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Pathogenesis of chronic obstructive pulmonary disease
... Previous studies of COPD pathogenesis based on murine models of disease, genetic association studies, or analyses of bulk human lung tissue have greatly expanded our understanding of disease pathogenesis. [3][4][5] The pathogenic cascade of COPD is initiated by repetitive insults to epithelial and endothelial cells within the distal airways and alveolar niche. This engenders activation of diverse cellular processes including immune cell infiltration, extracellular matrix proteolysis, cellular metabolic dysfunction, loss of proteostasis, DNA damage, autophagy, cellular senescence, and activation of regulated cell death pathways. ...
... This engenders activation of diverse cellular processes including immune cell infiltration, extracellular matrix proteolysis, cellular metabolic dysfunction, loss of proteostasis, DNA damage, autophagy, cellular senescence, and activation of regulated cell death pathways. 4,6,7 Consequently, there is an inability to maintain alveolar homeostasis, chronic inflammation, and alveolar septal destruction, particularly in advanced COPD. 4 However there remains limited knowledge of cell type-specific mechanisms or complex interactions amongst the multiple lung cell types that contribute to disease progression. ...
... 4,6,7 Consequently, there is an inability to maintain alveolar homeostasis, chronic inflammation, and alveolar septal destruction, particularly in advanced COPD. 4 However there remains limited knowledge of cell type-specific mechanisms or complex interactions amongst the multiple lung cell types that contribute to disease progression. ...
Chronic Obstructive Pulmonary Disease (COPD) pathogenesis involves a failure to maintain alveolar homeostasis due to repetitive injury and inflammation. In order to improve our understanding of cell-specific mechanisms contributing to COPD pathogenesis, we analysed single-cell RNA sequencing (scRNAseq) profiles of explanted parenchymal lung tissue from 17 subjects with advanced COPD requiring transplant and 15 control donor lungs. We identified a subpopulation of alveolar type II epithelial cells that uniquely express HHIP and have aberrant stress tolerance profiles in COPD. Amongst endothelial cells, we identified overlapping and unique shifts in transcriptional profiles of endothelial subtypes that may contribute to vascular inflammation and susceptibility to injury. We also identified population composition changes amongst alveolar macrophages. Finally, application of integrative analyses to our scRNAseq data identified cell-specific contributions to COPD heritability and dysfunctional cell-cell communication pathways that occur within the COPD alveolar niche. These findings provide cell type-specific resolution of transcriptional changes associated with advanced COPD that may underlie disease pathogenesis.
... Pathologically, COPD is characterized by a combination of chronic airway inflammation (chronic bronchitis) and a progressive loss of alveolar structures. The resulting airway thickening and mucus secretion combined with the loss of lung elastic recoil causes excessive airway narrowing during exhalation, limiting ventilation, and in-creasing the risk of infection (1)(2)(3)5). Observational studies suggest that exposure of susceptible individuals to cigarette smoke or other toxins leads to inflammation in multiple lung cell populations including alveolar macrophages (AMs) and epithelial cells, but several questions remain. ...
... Second, smokers usually begin to smoke in the second decade of life and continue for decades, but clinical manifestations of COPD are unusual before the seventh decade of life. Third, while smoking cessation slows the progression of COPD, the risk of disease is substantially increased even in individuals who stop smoking relatively early in life (1)(2)(3). These observations suggest that in some individuals, inflammation induced by cigarette smoke or other exposures early in life becomes independent of ongoing exposure, leading to progressive age-related lung dysfunction and clinical manifestations of COPD. ...
... Persistent inflammation in the lung epithelium has been linked to the development of COPD, but factors that regulate this inflammation remain unknown (1)(2)(3). We previously reported that the transcription factor Miz1 (also known as c-Myc-interacting zinc finger protein-1 and Zbtb17) is critical for the resolution of pulmonary inflammation through transcriptional repression of nuclear factor B (NF-B)-dependent proinflammatory gene Cebpd (13). ...
Cigarette smoking, the leading cause of chronic obstructive pulmonary disease (COPD), has been implicated as a risk factor for severe disease in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we show that mice with lung epithelial cell-specific loss of function of Miz1 , which we identified as a negative regulator of nuclear factor κB (NF-κB) signaling, spontaneously develop progressive age-related changes resembling COPD. Furthermore, loss of Miz1 up-regulates the expression of Ace2 , the receptor for SARS-CoV-2. Concomitant partial loss of NF- κ B/RelA prevented the development of COPD-like phenotype in Miz1 -deficient mice. Miz1 protein levels are reduced in the lungs from patients with COPD, and in the lungs of mice exposed to chronic cigarette smoke. Our data suggest that Miz1 down-regulation–induced sustained activation of NF-κB–dependent inflammation in the lung epithelium is sufficient to induce progressive lung and airway destruction that recapitulates features of COPD, with implications for COVID-19.
... Cigarette smoking (CS) is a leading cause of COPD [8], with other factors including ambient air pollution, airway hyperresponsiveness, and allergy [9]. e Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends long-acting bronchodilators for the management of patients with stable COPD [10]; however, the currently available drugs only relieve the symptoms of extracts and active component form pearl [25][26][27][28][29]. In a previous study, we had found that HSPT could improve the body's immunity by regulating the numbers of T cells [25]. ...
... Spleen. Inflammation is thought to play a major role in the pathogenesis of COPD [10]. T lymphocytes and T lymphocyte subpopulation play an important and diverse role in the establishment and suppression of inflammation [32]. ...
Chronic obstructive pulmonary disease (COPD) is predicted to become the third leading cause of death around the world. The present study is designed to investigate whether hydrolyzed seawater pearl tablet (HSPT) has immunoregulatory effects on the Th1/Th2 functionality in cigarette smoke-induced COPD model mice. The determination of the amino acid composition of HSPT was carried out by high-performance liquid chromatography (HPLC) with precolumn phenylisothiocyanate (PITC) derivatization. COPD model mice were constructed by cigarette smoking (CS) treatment and HSPT was administered. HSPT inhibited the infiltration of inflammation in the airway of the lung, reduced influx of eosinophils (EOSs), lymphocytes (LYMs), neutrophils (NEUs), and macrophages (MACs) in the bronchoalveolar lavage fluid (BALF), decreased the levels of IFN-γ, IL-2, IL-4, and IL-10 in the serum and lung, and decreased the expression of aforementioned cytokines in the spleen and lung in CS-treated mice. Besides, HSPT also had the ability to reduce the amount of CD3+CD4+ T cells and modulate the Th1/Th2 balance. Taken together, this study supports the consensus that CS is a critical factor to induce and aggravate COPD. HSPT could regulate the balance of Th1/Th2 in CS-induced COPD model mice, indicating its effects on inhibiting the development of COPD.
... Tobacco smoking is the most evidenced cause of this slowly progressive condition with high morbidity and mortality around the world [3,4]. In addition to established linkage between tobacco smoking and COPD, underlying pathophysiological mechanisms have been studied, resulting in detailed descriptions of pathophysiological respiratory changes in individuals with COPD [5]. Generally, two main components of COPD, chronic obstructive bronchitis and emphysema are broadly linked to pathology of COPD. ...
... Development and progression of COPD is associated with irritation of airways by repeated exposure to tobacco smoke, resulting in activation of persistent inflammatory response, characterized by involvement of many immune cells and release of multiple proinflammatory mediators including pro-inflammatory cytokines [6]. The resultant airway tissue inflammation progresses to airway remodeling, narrowing, and pulmonary tissue destruction [5]. ...
... It is estimated that COPD will become the third most common cause of death worldwide by 2030. [4] COPD was defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as a common treatable and preventable disease characterized by constant airflow limitation that is usually progressive and coupled with an enhanced chronic inflammatory response to noxious particles or gases in the airway and the lung. Chronic bronchitis and emphysema are associated with COPD. ...
... [5] The pulmonary injury involves three stages i.e, initiation (due to exposure to cigarette smoking, pollutants, and infectious agents), progression and consolidation. [4] Symptoms including cough with or without sputum, chest pain, breathlessness, decreased the quality of life (QOL) and loss of lung function become worst with acute exacerbations of COPD. During exacerbation of COPD airway inflammation is significantly increased, the number of lymphocytes, eosinophils and neutrophils are elevated in airways and sputum. ...
... Definiert ist die COPD zusätzlich durch die WHO als nicht reversible Erkrankung [105]. Die Diagnose der COPD wird mit Hilfe der Spirometrie gestellt und manifestiert sich in einer verminderten Einsekundenkapazität (FEV1), einem erhöhten Residualvolumen (RV), einem erhöhten intrathorakalen Gasvolumen (ITGV) und einer verminderten Diffusionskapazität [97,93]. Der Phänotyp der COPD ist jedoch von Individuum zu Individuum verschieden und stellt sich klinisch auch unterschiedlich dar. ...
... Die nachgewiesenen systemischen Entzündungsmediatoren können jedoch auf einen Zusammenhang hinweisen. Das veränderte Mikrobiom der Lunge von COPD Patienten und die chronische Entzündung führen zusätzlich zu einem deutlich erhöhten Risiko ein Lungenkarzinom zu entwickeln [93,20]. Es wird empfohlen alle Komorbiditäten leitliniengerecht zu behandeln, unabhängig von der Diagnose der COPD -und vice versa [5]. ...
... Known that COPD is a type of severe pulmonary inflammatory disease characterized by excessive inflammatory response, inappropriate immune activation, and lung injury, and that ln-cRNA MALAT1 contributes to the excessive inflammatory responses, aberrant macrophage activation, and injury of lung, [2][3][4]11 we speculated that lncRNA MALAT1 might be involved in the development and progression of COPD as well. Meanwhile, lncRNA MALAT1 accelerates inflammation via interacting with microRNA (miR)-125b, miR-133, miR-146a, or miR-203 in other inflammatory diseases (including sepsis, ischemia-reperfusion injury, acute lung injury, and myocardial-reperfusion injury) rather than COPD. ...
... (2) LncRNA MALAT1 might cause tissue damage and lung injury by regulating its downstream pathways (such as p38 MAPK/p65 NF-κB signaling pathway),which contributed to the exacerbation of COPD. Our finding was supported by the results of other mechanism studies that lncRNA MALAT1 stimulates inflammation and amplifies lung injury, which are vital in the progression and exacerbation of COPD.11,16,17 ...
Objective
The study aimed to explore the correlations of long non‐coding RNA MALAT1 (lncRNA MALAT1) and its targets microRNA (miR)‐125b, miR‐133, miR‐146a, and miR‐203 with acute exacerbation risk, inflammation, and disease severity of chronic obstructive pulmonary disease (COPD).
Methods
Plasma samples were obtained from 120 acute exacerbation COPD (AECOPD) patients, 120 stable COPD patients, and 120 healthy controls (HCs). RT‐qPCR was conducted to detect lncRNA MALAT1 expression and its target miRNAs, and ELISA was performed to detect the inflammatory cytokines.
Results
LncRNA MALAT1 was highest in AECOPD patients followed by stable COPD patients and then HCs, which distinguished AECOPD patients from HCs (AUC: 0.969, 95% CI: 0.951‐0.987) and stable COPD patients (AUC: 0.846, 95% CI: 0.798‐0.894). Furthermore, lncRNA MALAT1 positively correlated with GOLD stage in both AECOPD and stable COPD patients. Regarding inflammatory cytokines, lncRNA MALAT1 positively correlated with tumor necrosis factor‐α (TNF‐α), interleukin (IL)‐1β, IL‐6, IL‐8, IL‐17, and IL‐23 in both AECOPD and stable COPD patients. Besides, lncRNA MALAT1 negatively correlated with miR‐125b, miR‐146a, and miR‐203 in AECOPD patients and reversely correlated with miR‐125b and miR‐146a in stable COPD patients. Notably, miR‐125b, miR‐133, miR‐146a, and miR‐203 were the lowest in AECOPD patients, followed by stable COPD patients, and then HCs; miR‐125b, miR‐133, miR‐146a, and miR‐203 negatively correlated with inflammation and GOLD stage in AECOPD and stable COPD patients.
Conclusion
LncRNA MALAT1 exhibits clinical implications in acute exacerbation risk prediction and management of COPD via the inner‐correlation with its targets miR‐125b, miR‐146a, and miR‐203.
... Chronic obstructive pulmonary disease COPD is a multidimensional disease with a variety of intermediate and clinical phenotypes [33]. It is estimated that COPD will become the third most common cause of death worldwide by 2030 [34][35][36]. ...
... Exacerbations and comorbidities contribute to the overall severity in individual patient" [37]. The pulmonary injury involves three stages, i.e., initiation (due to exposure to cigarette smoking, pollutants, and infectious agents), progression, and consolidation [33]. Symptoms including breathlessness decreased the quality of life (QOL) and loss of lung function become worst with acute exacerbations of COPD [38,39]. ...
Since their identification, which was almost 80 years ago, steroids have played a prominent role in the treatment of many disease states such as chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, and inflammatory bowel disease. Many of the clinical roles of steroids are related to their potent anti-inflammatory and immune-modulating properties. Numerous skin diseases are successfully treated with systemic steroids. Corticosteroids, though they are lifesaving drugs, produce adverse reactions which may be mild or life threatening. Steroids have diverse effects on various systems of the body. Therefore, educational interventions among physician, patients, as well as students should be carried out to further enhance rational drug use. The purpose of this review was to identify the most commonly prescribed steroids and their side effects, basic pharmacology, complications, as well as the assessment of patient knowledge about the use of steroids in tertiary care teaching hospitals.
... Increased levels of autophagy have been observed in lung tissues from patients with COPD (15), and exposure to cigarette smoke extract results in increased autophagy in lung epithelial cells (15). In addition to cigarette smoke, infectious agents also contribute to COPD initiation and progression (16). However, whether and how infectious agents affect autophagy in lung epithelial cells remains unknown. ...
... Therefore, the findings from the present study suggest potential mechanisms by which lung epithelial cells react against invading bacteria and DNA viruses. As viral and bacterial infection is a common cause of the exacerbation of COPD (16), these findings may also provide clues to understanding the pathophysiology of COPD. ...
Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) is a newly identified cytosolic DNA sensor, but its function in lung epithelial cells is relatively unknown. In the present study, the effects of lipopolysaccharide (LPS) on the expression and function of cGAS in the A549 lung epithelial cell line was investigated. The cells were treated with LPS at different concentrations (e.g., 100, 200, 400 and 800 ng/ml), and the cGAS expression levels were examined via western blot analysis and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The cells were pretreated with LPS, followed by E. coli DNA transfection using Lipofectamine® 3000. After 24 h, interferon (IFN)-β production was measured using ELISA and the expression of the autophagic markers, microtubule-associated proteins 1A/1B light chain 3 and sequestosome-1, were determined using western blot analysis. The cells were also pretreated with either a toll-like receptor (TLR) 4 inhibitor, a serine/threonine-protein kinase TBK1 (TBK1) inhibitor or an nuclear factor (NF)-κB inhibitor, followed by LPS treatment, and the cGAS expression levels were examined via western blot analysis and RT-qPCR. The result showed that LPS treatment upregulated cGAS expression in a dose-dependent manner. E. coli DNA treatment could induce IFN-β production and autophagy via cGAS, which was enhanced by LPS pretreatment. The effect of LPS on cGAS expression was suppressed by treatment with a TLR4 inhibitor, a TBK1 inhibitor and an NF-κB inhibitor. In conclusion, LPS enhances DNA-induced IFN-β production and autophagy by upregulating cGAS expression through the myeloid differentiation primary response protein MyD88-independent TLR4 signaling pathway in A549 cells.
... There is conjecture regarding a proposed causal relationship between periodontal inflammation and systemic oxidative stress. Oxidative stress embraces an enormous impact on the pathophysiology of the aforementioned ailments [7,8,9,10] . It has been hypothesized that one of the primary manifestations of systemic inflammation may be oxidative stress which is exacerbated by periodontal diseases. ...
Inflammatory interactions that are uncontrolled integrating innate and adaptive responses leads to a persistent inflammatory response within the periodontal tissues, that constitutes the main hallmark of chronic periodontitis. The interface involving our external environment and the body's internal connective tissue is comprised of the periodontal epithelium, along with other mucosal surfaces. Chronic periodontitis may occur as the consequence of chemical or mechanical environmental stresses that aggravate or exacerbate oral disease. Additionally, chronic periodontitis has also been pertinent to environmental determinants that modulate the host response and systemic health status. When all factors are evaluated, pro-inflammatory processes that include both the environment and the host work together to promote a chronic state of inflammation in the periodontal tissues. This condition can be harmful and eventually result in bone resorption and tooth loss.
Periodontal disease is significantly impacted by steroid sex hormones. A steroid sex hormone correlated to periodontal health is estrogen. Considering receptors for estrogen are expressed in the oral cavity's mucosa and periodontium, the overall condition of the oral cavity has a direct association with the hormone's levels. In comparison with premenopausal women, postmenopausal women are more likely to experience periodontitis. This is consistent with investigations showing that postmenopausal women had a significantly greater plaque index than premenopausal and perimenopausal women. It also indicates that postmenopausal women may experience more severe periodontal degeneration in comparison to premenopausal and perimenopausal women. This menopausal symptom, although can occasionally be painless, is an effect of ageing. In general, oral discomfort is experienced among women as they approaches menopause.
One of the a multitude low molecular weight byproducts of lipid peroxidation (LPO) is malondialdehyde (MDA), that represents typically quantified as a peroxidation index. MDA has been proven to have substantial pathophysiologic effects. Thiobarbituric acid reactive substances screening is the most frequently employed technique for measuring MDA (TBARS). The quality of TBARS in biological samples is assessed using a range of spectrophotometer tests. Whole saliva is a crucial physiological fluid that is composed of an exceptionally complicated blend of molecules.
Immune response fluctuations attributed to psychological stress can enhance the risk of periodontitis. In addition to their diminished capacity to defend themselves, stress also presented an impact in immune response modulation. This mechanism amplifies the organism's susceptibility to inflammatory and psychological disorders. This modulation may facilitate the emergence or progression of periodontal disease, as stressors can exacerbate damage to the tooth's defensive and supporting structures.
Material and Methods
The research investigated included the recruitment of 64 patients, aged 47 to 55, who had recruited in the Periodontology department at the A. B. Shetty Memorial Institute of Dental Sciences which is located in Deralakatte, Mangalore. Thirty-two postmenopausal women with chronic periodontitis (Group A) and postmenopausal women without chronic periodontitis (Group B) (Healthy subjects) were the two distinct categories of patients. Each participant provided a thorough case history, and unstimulated whole salivary samples were taken in order to measure the levels of malondialdehyde in the saliva. The Perceived Stress Scale questionnaire was used to evaluate each participant's psychological stress. For statistical analysis, the collected data on psychological stress levels, salivary malondialdehyde levels, and their relationships in postmenopausal women with and without chronic periodontitis was submitted.
Results:
A Mann Whitney U test observed that the mean stress level between the two groups was also statistically significant, and an unpaired t-test showed that the mean value of malondialdehyde among subjects with chronic periodontitis compared to those in a healthy state was statistically significant. Stress and malondialdehyde (MDA) levels showed a weakly positive correlation (r = 0.12) in postmenopausal women with chronic periodontitis patients. By applying the Spearman's rank correlation method, the correlation was not statistically significant (p = 0.517). The multivariate linear regression model suggests that Periodontal probing depth and Stress level may be associated with MDA levels in chronic periodontitis patients, although the statistical significance is borderline when compared to Plaque Index and Clinical attachment loss.
Conclusion:
This study provides conclusive proof that free radical damage plays a significant etiologic role in postmenopausal women with CP. It showcases how the body's compensating mechanism is partially collapsed due to the unprecedented amount of free radicals and stress yielded during periodontitis and lacks the capacity to combat the increase degeneration of free radicals brought about by post menopause, thereby exacerbates the condition.
... Esses mecanismos levam às manifestações clínicas típicas da DPOC, que incluem: (a) bronquite crônica, uma condição de inflamação e remodelação das grandes vias aéreas; e (b) enfisema, uma doença das vias aéreas distais e do parênquima pulmonar em que há perda de área superficial para realização de troca gasosa. Como resultado, os pacientes com DPOC possuem uma limitação do fluxo aéreo, falta de ar e tosse produtiva crônica, que pode progredir para insuficiência respiratória crônica hipoxêmica e/ou hipercárbica (TUDER et al., 2012). ...
Introdução: O inflamassoma é um complexo multiproteico formado no citosol que apresenta como função gerar as formas ativas das citocinas IL-1β e IL-18 que irão promover a resposta inflamatória no indivíduo. A ativação do inflamassoma tem como consequência a piroptose, uma forma inflamatória de morte celular programada de macrófagos caracterizada pelo inchaço das células, perda da integridade da membrana plasmática e liberação de citocinas pró-inflamatórias (IL-1β, IL-18, TNF-α, IL-6 e IL-8). Assim, a participação do inflamassoma está confirmada na patogênese de várias doenças inflamatórias, cuja atuação é moldada pelo tipo de ativação e assim criando um perfil patogênico diferente para cada doença. Objetivo: Dessa forma, este estudo buscou abordar a relação da ativação do inflamassoma na patogênese das doenças do trato respiratório. Metodologia: Trata-se de uma revisão de literatura realizada a partir da análise de periódicos provenientes da plataforma acadêmica: Center for Biotechnology Information (PubMed). A pesquisa foi delimitada em um intervalo de 2001 a 2021, usando as palavras-chaves: Inflamassoma; Asma; DPOC; Infecção trato inferior; Câncer de pulmão; Tuberculose; COVID-19. Desenvolvimento: Os resultados obtidos nos estudos demonstraram que há uma influência do inflamassoma nas patogêneses do trato respiratório. Conclusão: Com base nas informações obtidas, foi possível observar a importância do inflamassoma no desenvolvimento da patogênese de algumas doenças do trato respiratório como a asma, doença pulmonar obstrutiva crônica (DPOC), infecções agudas do trato respiratório inferior, câncer de pulmão, tuberculose e COVID-19.
... COPD is characterized by chronic airway inflammation and progressively irreversible airflow limitation [2]. Cigarette smoking (CS) is considered as the predominant factor, accounting for approximately 80-90% of all COPD cases [3]. Oxidative stress is one key component in COPD pathogenesis [4]. ...
Chronic obstructive pulmonary disease (COPD) is mainly caused by cigarette smoking (CS), with oxidative stress being one key component during its pathogenesis. This study aimed to investigate the effects of quercitrin (QE) on cigarette smoke extract (CSE)-induced cell apoptosis and oxidative stress in human bronchial epithelial cells (HBECs) and its underlying mechanism. HBECs were treated with 2% CSE for 24 h to establish in vitro COPD cellular models. CCK-8 assay and flow cytometry analysis were performed to evaluate cell viability and apoptosis, respectively. Western blotting was applied to examine protein levels and ELISA kits were used to examine contents of the indicated oxidant/antioxidant markers. The results demonstrated that CSE promoted apoptosis and suppressed viability of HBECs and QE reversed these effects. CSE caused increase in T-AOC, superoxide dismutase, and glutathione (GSH) peroxidase contents and decrease in MDA, reactive oxygen species , and GSH contents in HBECs, which were rescued by QE treatment. The CSE-induced Nrf2 nuclear translocation and elevation of NAD(P)H: quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1) expression were also reversed by QE in HBECs. The mitogen-activated protein kinase (MAPK) signaling was activated by CSE and further suppressed by QE in HBECs. Collectively, QE exerts a protective role in HBECs against cell apoptosis and oxidative damage via inactivation of the Nrf2/HO-1/NQO1 pathway and the MAPK/ERK pathway.
... 10,11 These pathological processes are triggered by the complex interaction between cigarette smoke, environmental toxicants, genetics and infectious agents. 12,13 Bacterial and viral insults have been shown to disrupt host immune defense systems in patients with COPD; tuberculosis is well known for causing bronchiectasis and COPD patients with a history of tuberculosis are well known to have worse outcomes. [14][15][16][17][18][19] The small size of small airways renders imaging difficult and their inaccessibility makes obtaining biopsies challenging. ...
The response to treatment and progression of Chronic Obstructive Pulmonary Disease (COPD) varies significantly. Small airways disease (SAD) is being increasingly recognized as a key pathological feature of COPD. Studies have brought forward pathological evidence of small airway damage preceding the development of emphysema and the detection of obstruction using traditional spirometry. In recent years, there has been a renewed interest in the early detection of SAD and this has brought along an increased demand for physiological tests able to identify and quantify SAD. Early detection of SAD allows early targeted therapy and this suggests the potential for altering the course of disease. The aim of this article is to review the evidence available on the physiological testing of small airways. The first half will focus on the role of lung function tests such as maximum mid-expiratory flow, impulse oscillometry and lung clearance index in detecting and quantifying SAD. The role of Computed Tomography (CT) as a radiological biomarker will be discussed as well as the potential of recent CT analysis software to differentiate normal aging of the lungs to pathology. The evidence behind SAD biomarkers sourced from blood as well as biomarkers sourced from sputum and broncho-alveolar lavage (BAL) will be reviewed. This paper focuses on CC-16, sRAGE, PAI-1, MMP-9 and MMP-12.
... Toxicity of Cd in the lungs occurs due to formation of excessive reactive oxygen species (ROS) causing pulmonary oxidative stress [107,125]. The universal antioxidant transcription factor Nrf2 is involved in a wide range of responses implicated in both initiation and progression of injuries in the lungs [144]. ...
Cadmium (Cd) has been recognized as one of the most toxic heavy metals, which is continuously discharged into environments through anthropogenic (industrial activities, fertilizer production, and waste disposal) and natural sources with anthropogenic sources contributing greater than the natural sources. Therefore, Cd concentration sometimes increases in feeds, fodders, water bodies, and tissues of livestock including poultry in the vicinity of the industrial areas, which causes metabolic, structural, and functional changes of different organs of all animals. In poultry, bioaccumulation of Cd occurs in several organs mainly in the liver, kidney, lung, and reproductive organs due to its continuous exposure. Intake of Cd reduces growth and egg laying performance and feed conversion efficiency in poultry. Chronic exposure of Cd at low doses can also alter the microscopic structures of tissues, particularly in the liver, kidney, brain, pancreas, intestine, and reproductive organs due to increased content of Cd in these tissues. Continuous Cd exposure causes increased oxidative stress at cellular levels due to over-production of reactive oxygen species, exhausting antioxidant defense mechanisms. This leads to disruption of biologically relevant molecules, particularly nucleic acid, protein and lipid, and subsequently apoptosis, cell damage, and necrotic cell death. The histopatholocal changes in the liver, kidneys, and other organs are adversely reflected in hemogram and serum biochemical and enzyme activities. The present review discusses about Cd bioaccumulation and histopathological alterations in different tissues, pathogenesis of Cd toxicity, blood-biochemical changes, and its different ameliorative measures in poultry.
... Chronic inflammatory response incited by tissue damage that has occurred due to the prolonged exposure of lungs to pollutants is stated to prompt COPD. The inflammatory mediators instigated as the result of tissue damage are identified to exacerbate the severity and iterate the series of tissue damage and inflammatory response even in the absence of exposure to the pollutants (Tuder and Petrache 2012;Rovina et al. 2013;Simpson et al. 2013;Lago et al. 2014;Zuo et al. 2014). These events represent a strong correlation between inflammation and COPD (Man et al. 2012). ...
Flavonoids constitute a large group of plant phenolic metabolites with diverse structural compounds exhibiting multiple biological activities. Flavonoids have been used over centuries in folk medicine for tackling various human ailments and promoting the human health. With centuries old historical background, flavonoids still hold the valour to be captivated by researchers and clinicians for reframing the current medications to recuperate the equilibrium in human health. In this context, a vast range of biological activities of flavonoids has been documented by various research groups. These findings unwind the multi-targeting potential of flavonoids in various clinical conditions, which hints the ability of flavonoids to gratify the need of current treatment strategy mandating the handling of other complications accompanying a diseased condition. Moreover, the ubiquitous dietary sources of flavonoids underscore their innocuous nature as well as the likelihood to be used in clinical settings. This also enlightens that daily consumption of flavonoids from various dietary sources could act as better nutraceuticals for nourishing the health and assist the risk management of many complications. With this, a comprehensive overview on therapeutic applications of multipotent flavonoids has been provided in this chapter.
... COPD is a chronic and progressive disease with most cases as consequence of chronic bronchitis, smoking, air pollution and other environmental factors 160,161 . Pathologically, COPD causes major impairments in all lung compartments with small airways, and pulmonary vasculature [162][163][164][165][166][167] . ...
Showing first paragraph of article]Pulmonary hypertension is a progressive disease characterized by an elevation of pulmonary artery pressure and pulmonary vascular resistance, leading to right ventricular failure and death. It remains a challenging chronic progressive disease, but the current interest and advent of medical therapy in the last 20 years has significantly changed the perception of medical community in this disease. Pulmonary hypertension is not a specific disease; the majority of cases present with other diseases and various pathological processes that affect the pulmonary vasculature, and consequently increase pulmonary pressure and vascular resistance.
... An example is chronic obstructive pulmonary disease (COPD), which in its two pathological manifestations (chronic bronchitis and emphysema) is an increasing cause of morbidity and mortality (130,000 death worldwide). Long-term exposure to irritants (mainly tobacco smoking and air pollutants) triggers an inflammatory response in the lungs, resulting in narrowing of the small airways, breakdown of lung tissue and progressive alveolar destruction (emphysema), and onset of symptoms like dyspnea, cough, and sputum production [82]. Although respiratory symptoms are the hallmarks of COPD, non-pulmonary manifestations occur frequently; thus, increasing risk of significant cardiovascular, endocrine, and musculoskeletal comorbidities [83]. ...
Mycoplasmas are the smallest and simplest self-replicating prokaryotes. Located everywhere in nature, they are widespread as parasites of humans, mammals, reptiles, fish, arthropods, and plants. They usually exhibiting organ and tissue specificity. Mycoplasmas belong to the class named Mollicutes (mollis = soft and cutis = skin, in Latin), and their small size and absence of a cell wall contribute to distinguish them from other bacteria. Mycoplasma species are found both outside the cells as membrane surface parasites and inside the cells, where they become intracellular residents as “silent parasites”. In humans, some Mycoplasma species are found as commensal inhabitants, while others have a significant impact on the cellular metabolism and physiology. Mollicutes lack typical bacterial PAMPs (e.g., lipoteichoic acid, flagellin, and some lipopolysaccharides) and consequently the exact molecular mechanisms of Mycoplasmas’ recognition by the cells of the immune system is the subjects of several researches for its pathogenic implications. It is well known that several strains of Mycoplasma suppress the transcriptional activity of p53, resulting in reduced apoptosis of damaged cells. In addition, some Mycoplasmas were reported to have oncogenic potential since they demonstrated not just accumulation of abnormalities but also phenotypic changes of the cells. Aim of this review is to provide an update of the current literature that implicates Mycoplasmas in triggering inflammation and altering critical cellular pathways, thus providing a better insight into potential mechanisms of cellular transformation.
... tobacco smoke, causing airway remodeling and consecutive obstruction. Progressive air trapping leads to the development of emphysema, further deteriorating ventilatory mechanics in COPD patients 4 . ...
Background
Patients with chronic obstructive pulmonary disease (COPD) and lung emphysema may benefit from surgical or endoscopic lung volume reduction (ELVR). Previously reported outcomes of nitinol-coil-based endoscopic lung volume reduction techniques have been ambiguous.
Objectives
The analysis was done to analyze outcomes of ELVR with nitinol-coils in patients with severe pulmonary emphysema.
Methods
From September 2013 to November 2014, our center performed a total of 41 coil implantations on 29 patients with severe emphysema. Coils were bronchoscopically placed during general anesthesia. 12 out of 29 patients received contralateral treatments 4-6 weeks later to avoid bilateral pneumothorax. Lung function and 6-minute walking distance were assessed one week prior, one week after as well as 6 to 12 months after the procedure. Patients were followed up to 48 months after ELVR and overall mortality was compared to a historic cohort.
Results
While coil-based ELVR led to significant short-term improvement of vital capacity (VC, + 0.14 l ± 0.39 l, p = 0.032) and hyperinflation (ΔRV / TLC -2.32% ± 6.24%, p = 0.022), no significant changes were observed in 6-minute walking distance (6-MWD) or forced expiratory volume in one second (FEV1). Benefits were short-lived, with only 15.4% and 14.3% of patients showing sustained improvements in FEV1 or residual volume (RV) after 6 months. Adverse events included hemoptysis (40 %) and pneumothorax (3.4 %), major complications occurred in 6.9% of cases. Overall survival without lung transplant was 63.8% after 48 months following ELVR, differing insignificantly from what BODE indices of patients would have predicted as median 4-year survival (57%) at the time of ELVR treatment.
Conclusion
Endoscopic lung volume reduction coils can achieve small and short-lived benefits in lung function at the cost of major complications in a highly morbid cohort. Treatment failed to improve 4-year overall survival. ELVR coils are not worthwhile the risk for most patients with severe emphysema.
... No thickening of alveolar walls and no gradual development of emphysema was observed with the internal exposure, suggesting a unique internal radiation pathology. Pulmonary emphysema is characterized histologically by the destruction of alveolar walls and enlargement of air spaces by lung epithelial cell apoptosis [14], and in cigarette smoking by oxidative stress, cell death by apoptosis, and senescence with decreased repair [15,16]. This is a similar mechanism to models of apoptosis-dependent emphysema [17,18] or emphysema following high-dose ionizing radiation exposures [19,20]. ...
Internal radiation exposure from neutron-induced radioisotopes environmentally activated following atomic bombing or nuclear accidents should be considered for a complete picture of pathologic effects on survivors. Inhaled hot particles expose neighboring tissues to locally ultra-high doses of β-rays and can cause pathologic damage. 55MnO2 powder was activated by a nuclear reactor to make 56MnO2 which emits β-rays. Internal exposures were compared with external γ-rays. Male Wistar rats were administered activated powder by inhalation. Lung samples were observed by histological staining at six hours, three days, 14 days, two months, six months and eight months after the exposure. Synchrotron radiation - X-ray fluorescence - X-ray absorption near-edge structure (SR–XRF–XANES) was utilized for the chemical analysis of the activated 56Mn embedded in lung tissues. 56Mn beta energy spectrum around the particles was calculated to assess the local dose rate and accumulated dose. Hot particles located in the bronchiole and in damaged alveolar tissue were identified as accumulations of Mn and iron. Histological changes showed evidence of emphysema, hemorrhage and severe inflammation from six hours through eight months. Apoptosis was observed in the bronchiole epithelium. Our study shows early event damage from the locally ultra-high internal dose leads to pathogenesis. The trigger of emphysema and hemorrhage was likely early event damage to blood vessels integral to alveolar walls.
... 10,11 Important risk factors for emphysema are age and genetic predisposition, cigarette smoking, or occupational exposures. 10,12 It is known that ongoing inflammation, oxidative stress, and protease/antiprotease imbalance lead to matrix degradation and progressive tissue destruction in emphysema. Importantly, endogenous regenerative mechanisms of the lung are severely compromised in emphysema. ...
Wnt/β-catenin signaling regulates progenitor cell fate decisions during lung development and in various adult tissues. Ectopic activation of Wnt/β-catenin signaling promotes tissue repair in emphysema, a devastating lung disease with progressive loss of parenchymal lung tissue. The identity of Wnt/β-catenin responsive progenitor cells and the potential impact of Wnt/β-catenin signaling on adult distal lung epithelial progenitor cell function in emphysema are poorly understood. Here, we used a TCF/Lef:H2B/GFP reporter mice to investigate the role of Wnt/β-catenin signaling in lung organoid formation. We identified an organoid-forming adult distal lung epithelial progenitor cell population characterized by a low Wnt/β-catenin activity, which was enriched in club and alveolar epithelial type (AT)II cells. Endogenous Wnt/β-catenin activity was required for the initiation of multiple subtypes of distal lung organoids derived from the Wntlow epithelial progenitors. Further ectopic Wnt/β-catenin activation specifically led to an increase in alveolar organoid number; however, the subsequent proliferation of alveolar epithelial cells in the organoids did not require constitutive Wnt/β-catenin signaling. Distal lung epithelial progenitor cells derived from the mouse model of elastase-induced emphysema exhibited reduced organoid forming capacity. This was rescued by Wnt/β-catenin signal activation, which largely increased the number of alveolar organoids. Together, our study reveals a novel mechanism of lung epithelial progenitor cell activation in homeostasis and emphysema.
... The high altitude exposure results under decreased partial pressure of oxygen and enhanced formation of ROS through mitochondrial electron transport chains, xanthine oxidase/reductase, NADPH oxidase, nitric oxide synthase enzymes, and inflammatory process (Dosek et al. 2007;Winterbourn 2008;Arya et al. 2013), which cause oxidative stress (Jayalakshmi et al. 2005;Maiti et al. 2006). This hypoxia-induced redox imbalance is a primary factor for lung pathological processes, such as increased pulmonary artery pressure, vascular proliferation, edoema, right heart failure and inflammation (Rosanna and Salvatore 2012;Sylvester et al. 2012;Tuder and Petrache 2012). Oxidative stressrelated proteins are known to be controlled in redox regulation. ...
Context
Environmental hypobaric hypoxia induces several physiological or pathological responses in individuals in high-altitude regions. Salvia przewalskii Maxim (Labiatae) (SPM) is a traditional Chinese herbal medicine and has known antibacterial, antiviral, antioxidant, anti-thrombotic, and anti-depressant activities.
Objective
This study examined the antihypoxia effects of SPM in vivo.
Materials and methods
The dried and pulverised of SPM was extracted from root crude drug with 70% ethanol with ultrasound. Male Sprague-Dawley rats were divided into three groups (n = 10): normal group, hypoxia group (altitude of 4260 m), and hypoxia + SPM group (altitude of 4260 m, SPM of 1.0 g/kg/day). The experiment persisted for 4 weeks. The mean pulmonary arterial pressure (mPAP), hypoxia-inducible factor-1α (HIF-1α) mRNA, and lung pathology were analysed using pulmonary artery pressure recorder, quantitative polymerase chain reaction, and histopathological analysis. Moreover, the effects of SPM on lung proteomes during hypoxia were observed by a TMT-based proteomic approach.
Results
Pre-treatment with SPM decreased mPAP (24.86%) and HIF-1α (31.24%), and attenuated the pathological changes in lung tissues. In addition, a total of 28 proteins were differentially expressed in lung of hypoxia + SPM group (fold change > ± 1.2 and p < 0.05). The differentially altered proteins were primarily associated with antioxidative stress, as evidenced by the downregulated expression of Adh7, Cyp2d1, Plod2, Selenow, ND3, and Fabp1, and fructose metabolism, as evidenced by the downregulated expression of Khk and Aldob.
Discussion and conclusions
These results suggested that SPM is a promising drug for antihypoxia. The mechanism of action might be related to increasing antioxidant capacity and inhibiting fructose metabolism.
... It is also subsequently found that covalent modification of KEAP1 through Cys249, Cys368 and/or Cys613 are involved in Cd-mediated activation of NRF2 [163]. NRF2 has also been implicated in responses to lung injuries caused by Cd originating from cigarettes [164]. For example, NRF2 knockdown enhances Cd cytotoxicity, whereas KEAP1 knockdown diminishes such a heavy-metal toxicity in the vascular endothelial cells [163]. ...
Living organisms are surrounded with heavy metals such as methylmercury, manganese, cobalt, cadmium, arsenic, as well as pesticides such as deltamethrin and paraquat, or atmospheric pollutants such as quinone. Extensive studies have demonstrated a strong link between environmental pollutants and human health. Redox toxicity is proposed as one of the main mechanisms of chemical-induced pathology in humans. Acting as both a sensor of oxidative stress and a positive regulator of antioxidants, the nuclear factor erythroid 2-related factor 2 (NRF2) has attracted recent attention. However, the role NRF2 plays in environmental pollutant-induced toxicity has not been systematically addressed. Here, we characterize NRF2 function in response to various pollutants, such as metals, pesticides and atmospheric quinones. NRF2 related signaling pathways and epigenetic regulations are also reviewed.
... Notably, these mice were also found to have increased ceramide levels within their islets. The lung, which is directly exposed via inhalation to the toxic effects of tobacco smoking, exhibits a multitude of cellular responses to chronic CS exposure that include oxidative stress, inflammation, lung cell injury that results in cell death and tissue remodeling, as well as neoplasia [36]. In particular, in pulmonary emphysema, which is primarily caused by chronic CS, excessive ceramide production has been a major contributor to the apoptotic loss of lung endothelial cells that participate in gas exchange [19]. ...
Objectives
Epidemiological studies indicate that first- and second-hand cigarette smoke (CS) exposure are important risk factors for the development of type 2 diabetes (T2D). Additionally, elevated diabetes risk has been reported to occur within a short period of time after smoking cessation, and health risks associated with smoking are increased when combined with obesity. At present, the mechanisms underlying these associations remain incompletely understood. The objective of this study was to test the impact of CS exposure on pancreatic β-cell function using rodent and in vitro models.
Methods
Beginning at 8 weeks of age, C57BL/6J mice were concurrently fed high fat-diet (HFD) and exposed to CS for 11 weeks, followed by an additional 11 weeks of smoking cessation with continued HFD exposure. Glucose tolerance testing was performed during CS exposure and during the cessation period. Cultured INS-1 β-cells and primary islets were exposed ex vivo to CS extract (CSE), and β-cell function and viability were tested. Since CS increases ceramide accumulation in the lung and these bioactive sphingolipids have been implicated in pancreatic β-cell dysfunction in diabetes, islet and β-cell sphingolipid levels were measured in islets from CS-exposed mice and in CSE-treated islets and INS-1 cells using liquid chromatography-tandem mass spectrometry.
Results
Compared to HFD-fed ambient air-exposed mice, HFD-fed and CS-exposed mice had reduced weight gain and better glucose tolerance during the active smoking period. Following smoking cessation, CS-mice exhibited rapid weight gain and had accelerated worsening of their glucose tolerance. CS-exposed mice had higher serum proinsulin/insulin ratios, indicative of β-cell dysfunction, significantly lower β-cell mass (p=0.017), reduced β-cell proliferation (p=0.006), and increased islet ceramide content compared to non-smoking control mice. Ex vivo exposure of isolated islets to CSE was sufficient to increase islet ceramide levels, which was correlated with reduced insulin gene expression and glucose-stimulated insulin secretion, and increased β-cell oxidative and ER stress. Treatment with the antioxidant N-acetylcysteine, markedly attenuated the effects of CSE on ceramide levels, restored β-cell function and survival, and increased cyclin D2 expression, while also reducing activation of β-cell ER and oxidative stress.
Conclusions
Our results indicate that CS exposure leads to impaired insulin production, processing, and secretion and reduced β-cell viability and proliferation. These effects were linked to increased β-cell oxidative and ER stress and ceramide accumulation. Mice fed HFD continued to experience detrimental effects of CS exposure even during smoking cessation. Elucidation of the mechanisms by which CS exposure impairs β-cell function in synergy with obesity will help design therapeutic and preventive interventions for both active and former smokers.
... Macrophages play a crucial role in orchestrating chronic inflammation in COPD patients and their number markedly increases in both the airways and lung parenchyma 22 . Neutrophils provide powerful proteases and are broadly present in acute exacerbations in the lung airways 34 . The role of B cells and T cells in COPD pathogenesis has growing support from the basic science studies of COPD 7,35-37 . ...
Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous syndrome. Network-based analysis implemented by SWIM software can be exploited to identify key molecular switches - called “switch genes” - for the disease. Genes contributing to common biological processes or defining given cell types are usually co-regulated and co-expressed, forming expression network modules. Consistently, we found that the COPD correlation network built by SWIM consists of three well-characterized modules: one populated by switch genes, all up-regulated in COPD cases and related to the regulation of immune response, inflammatory response, and hypoxia (like TIMP1, HIF1A, SYK, LY96, BLNK and PRDX4); one populated by well-recognized immune signature genes, all up-regulated in COPD cases; one where the GWAS genes AGER and CAVIN1 are the most representative module genes, both down-regulated in COPD cases. Interestingly, 70% of AGER negative interactors are switch genes including PRDX4, whose activation strongly correlates with the activation of known COPD GWAS interactors SERPINE2, CD79A, and POUF2AF1. These results suggest that SWIM analysis can identify key network modules related to complex diseases like COPD.
... The main cause of COPD in developed countries is smoking [24], while in developing countries COPD is also frequently seen in patients exposed to environmental air-polluting agents (for example burning fuel for cooking). COPD is characterized by chronic inflammation leading to progressive lung damage, which ultimately contributes to irreversible airflow obstruction [25]. An acute exacerbation of COPD is defined as increased shortness of breath and sputum production, a change in the color of the sputum from clear to green or yellow, or an increase in cough. ...
Studies of the human microbiome have elucidated an array of complex interactions between prokaryotes and their hosts. However, precise bacterial pathogen–cancer relationships remain largely elusive, although several bacteria, particularly those establishing persistent intra-cellular infections, like mycoplasmas, can alter host cell cycles, affect apoptotic pathways, and stimulate the production of inflammatory substances linked to DNA damage, thus potentially promoting abnormal cell growth and transformation. Consistent with this idea, in vivo experiments in several chemically induced or genetically deficient mouse models showed that germ-free conditions reduce colonic tumor formation. We demonstrate that mycoplasma DnaK, a chaperone protein belonging to the Heath shock protein (Hsp)-70 family, binds Poly-(ADP-ribose) Polymerase (PARP)-1, a protein that plays a critical role in the pathways involved in recognition of DNA damage and repair, and reduces its catalytic activity. It also binds USP10, a key p53 regulator, reducing p53 stability and anti-cancer functions. Finally, we showed that bystander, uninfected cells take up exogenous DnaK—suggesting a possible paracrine function in promoting cellular transformation, over and above direct mycoplasma infection. We propose that mycoplasmas, and perhaps certain other bacteria with closely related DnaK, may have oncogenic activity, mediated through the inhibition of DNA repair and p53 functions, and may be involved in the initiation of some cancers but not necessarily involved nor necessarily even be present in later stages.
... Other COPD cases are related to problems with self-repair mechanisms. It is also known that epigenetic changes and cell senescence can both increase inflammation and decrease tissue repair (24). Genetic association studies suggest that the best candidate genes for COPD are CHRNA3, CHRNA5, IREB2, HHIP, FAM13A and AGER [25]. ...
A gene regulatory process is the result of the concerted action of transcription factors, co-factors, regulatory non-coding RNAs (ncRNAs) and chromatin interactions. Therefore, the combination of protein–DNA, protein–protein, ncRNA–DNA, ncRNA–protein and DNA–DNA data in a single graph database offers new possibilities regarding generation of biological hypotheses. GREG (The Gene Regulation Graph Database) is an integrative database and web resource that allows the user to visualize and explore the network of all above-mentioned interactions for a query transcription factor, long non-coding RNA, genomic range or DNA annotation, as well as extracting node and interaction information, identifying connected nodes and performing advanced graphical queries directly on the regulatory network, in a simple and efficient way. In this article, we introduce GREG together with some application examples (including exploratory research of Nanog’s regulatory landscape and the etiology of chronic obstructive pulmonary disease), which we use as a demonstration of the advantages of using graph databases in biomedical research.
Database URL: https://mora-lab.github.io/projects/greg.html, www.moralab.science/GREG/
... [3] Smoking is the most important risk factor associated with COPD, followed by lung inflammation, which is responsible for small airways thickening, alveolar destruction, and airway remodeling. [4] In both psoriasis and COPD, T-cell-mediated immunity is elevated, tumor necrosis factor-alpha (TNF-α) and other pro-inflammatory cytokines that play roles in the pathogenesis of both diseases, including interleukin-1 (IL-1), IL-6, and IL-8 are secreted to trigger neutrophil activation and migration of cells to the lung. T-cell cytokines, including interferon-γ, IL-13, and IL-17, may induce expression of TNF-α, IL-1, and IL-8, and also, IL-23, chemokines, receptors, adhesion molecules, and proteases. ...
BACKGROUND: The inflammation that occurs with psoriasis can affect both lungs and raise the risk for chronic obstructive airway disease, and hence, pulmonary function should be studied in patients with psoriasis.
AIM OF THE WORK: The study aimed to detect the relationship between psoriasis and chronic obstructive pulmonary disease (COPD).
SUBJECTS AND METHODS: A case–control study was conducted at El-Hussein University Hospital, Al-Azhar University. Sixty patients with psoriasis and sixty control patients were involved in this study. Spirometry was performed in all the study patients.
RESULTS: The present study included 60 psoriasis patients and age- and gender-matched 60 controls fulfilling inclusion criteria. No statistically significant differences were found between two groups as regards age, gender, and residence. However, patients with psoriasis were significantly more frequently smokers, overweight, obese, and diabetic. In addition, obstructive pulmonary functions were significantly higher among psoriasis patients. Overall, COPD was diagnosed in 10.0% of psoriasis patients compared with 5.0% of controls but with no statistically significant difference. The mean forced expiratory volume in 1 s/forced vital capacity ratio and forced expiratory flow at 25%–75% were significantly lower in the psoriasis patients than in the controls (80.4 ± 5.6 vs. 93.1 ± 5.4, P < 0.001 and 85.6 ± 9.1 vs. 95.5 ± 5.8, P < 0.001, respectively). Overweight, obese, and diabetic psoriasis patients were at increased risk of COPD than controls (odds ratio = 2.0, 2.5, and 1.7; 95% confidence interval, 0.89–4.45, 0.86–7.31, and 0.92–3.32), respectively.
CONCLUSIONS: Psoriasis patients were likely to develop COPD.
RECOMMENDATION: COPD should be screened by spirometry among psoriasis patients and advise them to stop smoking and control weight and diabetes to reduce COPD development.
... Four fundamental mechanisms have been studied in the pathogenesis of COPD, such as oxidative stress, inflammation, imbalance of the protease/anti-protease system and apoptosis [24,49]. Each of these mechanisms has a different contribution to the development and progression of COPD. ...
The pathogenesis of both chronic obstructive pulmonary disease (COPD) and arterial hypertension (AH) is closely related to oxidative stress, which is characterized by an imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense.
Aim:
The aim of the study was to assess the status of glutathione-based antioxidant protection system in lymphocytes of blood in patients with associated COPD and AH.
Materials and methods:
Lymphocytes were isolated from peripheral blood using A. Boyum technique. The quantification assay for reduced glutathione (GSH) level, glutathione reductase (GR), glutathione peroxidase (GP) and glutathione S transferase activities were assessed with spectrophotometry method.
Results:
The study population included 73 patients admitted to the Ternopil University Hospital. The subjects were distributed across three groups: group 1 (25 patients with COPD), group 2 (28 patients with COPD and AH) and the group 3 (control group of 20 healthy subjects). The analysis of parameters of lymphocytic glutathione system has not revealed any significant changes in GSH in patients with COPD only and a significant (20.5%) decrease in reduced glutathione in a COPD + AH combination. The group of patients with COPD was found to have decreased GP and GST activities, as well as increased GR activities. Patients with concomitant COPD and AH had uniform changes in the enzymes of the glutathione system. These changes were seen as significant decreases in GP activity (by 31.6%), GST activity (by 28.4%) and GR activity (by 18.8%). In patients with COPD+AH, positive correlations were found between GSH and GR/GST. In this respect, GST activity was directly correlated with GR activity and inversely correlated with GP activity.
Conclusions:
Overall, the results of our research suggest the glutathione-based antioxidant protection system to change differently in patients with COPD (GR activity increases, GP and GST activities decreases, GSH level does not change) and in patients with COPD+AH (GSH level and activities of glutathione-based antioxidant enzymes [GR, GP and GST] decreases). The changes found in the glutathione redox system suggest an important contribution of arterial hypertension to adverse course of COPD.
... Four fundamental mechanisms have been studied in the pathogenesis of COPD, such as oxidative stress, inflammation, imbalance of the protease/anti-protease system and apoptosis [24,49]. Each of these mechanisms has a different contribution to the development and progression of COPD. ...
The pathogenesis of both chronic obstructive pulmonary disease (COPD) and arterial hypertension (AH) is closely related to oxidative stress, which is characterized by an imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense.
The aim of the study was to assess the status of glutathione-based antioxidant protection system in lymphocytes of blood in patients with associated COPD and AH.
Lymphocytes were isolated from peripheral blood using A. Boyum technique. The quantification assay for reduced glutathione (GSH) level, glutathione reductase (GR), glutathione peroxidase (GP) and glutathione S transferase activities were assessed with spectrophotometry method.
The study population included 73 patients admitted to the Ternopil University Hospital. The subjects were distributed across three groups: group 1 (25 patients with COPD), group 2 (28 patients with COPD and AH) and the group 3 (control group of 20 healthy subjects). The analysis of parameters of lymphocytic glutathione system has not revealed any significant changes in GSH in patients with COPD only and a significant (20.5%) decrease in reduced glutathione in a COPD + AH combination. The group of patients with COPD was found to have decreased GP and GST activities, as well as increased GR activities. Patients with concomitant COPD and AH had uniform changes in the enzymes of the glutathione system. These changes were seen as significant decreases in GP activity (by 31.6%), GST activity (by 28.4%) and GR activity (by 18.8%). In patients with COPD+AH, positive correlations were found between GSH and GR/GST. In this respect, GST activity was directly correlated with GR activity and inversely correlated with GP activity.
Overall, the results of our research suggest the glutathione-based antioxidant protection system to change differently in patients with COPD (GR activity increases, GP and GST activities
decreases, GSH level does not change) and in patients with COPD+AH (GSH level and activities of glutathione-based antioxidant enzymes [GR, GP and GST] decreases). The changes found in the glutathionredox system suggest an important contribution of arterial hypertension to adverse course of COPD.
... Further studies of women in China (37) and Taiwan (38,39) have reported a dose-response relationship for lung cancer risk and use of volatilised oils, citing the mutagenic or oxidative effects of various components found Phenotypically, COPD and lung cancer present as very dissimilar diseases. COPD has features of chronic lung damage, characterised by irreversible airflow limitation, inflammation of small airways and progressive destruction of distal lung parenchyma resulting in emphysema (42). In comparison, lung cancer is characterised by DNA damage resulting in the overproduction of stimulatory proteins, excessive unregulated proliferation and defective cell cycle checkpoint regulation which confers selective biological advantage over normal cells (43). ...
Chronic obstructive pulmonary disease (COPD) and lung cancer comprise the leading causes of lung disease-related mortality worldwide. Exposure to tobacco smoke is a mutual aetiology underlying the two diseases, accounting for almost 90% of cases. There is accumulating evidence supporting the role of immune dysfunction, the lung microbiome, extracellular vesicles and underlying genetic susceptibility in the development of COPD and lung cancer. Further, epigenetic factors, involving DNA methylation and microRNA expression, have been implicated in both diseases. Chronic inflammation is a key feature of COPD and could be a potential driver of lung cancer development. Using next generation technologies, further studies investigating the genomics, epigenetics and gene-environment interaction in key molecular pathways will continue to elucidate the pathogenic mechanisms underlying the development of COPD and lung cancer, and contribute to the development of novel diagnostic and prognostic tools for early intervention and personalised therapeutic strategies.
... The process of lung tissue damage induced by cigarette smoke progresses due to multifaceted interactions among oxidative stress, inflammation, extracellular matrix proteolysis, and apoptotic and autophagic cell death [18]. This process however varies significantly between patients. ...
Chronic obstructive pulmonary disease (COPD) is a collective term for a condition associated with irreversible airways obstruction causing breathlessness and risk of recurring chest infections, termed exacerbations. Malnutrition has been shown to play an important role in many chronic diseases, but in COPD the extent that differences in nutritional wellbeing determine the patient’s risk of exacerbation, resilience to infection or response to treatment, has not been adequately addressed and so nutritional aspects of care have not been considered primary concerns in the management of the disease.COPD exacerbations are assumed a major driver for the progression of COPD and of healthcare utilisation. Current respiratory variables measured in routine clinical practice are insufficient to identify patients at risk of exacerbation in the short- to medium-term and hence interventions to ameliorate exacerbation risk are limited. There is a real need to explore other non-respiratory markers for risk assessment in COPD patients. Whilst nutritional assessment has been established as an important tool in understanding risk of long-term outcomes, especially mortality, its role in assessing patient’s risk of and response to exacerbations is less well understood. This thesis sought to explore the nutritional status in COPD patients with different disease presentations and clinical outcomes, in order to identify nutritional markers of exacerbation risk. Analysis focused on exploring the relative importance of disease history on nutritional status at baseline (how does previous disease impact on nutritional status), associations between disease status and nutritional status in stable COPD and relationship between nutritional status and clinical outcomes like time to first exacerbation (TTFE) and exacerbation rate over 12 month.Systematic review of the literature demonstrated variability in methods used to assess structural and functional markers of lean mass of COPD patients, which limited the conclusions that could be made. To address this a comparison of methods used in COPD patients was devised and conducted, showing comparability of the results of these methods.To explore the relationship between the nutritional status and clinical outcomes in COPD, a longitudinal, 12 months prospective cohort study, comprised of 127 COPD patients with a previous history of exacerbations was carried out. Nutritional status was assessed using markers of body composition, appetite and functional capacity (grip strength, grip endurance, walk test) at baseline and quarterly basis. These nutritional markers were used to explore their relationship with past medical history, baseline disease markers (spirometry, inflammation) and clinical outcomes, with further assessment of their predictive value for clinical outcomes measured as TTFE.In the studied cohort, 7 to 25% men and approximately 33% women had lean depletion (depending on applied criteria), and unexpectedly, low lean mass was not associated with a shorter time to first exacerbation. Those who had poor appetite were at higher risk of exacerbation in the following month (HR 1.6, p=0.023), which was independent of the exacerbations history and disease severity. Functional limitations including stopping during the 6- minute walk test (HR 1.90, p=0.001) and distance of less than 350m (HR 1.95, p=0.002) were related to TTFE. As none of the domains was sufficient to independently identify patients at high risk of exacerbation with sufficient accuracy in the next month, a multicomponent approach was taken by combining appetite score, body composition and walk test. Poor nutritional status marked by two or more components showed a higher risk of exacerbation, compared with those identified by any single component (HR 3.47 p<0.001). Use of history of exacerbation as additional component did not improve relevance to clinical outcomes and appetite score appeared to be of the greatest relevance to time to first exacerbation.In summary, the findings of this thesis demonstrate that nutritional status is not determined by the history of exacerbations, yet relates to markers of disease status in stable COPD and clinical outcomes in the future. Multicomponent nutritional assessment showed potential to identify patients with high risk of exacerbation in the near future, which was not possible when using standard respiratory measures alone. This thesis emphasises the role of assessing nutritional status in COPD patients and the relevance and need for recognizing different nutritional phenotypes in the disease management.
... Macrophages play a key role in orchestrating chronic inflammation in patients with COPD and are found in markedly increased numbers in both the airways and lung parenchyma. Neutrophils provide powerful proteases and are most prominent in acute exacerbations in the lung airways [Tuder 2012]. The role of T and B cells in COPD pathogenesis has growing support from the basic science studies of COPD [Hogg 2004, Seys 2015, Polverino 2016, Morrow 2017]. ...
Chronic obstructive pulmonary disease (COPD) is a heterogeneous and complex syndrome. Network-based analysis implemented by SWIM software can be exploited to identify key molecular switches - called "switch genes" - for disease. Genes contributing to common biological processes or define given cell types are frequently co-regulated and co-expressed, giving rise to expression network modules. Consistently, we found that the COPD correlation network built by SWIM consists of three well-characterized modules: one populated by switch genes, all up-regulated in COPD cases and related to the regulation of immune response, inflammatory response, and hypoxia (like TIMP1, HIF1A, SYK, LY96, BLNK and PRDX4); one populated by well-recognized immune signature genes, all up-regulated in COPD cases; one where the GWAS genes AGER and CAVIN1 are the most representative module genes, both down-regulated in COPD cases. Interestingly, 70% of AGER negative interactors are switch genes including PRDX4, whose activation strongly correlates with the activation of known COPD GWAS interactors SERPINE2, CD79A, and POUF2AF1. These results suggest that SWIM analysis can identify key network modules related to complex diseases like COPD.
... The lung, which is directly exposed via inhalation to the toxic effects of tobacco smoking, exhibits a multitude of cellular responses to chronic CS exposure that include oxidative stress, inflammation, lung cell injury that results in cell death and tissue remodeling, as well as neoplasia [35]. In particular, in pulmonary emphysema, which is primarily caused by chronic CS, excessive ceramide not certified by peer review) is the author/funder. ...
Objectives: Epidemiological studies indicate that first- and second-hand cigarette smoke (CS) exposure are important risk factors for the development of type 2 diabetes (T2D). Additionally, elevated diabetes risk has been reported to occur within a short period of time after smoking cessation, and health risks associated with smoking are increased when combined with obesity. At present, the mechanisms underlying these associations remain incompletely understood. The objective of this study was to test the impact of CS exposure on pancreatic β-cell function using rodent and in vitro models.
Methods: Beginning at 8 weeks of age, C57BL/6J mice were concurrently fed high fat-diet (HFD) and exposed to CS for 11 weeks, followed by an additional 11 weeks of smoking cessation with continued HFD exposure. Glucose tolerance testing was performed during CS exposure and during the cessation period. Cultured β-cells (INS-1) and primary islets were exposed ex vivo to CS extract (CSE), and β-cell function and viability were tested. Since CS increases ceramide in lungs cells and these bioactive sphingolipids have been implicated in pancreatic β-cell dysfunction in diabetes, islet and β-cell sphingolipid levels were measured in islets from CS-exposed mice and in CSE-treated islets and INS-1 cells using liquid chromatography-tandem mass spectrometry.
Results: Compared to HFD-fed ambient air-exposed mice, HFD-fed and CS-exposed mice had reduced weight gain and better glucose tolerance during the active smoking period. Following smoking cessation, CS-mice exhibited rapid weight gain and a significantly greater increase in glucose intolerance compared to non-smoking control mice. CS-exposed mice had higher serum proinsulin/insulin ratios, indicative of β-cell dysfunction, significantly lower β-cell mass (p=0.02), and reduced β-cell proliferation (p=0.006), and increased islet ceramide accumulation. Ex vivo exposure of isolated islets to CSE was sufficient to increase islet ceramide accumulation, reduce insulin gene expression and glucose-stimulated insulin secretion, and increase β-cell oxidative and ER stress. Treatment with the antioxidant N-acetylcysteine, markedly attenuated the effects of CSE on ceramide levels, restored β-cell function and survival, and increased cyclin D2 expression, while also reducing activation of β-cell ER and oxidative stress.
Conclusions: Our results indicate that CS exposure inhibits insulin production, processing, and secretion and reduced β-cell viability and proliferation. These effects were linked to increased β-cell oxidative and ER stress and ceramide accumulation. Mice fed HFD continued to experience detrimental effects of CS exposure even during smoking cessation. Elucidation of mechanisms by which CS exposure impairs β-cell function in synergy with obesity will help design therapeutic and preventive interventions for both active and former smokers.
... Increased oxidative stress as a result of the inhalation of noxious particles, particularly those derived from cigarette smoke, is a key driving mechanism in the pathogenesis of COPD and leads to the destruction of lung parenchyma [44]. This process is mediated by cytotoxic CD8 + T cells, macrophages and neutrophils. ...
Around three million patients die due to airway inflammatory diseases each year. The most notable of these diseases are asthma and chronic obstructive pulmonary disease (COPD). Therefore, new therapies are urgently needed. Promising targets are histone deacetylases (HDACs), since they regulate posttranslational protein acetylation. Over a thousand proteins are reversibly acetylated, and acetylation critically influences aberrant intracellular signaling pathways in asthma and COPD. The diverse set of selective and non-selective HDAC inhibitors used in pre-clinical models of airway inflammation show promising results, but several challenges still need to be overcome. One such challenge is the design of HDAC inhibitors with unique selectivity profiles, such as selectivity towards specific HDAC complexes. Novel strategies to disrupt HDAC complexes should be developed to validate HDACs further as targets for new anti-inflammatory pulmonary treatments.
... Pulmonary emphysema is a life-threatening disease caused mainly by smoking [1][2][3] . It is associated with alveolar wall destruction and effective therapy against this disease is very limited. ...
DJ-1 is a multifunctional protein with cytoprotective functions. It is localized in the cytoplasm, nucleus, and mitochondria. The conserved cysteine residue at position 106 (Cys106) within DJ-1 serves as a sensor of redox state and can be oxidized to both the sulfinate (-SO2−) and sulfonate (-SO3−) forms. DJ-1 with Cys106-SO2− has cytoprotective activity but high levels of reactive oxygen species can induce its overoxidation to Cys106-SO3−. We found increased oxidative stress in alveolar type II (ATII) cells isolated from emphysema patients as determined by 4-HNE expression. DJ-1 with Cys106-SO3− was detected in these cells by mass spectrometry analysis. Moreover, ubiquitination of Cys106-SO3− DJ-1 was identified, which suggests that this oxidized isoform is targeted for proteasomal destruction. Furthermore, we performed controlled oxidation using H2O2 in A549 cells with DJ-1 knockout generated using CRISPR-Cas9 strategy. Lack of DJ-1 sensitized cells to apoptosis induced by H2O2 as detected using Annexin V and propidium iodide by flow cytometry analysis. This treatment also decreased both mitochondrial DNA amount and mitochondrial ND1 (NADH dehydrogenase 1, subunit 1) gene expression, as well as increased mitochondrial DNA damage. Consistent with the decreased cytoprotective function of overoxidized DJ-1, recombinant Cys106-SO3− DJ-1 exhibited a loss of its thermal unfolding transition, mild diminution of secondary structure in CD spectroscopy, and an increase in picosecond–nanosecond timescale dynamics as determined using NMR. Altogether, our data indicate that very high oxidative stress in ATII cells in emphysema patients induces DJ-1 overoxidation to the Cys106-SO3− form, leading to increased protein flexibility and loss of its cytoprotective function, which may contribute to this disease pathogenesis.
Background: Chronic obstructive pulmonary disease (COPD) typically causes airflow blockage and breathing difficulties, which may result in the abnormal morphology and motion of the lungs or diaphragm. Purpose: This study aims to quantitatively evaluate respiratory diaphragm motion using a thoracic sagittal magnetic resonance imaging (MRI) series, including motion asynchronization and limitations. Method: First, the diaphragm profile is extracted using a deep-learning-based field-segmentation approach. Next, by measuring the motion waveforms of each position in the extracted diaphragm profile, obvious differences in the independent respiration cycles, such as the period and peak amplitude, are verified. Finally, focusing on multiple breathing cycles, the similarity and amplitude of the motion waveforms are evaluated using the normalized correlation coefficient (NCC) and absolute amplitude. Results and Contributions: Compared with normal subjects, the patients with severe COPD tend to have lower NCC and absolute amplitude values, suggesting motion asynchronization and limitation of their diaphragms. Our proposed diaphragmatic motion evaluation method may assist in the diagnosis and therapeutic planning of COPD.
The fibrotic remodeling in chronic obstructive pulmonary disease (COPD) is held responsible for narrowing of small airways and thus for disease progression. Oxidant damage and cell senescence factors are recently involved in airways fibrotic remodeling. Unfortunately, we have no indications on their sequential expression at anatomical sites in which fibrotic remodeling develops in smoking subjects. Using immunohistochemical techniques, we investigated in two strains of mice after cigarette smoke (CS) exposure what happens at various times in airway areas where fibrotic remodeling occurs, and if there also exists correspondence among DNA damage induced by oxidants, cellular senescence, the presence of senescence-secreted factors involved in processes that affect transcription, metabolism as well as apoptosis, and the onset of fibrous remodeling that appears at later times in mice exposed to CS. A clear positivity for fibrogenic cytokines TGF-β, PDGF-B, and CTGF, and for proliferation marker PCNA around airways that will be remodeled is observed in both strains. Increased expression of p16 ink4A senescence marker and MyoD is also seen in the same areas. p16 ink4A and MyoD can promote cell cycle arrest, terminal differentiation of myofibroblasts, and can oppose their dedifferentiation. Of interest, an early progressive attenuation of SIRT-1 is observed after CS exposure. This intracellular regulatory protein can reduce premature cell senescence. These findings suggest that novel agents, which promote myofibroblast dedifferentiation and/or the apoptosis of senescent cells, may dampen progression of airway changes in smoking COPD subjects.
El síndrome de dificultad respiratoria aguda (SDRA), la enfermedad pulmonar obstructiva crónica (EPOC) y la COVID-19 tienen en común provocar lesión inflamatoria del epitelio pulmonar. El tratamiento actual suele asociarse con infecciones oportunistas, hiperglicemia y afectación suprarrenal, por lo que es importante proponer opciones relacionadas con la disminución de la inflamación y estimulación de la reepitelización del tejido dañado. En esta revisión se detallan las características fisiopatológicas relevantes de dichas enfermedades y se evalúan los hallazgos recientes del efecto inmunomodulador, antiinflamatorio y regenerativo de las células troncales mesenquimales (MSC) y sus aplicaciones terapéuticas. Se seleccionaron los estudios sobresalientes del tema, publicados entre 2003 y 2022 en PubMed, siguiendo los criterios de la guía PRISMA. Las células troncales mesenquimales representan una opción importante de tratamiento regenerativo en pacientes con EPOC, SDRA y COVID-19, pues se diferencian a neumocitos tipo II, y mantienen el tamaño y la función del tejido pulmonar, supliendo a las células muertas o dañadas.
Lung function reflects the ability of the respiratory system and is utilized for the assessment of respiratory diseases. Because type 2 airway inflammation influences lung function, genome wide association studies (GWAS) for lung function would be improved by adjustment with an indicator of the inflammation. Here, we performed a GWAS for lung function with adjustment for exhaled nitric oxide (FeNO) levels in two independent Japanese populations. Our GWAS with genotype imputations revealed that the RNF5/AGER locus including AGER rs2070600 SNP, which introduces a G82S substitution of AGER, was the most significantly associated with FEV 1 /FVC. Three other rare missense variants of AGER were further identified. We also found genetic loci with three candidate genes ( NOS2, SPSB2 and RIPOR2 ) associated with FeNO levels. Analyses with the BioBank-Japan GWAS resource revealed genetic links of FeNO and asthma-related traits, and existence of common genetic background for allergic diseases and their biomarkers. Our study identified the genetic locus most strongly associated with airway obstruction in the Japanese population and three genetic loci associated with FeNO, an indicator of type 2 airway inflammation in adults.
The main physiological function of the lung is gas exchange, mediated at the interface between the alveoli and the pulmonary microcapillary network and facilitated by conducting airway structures that regulate the transport of these gases from and to the alveoli. Exposure to microbial and environmental factors such as allergens, viruses, air pollution, and smoke contributes to the development of chronic lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and lung cancer. Respiratory diseases as a cluster are the commonest cause of chronic disease and of hospitalization in children and are among the three most common causes of morbidity and mortality in the adult population worldwide. Many of these chronic respiratory diseases are associated with inflammation and structural remodelling of the airways and/or alveolar tissues. They can often only be treated symptomatically with no disease-modifying therapies that normalize the pathological tissue destruction driven by inflammation and remodelling. In search for novel therapeutic strategies for these diseases, several lines of evidence revealed the WNT pathway as an emerging target for regenerative strategies in the lung. WNT proteins, their receptors, and signalling effectors have central regulatory roles under (patho)physiological conditions underpinning lung function and (chronic) lung diseases and we summarize these roles and discuss how pharmacological targeting of the WNT pathway may be utilized for the treatment of chronic lung diseases.
Abstract
Background
Rosacea is a chronic inflammatory skin disease that has been reported to be associated with many systemic disorders including respiratory diseases.
Aims
This study aims to investigate respiratory function in patients with rosacea.
Patients/Methods
Patients with rosacea and age- and gender-matched healthy volunteers were included in this cross-sectional study. Spirometric pulmonary function tests including the percentage of forced vital capacity (FVC%), percentage of forced expiratory volume in one second (FEV 1%), forced expiratory flow at 25–75% of FVC (FEF 25–75%), and FEV 1/FVC ratio was assessed in both patient and controls. The potential relationship between rosacea severity and pulmonary functions was assessed.
Results
A total of 120 patients with rosacea and 120 healthy controls were enrolled in the study. Compared to the controls, FEV 1%, FEV 1/FVC%, and FEF 25–75% values were significantly lower in patients with rosacea. Lower FEV 1/FVC% values were found to be associated with disease severity. FEV 1%, FEV 1/FVC%, and FEF 25–75% values were found to be more useful in differentiating the patients from healthy subjects.
Conclusions
This study showed that patients with rosacea may have abnormal respiratory function compared to healthy subjects. Besides, disease severity was associated with worse respiratory functions. We believe that patients with rosacea, particularly those with additional risk factors, should be screened for respiratory disorders.
An initial historical profile should identify the patient; determine the chief complaint; reflect the dental history; document drug allergies or other adverse drug effects; identify medications, vitamins, dietary supplements, or special diets; and provide a record of past and present illness, major hospitalizations, and a review of major organ systems. The basic biographical data should include the patient's name, age, sex, ethnic extraction, marital status, occupation, and place of residence. Not only are these items essential for patient identification but also they may provide invaluable background information for the differential diagnosis of certain conditions, or identify patients in a high‐risk category for a variety of diseases. The chief complaint and the medical, family, and social histories of the patient should guide the clinician to investigate areas of special concern. All signs and symptoms related to specific organ systems should be recorded.
Die chronisch obstruktive Lungenerkrankung (COPD) ist eine progressive, chronische Erkrankung. Sie gehört, neben Asthma bronchiale, zu den obstruktiven Atemwegserkrankungen. Es wird erwartet, dass die COPD im Jahr 2020 auf den dritten Platz in der Mortalitätsstatistik rücken wird. Knapp 90% der Erkrankten haben einen Nikotinabusus in ihrer Anamnese. Die Hauptsymptome der COPD sind Dyspnoe, chronischer Husten und Auswurf. In Verbindung mit der Obstruktion entsteht eine Ventilationsinhomogenität, die zu einer ungleichmäßigen Verteilung der Atemluft in der Lunge führt. Dieser Mechanismus ist mit der Spirometrie und Bodyplethysmographie nicht messbar, da sich die Erkrankung hauptsächlich in den kleinen Atemwegen manifestiert, die heutige Standarddiagnostik aber überwiegend an den zentralen Atemwegen misst. Ein alter, aber erst jetzt praktisch umsetzbarer Ansatz, stellt die Methode des Multiple-Breath-Washouts (MBW) dar. Möglich gemacht wurde dies vor allem durch die Entwicklung des photoakustischen Gasanalysators. Während der Messung atmen die Patienten ein Gasgemisch aus Raumluft und 94% O2, 1% SF6 und 5% N2O. Dieses Gemisch wird zunächst eingewaschen. Nach einem Konzentrationsausgleich in der Ein- und Ausatemluft beginnt die Auswaschphase. Hier wird gemessen, wie oft die funktionelle Reservekapazität vom Patienten aufsummiert ausgeatmet werden muss, um die SF6-Konzentration auf 2,5% der Ausgangskonzentration zu reduzieren. MBW-Messungen liefern drei neue Parameter: Der Lung Clearance Index (LCI), Parameter für die globale Ventilationsinhomogenität, sowie Scond und Sacin für die regionale Ventilationsinhomogenität. All diese Parameter wurden bei drei aufeinander folgenden Messungen ermittelt. Ziel der vorliegenden Arbeit war es, in einer klinischen Querschnittsstudie die Anwendbarkeit von MBWs mit SF6 als Tracergas bei Patienten mit COPD zu evaluieren. In die finale Analyse wurden 185 Probanden mit validen Datensätzen eingeschlossen, darunter 138 Patienten mit COPD (75%) und 47 Kontrollen (25%). Es konnte gezeigt werden, dass die MBW-Messungen äußerst reliabel sind. Bei COPD-Patienten waren alle neuen Parameter im Vergleich zur Kontrollgruppe signifikant erhöht. Es war möglich bei einigen Patienten, die noch ein normwertiges FEV1 aufwiesen, bereits einen veränderten LCI nachzuweisen. Es wurde untersucht, ob ein früherer Endpunkt der Messung bei 5% einsetzbar ist. Der LCI änderte sich signifikant, die benötigte Testdauer reduzierte sich jedoch ebenfalls sehr deutlich. Eine Korrelation von TLCO/VA und dem LCI-Wert konnte nachgewiesen werden. Es konnte gezeigt werden, dass MBW-Messungen SF6 als Tracergas bei Patienten mit COPD durchführbar sind. MBW-Messungen können also zusätzliche Informationen liefern, die mit den herkömmlichen Standardmessverfahren nicht zugänglich sind. Dies trifft vor allem auf die kleinen Atemwege zu, die mittels MBW-Messungen abgebildet werden können.
Given the fact that the oral cavity is contiguous with the trachea and lower airway, it is biologically plausible that conditions within the oral cavity might influence lung function. This chapter discusses the more common respiratory illnesses and explores the relationship between these conditions and oral health. There are several major oral health concerns for patients with upper respiratory infections. The most common cause of acute respiratory illness is viral infection, which occurs more commonly in children than in adults. The upper airway is the site of infection and inflammation during the course of a common cold, but respiratory viruses can affect any portion of the respiratory tree. The association between oral health and respiratory diseases has received renewed attention. Acute bronchitis is an acute respiratory infection involving the large airways that is manifested predominantly by cough with or without phlegm production that lasts up to 3 weeks.
Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease with high morbidity and mortality worldwide. So far, smoking is still its leading cause. The characteristics of COPD are emphysema and airway remodeling, as well as chronic inflammation, which were predominated by macrophages. Some studies have reported that macrophages were involved in emphysema and chronic inflammation, but whether there is a link between airway remodeling and macrophages remains unclear. In this study, we found that both acute and chronic cigarette smoke exposure led to an increase of macrophages in the lung and a decrease of ciliated cells in the airway epithelium of a mouse model. The results of in vitro experiments showed that the ciliary protein (β-tubulin-IV) levels of BEAS-2B cells could be inhibited when co-cultured with human macrophage line THP-1, and the inhibitory effect was augmented with the stimulation of cigarette smoke extract (CSE). Based on the results of transcriptome sequencing, we focused on the protein, bone morphogenetic protein-2 (BMP-2), secreted by the macrophage, which might mediate this inhibitory effect. Further studies confirmed that BMP-2 protein inhibited β-tubulin-IV protein levels of BEAS-2B cells under the stimulation of CSE. Coincidentally, this inhibitory effect could be nearly blocked by the BMP receptor inhibitor, LDN, or could be interfered with BMP-2 siRNA. This study suggests that activation and infiltration of macrophages in the lung induced by smoke exposure lead to a high expression of BMP-2, which in turn inhibits the ciliary protein levels of the bronchial epithelial cells, contributing to the remodeling of airway epithelium, and aggravates the development of COPD.
Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of death worldwide. To identify cell-specific mechanisms underlying COPD pathobiology, we analysed single-cell RNA sequencing (scRNAseq) profiles of explanted lung tissue from subjects with advanced COPD or control lungs. Findings were validated with scRNAseq of lungs from mice exposed to 10 months of cigarette smoke (CS), isolated human alveolar epithelial cells, and immunostaining of human lung tissue samples. We identified a subpopulation of alveolar epithelial type II cells with transcriptional evidence for aberrant cellular metabolism and reduced cellular stress tolerance, exemplified by decreased expression of the stress-response gene NUPR1. Network analyses identified an important role for inflamed capillary endothelial cells in COPD, particularly through CXCL-motif chemokine signalling. Finally, we detected a metallothionein expressing macrophage subpopulation unique to COPD. Collectively, these findings highlight cell-specific mechanisms involved in the pathobiology of advanced COPD.
Background and Objective
We tested whether the prostacyclin analog inhaled iloprost modulates dead space, dynamic hyperinflation (DH), and systemic inflammation/oxidative stress during maximal exercise in subjects with chronic obstructive pulmonary disease (COPD) who were not selected based on pulmonary hypertension (PH).
Methods
Twenty-four COPD patients with moderate-severe obstruction (age 59±7 years, FEV1 53±13% predicted) participated in a randomized, double-blind, placebo-controlled crossover trial. Each subject received a single nebulized dose of 5.0μg iloprost or placebo on non-consecutive days followed by maximal cardiopulmonary exercise tests. The primary outcome was DH quantified by end-expiratory lung volume/total lung capacity ratio (EELV/TLC) at metabolic isotime.
Results
Inhaled iloprost was well-tolerated and reduced submaximal alveolar dead-space fraction but did not significantly reduce DH (0.70±0.09 vs 0.69±0.07 following placebo and iloprost, respectively, p=0.38). Maximal exercise time (9.1±2.3 vs 9.3±2.2 minutes, p=0.31) and peak oxygen uptake (17.4±6.3 vs 17.9±6.9mL/kg/min, p=0.30) were not significantly different following placebo versus iloprost.
Conclusions
A single dose of inhaled iloprost was safe and reduced alveolar dead space fraction; however, it was not efficacious in modulating DH or improving exercise capacity in COPD patients who were not selected for the presence of PH.
Background and Purpose
Nicotinic ACh receptors containing the α7 sub‐unit (α7‐nAChRs) suppress inflammation through a wide range of pathways in immune cells. These receptors are thus potentially involved in a number of inflammatory diseases. However, the detailed mechanisms underlying the anti‐inflammatory effects of α7‐nAChRs remain to be described.
Experimental Approach
Anti‐inflammatory effects of α7‐nAChR agonists were assessed in both murine macrophages (RAW 264.7) and bone marrow‐derived macrophages (BMDM), stimulated with LPS, using immunoblotting, RT‐PCR and luciferase reporter assays. The role of adenylyl cyclase‐6 in the degradation of Toll‐like receptor 4 (TLR4) following endocytosis, was explored via overexpression and knockdown. A mouse model of chronic obstructive pulmonary disease (COPD) induced by porcine pancreatic elastase was used to confirm key findings.
Results
Anti‐inflammatory effects of α7‐nAChRs were largely dependent on adenylyl cyclase‐6 activation, as knockdown of adenylyl cyclase‐6 considerably reduced the effects of α7‐nAChR agonists while adenylyl cyclase‐6 overexpression promoted them. We found that α7‐nAChRs and adenylyl cyclase‐6 are co‐localized in lipid rafts of macrophages and directly interact. Activation of adenylyl cyclase‐6 led to increased degradation of TLR4. Administration of the α7‐nAChR agonist PNU‐282987 attenuated pathological and inflammatory end points in a mouse model of COPD.
Conclusion and Implications
The α7‐nAChRs inhibit inflammation through activating adenylyl cyclase‐6 and promoting degradation of TLR4. The use of α7‐nAChR agonists may represent a novel therapeutic approach for treating COPD and possibly other inflammatory diseases.
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