Ab resulted in a decrease in the influx of PMNs at 6 h, and influx of M phi at 24 h post-LPS challenge, an approximately 65% reduction in LPS-induced lung permeability to Evans blue, and a modest decrease in mortality at 24, but not 48 h post-LPS. Furthermore, passive immunization of mice with anti-MIP-1 alpha serum resulted in a 35% reduction in ICAM-1 mRNA levels within lung homogenates post-LPS. Finally, the pretreatment of animals with sTNFR:Fc (soluble TNF receptor:Ig construct) resulted in a 60% reduction in LPS-induced MIP-1 alpha mRNA expression within lung homogenates at 4 h post-LPS. Our studies indicate that MIP-1 alpha plays an integral role as a mediator of both PMN and M phi recruitment in murine endotoxemia.
Evidence from the selected epidemiologic studies presented in this review suggests a coherence of effects across a range of related health outcomes and a consistency of effects across independent studies with different investigators in different settings. This compilation also provides insights into the relative magnitude of effects being observed in various studies (Table 6). Total mortality is observed to increase by approximately 1% per 10 μg/m3 increase in PM10. Somewhat stronger associations are observed for cardiovascular mortality (approximately 1.4% per 10 μg/m3 PM10), and considerably stronger associations are observed for respiratory mortality (approximately 3.4% per 10 μg/m3 PM10). No acute effects are detected with cancer and other nonpulmonary and noncardiovascular causes of mortality. These relative differences in cause-specific mortality are plausible, given the respiratory route of particle exposures. If respiratory mortality is associated with particulate pollution, then health care visits for respiratory illness would also be expected to be associated with particulate pollution. Respiratory hospital admissions and emergency department visits increase by approximately 0.8% and 1.0% per 10 μg/m3 PM10 respectively. Emergency department visits for asthmatics (3.4% increase per 10 μg/m3 PM10) and hospital admissions for asthmatic attacks (1.9% increase per 10 μg/m3 PM10) are more strongly associated. Asthmatic subjects also report substantial increases in asthma attacks (an approximate 3% increase per 10 μg/m3 PM10) and in bronchodilator use (an approximate 3% increase per 10 μg/m3 PM10). Less severe measures of respiratory health also are associated with particle exposures. Lower respiratory symptom reporting increases by approximately 3.0% per 10 μg/m3 PM10 and cough by 2.5% per 10 μg/m3 PM10. Weaker effects are observed with upper respiratory symptoms (approximately 0.7% per 10 μg/m3 PM10). While lung function provides accurate objective measures, the observed mean effects are fairly modest: approximately 0.15% decrease for FEV1 or FEV.75 and 0.08% decrease for peak flow per 10 mg/m3 PM10. Despite the relatively small size of these lung-function effect estimates, they consistently achieve statistical significance. Moreover, mean changes in lung function may not reflect substantial changes in sensitive individuals. In this review, changes in health measures are reported for only small changes in daily particulate pollution: 10 μg/m3 increase in PM10 concentrations. Because daily concentrations of PM10 in some US cities average over 50 μg/m3 and often exceed 100 or 150 μg/m3, the effects of particulate pollution can be substantial for realistic acute exposures. For example, a 1% effect estimate per each 10 μg/m3 increase would produce a 5% increase in the health measure for a 50 μg/m3 increase in PM10 concentrations, and a 3% effect estimate would produce a 16% increase. Thus the estimated increase in attacks of asthma (3.0% per 10 μg/m3 PM10) would be 16% for a 50 μg/m3 increase in PM10 concentrations.
Previous experimental studies have suggested that nasal instillation of diesel exhaust particles (DEP) can enhance nasal IgE response and cytokine production. However, there is no experimental evidence for the relation of DEP to allergic asthma. We investigated the effects of DEP inoculated intratracheally on antigen-induced airway inflammation, local expression of cytokine proteins, and antigen-specific immunoglobulin production in mice. DEP aggravated ovalbumin-induced airway inflammation characterized by infiltration of eosinophils and lymphocytes and an increase in goblet cells in bronchial epithelium. DEP with antigen markedly increased interleukin-5 (IL-5) protein levels in lung tissue and bronchoalveolar lavage supernatants compared with either antigen or DEP alone. The combination of DEP and antigen induced significant increases in local expression of IL-4, granulocyte macrophage-colony stimulating factor (GM-CSF), and IL-2, whereas expression of interferon-gamma was not affected. In addition, DEP exhibited adjuvant activity for the antigen-specific production of IgG and IgE. These results provide the first experimental evidence that DEP can enhance the manifestations of allergic asthma. The enhancement may be mediated mainly by the increased local expression of IL-5, and also by the modulated expression of IL-4, GM-CSF, and IL-2.
We have previously shown that intratracheal instillation of suspension of diesel exhaust particles enhances allergen-related eosinophilic airway inflammation, airway hyperresponsiveness, and local expression of interleukin (IL)-5 and granulocyte macrophage-colony stimulating factor (GM-CSF) in mice. The present study was designed to elucidate the effects of daily inhalation of diesel exhaust (DE) on the allergen-related respiratory disease. ICR mice were exposed for 40 weeks to clean air or DE at a soot concentration of 0.3, 1.0, or 3.0 mg/m3 with aerosol allergen challenges (1% ovalbumin in isotonic saline for 6 min) at 3-week intervals during the last 24 weeks of exposures. Exposure to DE enhanced allergen-related eosinophil recruitment to the submucosal layers of the airways and to the bronchoalveolar space, and increased protein levels of GM-CSF and IL-5 in the lung in a dose-dependent manner compared to exposure to clean air. There were strong correlations between the number of eosinophils in bronchoalveolar lavage (BAL) fluid and IL-5 concentrations in BAL supernatants and lung tissue supernatants. In addition, the increases in eosinophil recruitment and local cytokine expression were accompanied by goblet cell proliferation in the bronchial epithelium and airway hyperresponsiveness to inhaled acetylcholine. In contrast, the control mice exposed for 40 weeks to clean air or DE at a soot concentration of 0.3, 1.0, or 3.0 mg/m3 without allergen provocation showed no eosinophil recruitment to the submucosal layers of the airways nor to the bronchoalveolar space and few goblet cells in the bronchial epithelium. The present study provides experimental evidence that daily inhalation of DE can enhance allergen-related respiratory diseases such as allergic asthma. This effect may be mediated by the enhanced local expression of IL-5 and GM-CSF. Increased ambient levels of DE may be implicated in the increasing prevalence of bronchial asthma in recent years.
The histopathologic changes in the murine airway induced by long-term exposure to diesel exhaust (DE), ovalbumin (OA), or both were investigated. The relationship between the histopathologic appearances in the airway and immunoglobulin production or local cytokine levels in the lungs was also studied. ICR mice were exposed to clean air or DE at a soot concentrations of 0.3, 1.0, or 3.0 mg/m3 for 34 weeks. Fifteen weeks after exposure to DE, mice were sensitized intraperitoneally with 10 micrograms of OA and challenged by an aerosol of 1% OA six times at 3-week intervals during the last 18 weeks of the exposure. DE exposure caused a dose-dependent increase of nonciliated cell proliferation and epithelial cell hypertrophy in the airway, but showed no effect on goblet cell proliferation in the bronchial epithelium and eosinophil recruitment in the submucosa of the airway. OA treatment induced very slight changes in goblet cell proliferation and eosinophil recruitment. The combination of OA and DE exposure produced dose-dependent increases of goblet cells and eosinophils, in addition to further increases of the typical changes induced by DE. OA treatment induced OA-specific IgG1 and IgE production in plasma, whereas the adjuvant effects of DE exposure on immunoglobulin production were not observed. Inhalation of DE led to increased levels of IL-5 protein in the lung at a soot concentration of 1.0 and 3.0 mg/m3 with OA, although these increases did not reach statistical significance. We conclude that the combination of antigen and chronic exposure to DE produces increased eosinophilic inflammation, and cell damage to the epithelium may depend on the degree of eosinophilic inflammation in the airway.
The link between particulate air pollution at relatively low levels and adverse effects both in the lungs and of the cardiovascular system remains a puzzling event. The authors have developed a hypothesis which suggests that ultrafine components of particulate air pollution may result in local and systemic oxidative stress, which produces lung inflammation, but also the systemic effects, resulting in mortality in susceptible individuals from cerebrovascular disease. Preliminary data in vitro and in vivo suggest that both local and systemic oxidative stress occur in response to ultrafine particles and that the effects of such oxidative stress on pro-inflammatory gene regulation and changes in blood coagulation may result in the adverse effects of particulate air pollution. In this article, the evidence which supports this hypothesis is reviewed.
To identify the characteristics of airway inflammation in persistent asthma and to examine the role of neutrophilic inflammation in noneosinophilic persistent asthma.
Nonsmoking adults (n = 56) with persistent asthma and healthy control subjects (n = 8) underwent hypertonic saline solution challenge and sputum induction. Selected sputum portions were dispersed with dithiothreitol and assayed for total cell count, cellular differential, supernatant eosinophil cationic protein (ECP), myeloperoxidase, and interleukin (IL)-8.
We identified two distinct inflammatory patterns. Typical eosinophilic inflammation occurred in 41% of subjects, whereas the remainder exhibited noneosinophilic asthma (59%). Both neutrophil percentage and absolute neutrophil counts were increased in subjects with noneosinophilic asthma (64%, 283 x 10(6)/mL) compared to eosinophilic asthma (14%, 41 x 10(6)/mL) and control subjects (34%, 49 x 10(6)/mL; p = 0.0001). Myeloperoxidase was elevated in both noneosinophilic (280 ng/mL) and eosinophilic groups (254 ng/mL) compared with control subjects (82 ng/mL; p = 0.002). Sputum IL-8 levels were highest in subjects with noneosinophilic asthma (45 ng/mL) compared to eosinophilic asthma (9.6 ng/mL) and control subjects (3.5 ng/mL; p = 0.0001). Neutrophils correlated with IL-8 levels (r = 0.72). ECP was highest in subjects with eosinophilic asthma (2,685 ng/mL) compared with noneosinophilic asthma (1,081 ng/mL) and control subjects (110 ng/mL; p = 0.0001).
Induced-sputum analysis in persistent asthma identifies two different inflammatory patterns. The most common pattern is noneosinophilic, associated with a neutrophil influx and activation, which may be mediated by IL-8 secretion. There is heterogeneity of airway inflammation in persistent asthma, which indicates differing mechanisms and may impact on treatment responses.
The mechanisms of particulate pollution-related cardiovascular morbidity and mortality are not well understood. We studied the passage of radioactively labeled ultrafine particles after their intratracheal instillation. Hamsters received a single intratracheal instillation of 100 microg albumin nanocolloid particles (nominal diameter < or = 80 nm) labeled with 100 microCi technetium-99m and were killed after 5, 15, 30, and 60 min. In blood, radioactivity, expressed as percentage of total body radioactivity per gram blood, amounted to 2.88 +/- 0.80%, 1.30 +/- 0.17%, 1.52 +/- 0.46%, and 0.21 +/- 0.06% at 5, 15, 30, and 60 min, respectively. Thin-layer chromatography showed only one peak of radioactivity corresponding to unaltered (99m)Tc-albumin nanocolloid. In the liver, radioactivity, expressed as percentage of total radioactivity per organ, amounted to 0.10 +/- 0.07%, 0.23 +/- 0.06%, 1.24 +/- 0.27%, and 0.06 +/- 0.02% at 5, 15, 30, and 60 min, respectively. Lower values were observed in the heart, spleen, kidneys, and brain. Dose dependence was assessed at 30 min following instillation of 10 microg and 1 microg (99m)Tc-albumin per animal (n = 3 at each dose), and values of the same relative magnitudes as after instillation of 100 microg were obtained. We conclude that a significant fraction of (99m)Tc-albumin, taken as a model of ultrafine particles, rapidly diffuses from the lungs into the systemic circulation.
Epidemiologic studies demonstrate acute and serious adverse effects of particulate air pollution on respiratory health, especially in people who are susceptible to bacterial infection. However, the underlying mechanism remains to be elucidated. To provide experimental evidence for the epidemiologic data, we determined the effects of diesel exhaust particles (DEP), major participants in particulate pollutants, on lung injury related to bacterial endotoxin in mice. Intratracheal instillation of DEPs synergistically enhanced lung injury related to endotoxin from gram-negative bacteria, which was characterized by neutrophil sequestration, interstitial edema, and alveolar hemorrhage. In the presence of endotoxin, DEPs further activated the nuclear translocation of p65 subunit of nuclear factor-kappaB (NF-kappaB) in the lung and increased the lung expression of intercellular adhesion molecule-1, interleukin-1beta, macrophage chemoattractant protein-1, keratinocyte chemoattractant (KC), macrophage inflammatory protein-1alpha, and Toll-like receptors. DEPs given alone increased the lung expression of Toll-like receptor 4 and the nuclear localization of p50 subunit of NF-kappaB. The combined exposure to DEPs and endotoxin decreased nuclear localization of CCAAT/enhancer binding protein beta. These results provide the first experimental evidence that DEPs enhance neutrophilic lung inflammation related to bacterial endotoxin. The enhancement is mediated by the induction of proinflammatory molecules, likely through the expression of Toll-like receptors and the activation of p65-containing dimer(s) of NF-kappaB, such as p65/p50.
There is increasing evidence that inflammatory mechanisms other than eosinophilic inflammation may be involved in producing the final common pathway of enhanced bronchial reactivity and reversible airflow obstruction that characterises asthma. A review of the literature has shown that, at most, only 50% of asthma cases are attributable to eosinophilic airway inflammation. It is hypothesised that a major proportion of asthma is based on neutrophilic airway inflammation, possibly triggered by environmental exposure to bacterial endotoxin, particulate air pollution, and ozone, as well as viral infections. If there are indeed two (or more) subtypes of asthma, and if non-eosinophilic (neutrophil mediated) asthma is relatively common, this would have major consequences for the treatment and prevention of asthma since most treatment and prevention strategies are now almost entirely focused on allergic/eosinophilic asthma and allergen avoidance measures, respectively. It is therefore important to study the aetiology of asthma further, including the underlying inflammatory profiles.
Epidemiological and experimental studies have suggested that diesel exhaust particles (DEP) may be involved in recent increases in lung diseases. DEP has been shown to generate reactive oxygen species. Intratracheal instillation of DEP induces lung inflammation and edema in mice. Rosmarinic acid is a naturally occurring polyphenol with antioxidative and anti-inflammatory activities. We investigated the effects of rosmarinic acid on lung injury induced by intratracheal administration of DEP (500 microg/body) in mice. Oral supplementation with administration of rosmarinic acid (2 mg/body for 3 d) inhibited DEP-induced lung injury, which was characterized by neutrophil sequestration and interstitial edema. DEP enhanced the lung expression of keratinocyte chemoattractant (KC), interleukin-1beta, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1alpha, which was inhibited by treatment with rosmarinic acid. DEP enhanced expression of iNOS mRNA and formation of nitrotyrosine and 8-OHdG in the lung, which was also inhibited by rosmarinic acid. These results suggest that rosmarinic acid inhibits DEP-induced lung injury by the reduction of proinflammatory molecule expression. Antioxidative activities of rosmarinic acid may also contribute to its protective effects.
With the increased presence of nanomaterials in commercial products, a growing public debate is emerging on whether the environmental and social costs of nanotechnology outweigh its many benefits. To date, few studies have investigated the toxicological and environmental effects of direct and indirect exposure to nanomaterials and no clear guidelines exist to quantify these effects.
Although the role of interleukin (IL)-6 in inflammatory diseases has been previously examined, its role in hemostasis, fibrinolysis, and coagulation during inflammation remains to be established. The present study elucidated the role of IL-6 in hemostatic and coagulatory changes during severe inflammation induced by intraperitoneal administration of lipopolysaccharide (LPS: 1 mg/kg) using IL-6 null (-/-) mice. After LPS challenge, IL-6 (-/-) mice revealed significant prolongation of prothrombin time and activated partial thromboplastin time and a significant decrease in platelet counts as compared with wild type mice. LPS treatment induced marked pulmonary hemorrhage with neutrophilic inflammation in IL-6 (-/-) mice, in contrast, only mild neutrophilic infiltration in WT mice confirmed by macroscopic and histological findings. The protein levels of proinflammatory mediators, such as IL-1 beta, macrophage inflammatory protein (MIP)-1 alpha, MIP-2, macrophage chemoattractant protein-1, granulocyte/macrophage-colony-stimulating factor, and keratinocyte chemoattractant in the lungs were significantly greater in IL-6 (-/-) mice than in WT mice after LPS challenge. These results directly indicate that IL-6 is protective against coagulatory and hemostatic disturbance and subsequent pulmonary hemorrhage induced by bacterial endotoxin, at least partly, via the modulation of proinflammatory processes.
Diesel exhaust particles (DEP) enhance allergic airway inflammation in mice (Takano et al., Am J Respir Crit Care Med 1997; 156: 36-42). DEP consist of carbonaceous nuclei and a vast number of organic chemical compounds. However, it remains to be identified which component(s) from DEP are responsible for the enhancing effects. 9,10-Phenanthraquinone (PQ) is a quinone compound involved in DEP.
To investigate the effects of PQ inoculated intratracheally on allergic airway inflammation related to ovalbumin (OVA) challenge.
We evaluated effects of PQ on airway inflammation, local expression of cytokine proteins, and allergen-specific immunoglobulin production in mice in the presence or absence of OVA. Results In the presence of OVA, PQ (2.1 ng/animal) significantly increased the numbers of eosinophils and mononuclear cells in bronchoalveolar lavage fluid as compared with OVA alone. In contrast, the numbers of these cells around the airways were not significantly different between OVA challenge and OVA plus PQ challenge in lung histology. PQ exhibited adjuvant activity for the allergen-specific production of IgG1 and IgE. OVA challenge induced significant increases in the lung expression of IL-4, IL-5, eotaxin, macrophage chemoattractant protein-1, and keratinocyte chemoattractant as compared with vehicle challenge. However, the combination of PQ with OVA did not alter the expression levels of these proteins as compared with OVA alone.
These results indicate that PQ can enhance the immunoglobulin production and the infiltration of inflammatory cells into alveolar spaces that are related to OVA, whereas PQ seems to be partially responsible for the DEP toxicity on the allergic airway inflammation.
Three types of latex nanoparticles carrying naltrindole (NTI) derivatives were synthesized as probes for the affinity isolation of their binding proteins including the delta-opioid receptor. The effect of the attachment of NTI to different positions on the linker was investigated. Only latex nanoparticles in which the NTI derivative was linked through the phenol group were useful for isolating the recombinant delta-opioid receptor solubilized from CHO cell membrane. These latex nanoparticles could be a useful tool for investigations of the pharmacological activity of NTI.
The authors sought to investigate the detection of non-eosinophilic asthma using induced sputum. Although this is an important subtype of clinical asthma, its recognition is not standardized.
Adult non-smokers with asthma and healthy controls underwent sputum induction and hypertonic saline challenge. Non-eosinophilic asthma was defined as symptomatic asthma with normal sputum eosinophil counts. The normal range for sputum eosinophil count was determined using the 95th percentile from the healthy control group as a cut-off point.
The recognition of non-eosinophilic asthma using eosinophil proportion was in agreement with a definition based on absolute eosinophil count (kappa 0.67). Non-eosinophilic asthma was a stable subtype over both the short term (4 weeks) and longer term (5 years, kappa 0.77). Airway inflammation in asthma could be categorized into four inflammatory subtypes based on sputum eosinophil and neutrophil proportions. These subtypes were neutrophilic asthma, eosinophilic asthma, mixed granulocytic asthma and paucigranulocytic asthma. Subjects with increased neutrophils (neutrophilic asthma and mixed granulocytic asthma) were older and had an increased total cell count and cell viability compared with other subtypes.
Induced sputum eosinophil proportion is a good discriminator for eosinophilic asthma, providing a reproducible definition of a homogenous group. The remaining non-eosinophilic subjects are heterogeneous and can be further classified based on the presence of neutrophils. These inflammatory subtypes have important implications for the investigation and characterization of airway inflammation in asthma.
Particulate matter (PM) can exacerbate allergic airway diseases. Health effects of PM with a diameter of less than 100 nm, called nano particles, have been focused. We have recently demonstrated that carbon nano particles (14, 56 nm) exaggerate allergic airway inflammation in mice. In the present study, we investigated the effects of repeated pulmonary exposure to carbon nano particles on the expression of a variety of cytokines in the absence or presence of allergen in mice. ICR mice were divided into six experimental groups. Vehicle, two sizes of carbon nano particles, ovalbumin (OVA), and OVA + nano particles were administered intratracheally. Nano particles increased the lung protein levels of thymus and activation-regulated chemokine (TARC), macrophage inflammatory protein (MIP)-1alpha, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the absence or presence of allergen. The enhancement was more prominent with 14 nm of nano particles than with 56 nm of nano particles in overall trend. 14 nm nano particle exposure significantly enhanced the lung expressions of interleukin (IL)-2 and IL-10 in the presence of allergen as compared with allergen exposure. These results suggest that pulmonary exposure to nano particles can induce the lung expression of TARC, MIP-1alpha, GM-CSF in the absence of allergen and can enhance that of TARC, MIP-1alpha, GM-CSF, IL-2, and IL-10 in the presence of allergen. The enhancing effects are more prominent with smaller particles.
Diesel exhaust particles (DEP) can enhance various respiratory diseases. However, it is unclear as to which components in DEP are associated with the enhancement. We investigated the effects of DEP components on antigen-related airway inflammation, using residual carbonaceous nuclei of DEP after extraction (washed DEP), extracted organic chemicals (OC) in DEP (DEP-OC), and DEP-OC plus washed DEP (whole DEP) in the presence or absence of ovalbumin (OVA).
Male ICR mice were intratracheally administrated with OVA and/or DEP components. We examined the cellular profile of bronchoalveolar lavage (BAL) fluid, histological changes, lung expression of inflammatory molecules, and antigen-specific production of IgG1 in the serum.
DEP-OC, rather than washed DEP, enhanced infiltration of inflammatory cells into BAL fluid, magnitude of airway inflammation, and proliferation of goblet cells in the airway epithelium in the presence of OVA, which was paralleled by the enhanced lung expression of eotaxin and IL-5 as well as the elevated concentration of OVA-specific IgG1. In contrast, washed DEP with OVA showed less change and increased the lung expression of IFN-gamma. The combination of whole DEP and OVA caused the most remarkable changes in the entire enhancement, which was also accompanied by the enhanced expression of IL-13 and macrophage inflammatory protein-1 alpha.
DEP-OC, rather than washed DEP, exaggerated allergic airway inflammation through the enhancement of T-helper type 2 responses. The coexistence of OC with carbonaceous nuclei caused the most remarkable aggravation. DEP components might diversely affect various types of respiratory diseases, while whole DEP might mostly aggravate respiratory diseases.
By considering risk in the early stages of a technology, costs of identifying important health and environmental impacts after a technology has widely diffused can be avoided. Nanotechnology, involving materials and objects less than 100 nm in size, is an important case in point. In this paper we analyze the research priorities discussed by various interest groups concerned with the environmental risks of nanotechnology, evaluate the distribution of federal environmental nanotechnology R&D funding, and discuss research in this field. Overall federal environmental R&D funding to date is limited and focuses more on the positive environmental applications of nanotechnology than on basic knowledge/research, tools for nanoenvironmental research, or the potential risks of nanotechnology. The situation began to change in 2004 when a significant increase occurred in federal R&D funding for the environmental implications of engineered nanomaterials. Though literature exits on the exposure, transport, and toxicity of incidental nanoparticles, little work has been published on the environmental risks of engineered nanoparticles.
Pulmonary exposure to diesel exhaust particles (DEP) enhances lung inflammation related to bacterial endotoxin (lipopolysaccharide [LPS]) in mice. Severe lung inflammation can reportedly induce coagulatory abnormalities and systemic inflammation. This study examined the effects of components of DEP on lung inflammation, pulmonary permeability, coagulatory changes, systemic inflammatory response, and lung-to-systemic translocation of LPS in a murine model of lung inflammation. ICR mice were divided into six experimental groups that intratracheally received vehicle, LPS (2.5 mg/kg), organic chemicals in DEP (DEP-OC; 4 mg/kg) extracted with dicloromethane), residual carbonaceous nuclei of DEP (washed DEP: 4 mg/kg), DEP-OC + LPS, or washed DEP + LPS. Both DEP components exacerbated lung inflammation, vascular permeability, and the increased fibrinogen and E-selectin levels induced by LPS. With overall trends, the exacerbation was more prominent with washed DEP than with DEP-OC. Washed DEP + LPS significantly decreased activated protein C and antithrombin-III and elevated circulatory levels of interleukin (IL)-6, keratinocyte chemoattractant (KC), and LPS as compared with LPS alone, whereas DEP-OC + LPS elevated IL-6, KC, and LPS without significance. These results show that DEP components, especially washed DEP, amplify the effects if LPS on the respiratory system and suggest that they contribute to the adverse health effects of particulate air pollution on the sensitive populations with predisposing vascular and/or pulmonary diseases, including ischemic vascular diseases and respiratory infection.
The current authors have previously demonstrated that diesel exhaust particles (DEP) enhance antigen-related airway inflammation in mice. Furthermore, a recent study has shown that organic chemicals in DEP, rather than their carbonaceous nuclei, are important contributors to the aggravating effects of airway inflammation. However, the components in DEP responsible for the enhancing effects on the model remain to be identified. The current authors investigated the effects of naphthoquinone (NQ), one of the extractable chemical compounds of DEP, on antigen-related airway inflammation, local expression of cytokine proteins, and antigen-specific immunoglobulin (Ig) production in mice. Pulmonary exposure to NQ dose-dependently aggravated antigen-related airway inflammation, as characterised by infiltration of eosinophils and lymphocytes around the airways and an increase in goblet cells in the bronchial epithelium. Combined exposure to NQ and antigen enhanced the local expression of interleukin (IL)-4, IL-5, eotaxin, macrophage chemoattractant protein-1 and keratinocyte chemoattractant, compared with exposure to antigen or NQ alone. Also, NQ exhibited adjuvant activity for the antigen-specific production of IgG(1) and IgG(2a). These results provide the first experimental evidence that naphthoquinone can enhance antigen-related airway inflammation in vivo, and that naphthoquinone can, to some extent, partly play a role in the pathogenesis of diesel exhaust particle toxicity on the condition.
Airborne particulate matter (PM) is an important factor associated with the enhanced prevalence of respiratory allergy. The PM adjuvant activity on allergic sensitization is a possible mechanism of action involved, and the induction of airway inflammation is suggested to be of importance in PM-induced adjuvant activity.
Because differently sized PM have different toxic potentials, we studied the role of particle size in the induction of airway inflammation and allergic sensitization. This was done using fine (0.250 and 0.260 micro m) and ultrafine (0.029 and 0.014 micro m) titanium dioxide (TiO(2)) and carbon black particles (CBP) with known differences in airway toxicity.
Mice were intranasally exposed to ovalbumin (OVA) alone or in combination with one of the different particles. The induction of airway inflammation and the immune adjuvant activity were studied in the lungs and lung-draining peribronchial lymph nodes (PBLN) at day 8. OVA-specific antibodies were measured at day 21, and the development of allergic airway inflammation was studied after OVA challenges (day 28).
When administered at the same total particle mass (200 micro g), exposure to ultrafine TiO(2) and CBP-induced airway inflammation, and had immune adjuvant activity. The latter was shown by increasing both the PBLN cell numbers and the production of OVA-specific T-helper type 2 (Th2) cytokines (IL-4, IL-5, IL-10 and IL-13). Whereas OVA-specific IgE and IgG1 levels in serum were only increased in animals exposed to the ultrafine TiO(2), allergic airway inflammation could be detected in both ultrafine TiO(2)-and CBP-treated groups after challenges with OVA.
Our data show that only the ultrafine particles, with a small diameter and a large total surface area/mass, cause airway inflammation and have immune adjuvant activity in the current model supporting the hypothesis that particle toxicity is site-dependent and related to adjuvant activity.
Asthma is a complex disease with a significant inflammatory component. Multiple cell types are involved in its pathophysiology. The presence of eosinophils, the cell usually associated with allergic diseases, does not fully explain the inflammation found in asthma. Neutrophils are present in the airway of the patient with asthma in special circumstances and may represent different asthma phenotypes. Neutrophils are activated and are able to release mediators that promote and prolong asthma symptoms. Increasing evidence suggest that neutrophils may be central players with an important role in the pulmonary inflammatory process present in asthma.
The potential environmental impact of engineered nanomaterials
- Colvin
Long-term exposure to diesel exhaust enhances antigen-induced eosinophilic inflammation and epithelial damage in the murine airway
- Ichinose