Figure 1 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Changes in body weight of wild-type (WT) and cystic fibrosis (CF) mice suffering from chronic lung infection with Pseudomonas aeruginosa MDR-RP73 over 6 days (7 treatments with aerosol administration of 50 µL sterile saline or 200 µg/50 µL bovine lactoferrin (bLf)). Statistical significance is indicated as follows: *: p < 0.05 (Two-way ANOVA with Bonferroni's multiple comparison test).
Source publication
Cystic fibrosis (CF) is a genetic disorder affecting several organs including airways. Bacterial infection, inflammation and iron dysbalance play a major role in the chronicity and severity of the lung pathology. The aim of this study was to investigate the effect of lactoferrin (Lf), a multifunctional iron-chelating glycoprotein of innate immunity...
Contexts in source publication
Context 1
... the impact of bLf treatment on this read-out was recorded. The body weight of the infected mice decreased rapidly after infection for all groups (Figure 1). After six days of chronic infection and seven treatments, bLf-treated CF mice had significantly lower loss of body weight compared to the group of vehicles. ...
Context 2
... six days of chronic infection and seven treatments, bLf-treated CF mice had significantly lower loss of body weight compared to the group of vehicles. No difference between bLf-treated WT mice and vehicle was observed with poor recovery in body weight (Figure 1). ...
Context 3
... the impact of bLf treatment on this read-out was recorded. The body weight of the infected mice decreased rapidly after infection for all groups (Figure 1). After six days of chronic infection and seven treatments, bLftreated CF mice had significantly lower loss of body weight compared to the group of vehicles. ...
Context 4
... six days of chronic infection and seven treatments, bLftreated CF mice had significantly lower loss of body weight compared to the group of vehicles. No difference between bLf-treated WT mice and vehicle was observed with poor recovery in body weight (Figure 1). Figure 1. ...
Context 5
... difference between bLf-treated WT mice and vehicle was observed with poor recovery in body weight (Figure 1). Figure 1. Changes in body weight of wild-type (WT) and cystic fibrosis (CF) mice suffering from chronic lung infection with Pseudomonas aeruginosa MDR-RP73 over 6 days (7 treatments with aerosol administration of 50 μL sterile saline or 200 μg/50 μL bovine lactoferrin (bLf)). ...
Citations
... 34 Similarly, the glycoprotein lactoferrin can modulate the inflammatory process by inhibiting the produc-tion of proinflammatory cytokines and by regulating the expression of iron homeostasis proteins (such as ferritin, ceruloplasmin and transferrin receptor 1). 35 Among the most helpful nutrients in the prevention and treatment of COVID-19, omega-3 fatty acids can play a pivotal role, as well as in the therapy of many inflammation-related diseases. Among the physiological processes of phlogosis resolution is the enzymatic conversion of omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into specialized pro-resolution mediators (including resolvins and protectins) participating in the resolu-tion of phlogistic status and helping solve the cytokine storm and COVID-19 associated complications. ...
The mechanisms of COVID-19 complications are multifactorial, including long-term tissue dam-ages from direct viral attack, dysregulation of both immunity and renin-angiotensin-aldosterone system and coagulation system, unresolved systemic inflammation and oxidative stress. Omega-3 polyunsaturated fatty acids (omega-3 or n-3 PUFAs) might have favorable effects on immunity, inflammation, oxidative stress at different stages of SARS-CoV-2 infection. Omega-3 and their metabolites including specialized proresolvin mediators, have shown effects in reducing pro-inflammatory cytokines, accelerating the resolution of chronic inflammation and restoring tissue homeostasis, and therefore offer a promising strategy against COVID-19. This article will discuss the inflammatory condition during COVID-19 pandemic, focus on the mechanisms that may contribute to the likely benefits of omega-3 and provide potential recommendations to pro-mote strategies for wellness.
... Therefore, iron metabolism and its regulatory mechanism may serve as a new diagnostic and therapeutic target in lung cancer [11]. In addition, during the pathophysiological process of infection caused by various bacteria or viruses, lactoferrin (Lfn) can rebalance the systemic iron concentrations, and impact the host immune response, so as to modulate the inflammation response and the promotion of antiviral gene expression [12][13][14]. ...
Acute lung injury (ALI) has been challenging health care systems since before the COVID-19 pandemic due to its morbidity, mortality, and length of hospital stay. In view of the complex pathogenesis of ALI, effective strategies for its prevention and treatment are still lacking. A growing body of evidence suggests that iron dysregulation is a common characteristic in many subtypes of ALI. On the one hand, iron is needed to produce reactive oxygen species (ROS) as part of the immune response to an infection; on the other hand, iron can accelerate the occurrence of ferroptosis and extend host cell damage. Iron chelation represents a novel therapeutic strategy for alleviating lung injury and improving the survival of patients with ALI. This article reviews the current knowledge of iron homeostasis, the role of iron in ALI development, and potential therapeutic targets.
... Moreover, Lf is emerging as a modulator of iron homeostasis [22]. In recent years, our group has demonstrated the efficacy of bLf in reverting iron dysregulation in different models of inflammation/infection, both in vitro [23,24] and in vivo [25], as well as in clinical trials [26,27]. The effect of Lf on iron homeostasis can be related to its ability to chelate free iron, modulate iron proteins, and downregulate pro-inflammatory cytokines, such as IL-1β and IL-6, thus boosting antioxidant and anti-inflammatory host response, also after viral infection. ...
The Trans-Activator of Transcription (Tat) of Human Immunodeficiency Virus (HIV-1) is involved in virus replication and infection and can promote oxidative stress in human astroglial cells. In response, host cells activate transcription of antioxidant genes, including a subunit of System Xc− cystine/glutamate antiporter which, in turn, can trigger glutamate-mediated excitotoxicity. Here, we present data on the efficacy of bovine Lactoferrin (bLf), both in its native (Nat-bLf) and iron-saturated (Holo-bLf) forms, in counteracting oxidative stress in U373 human astroglial cells constitutively expressing the viral protein (U373-Tat). Our results show that, dependent on iron saturation, both Nat-bLf and Holo-bLf can boost host antioxidant response by up-regulating System Xc− and the cell iron exporter Ferroportin via the Nuclear factor erythroid 2-related factor (Nrf2) pathway, thus reducing Reactive Oxygen Species (ROS)-mediated lipid peroxidation and DNA damage in astrocytes. In U373-Tat cells, both forms of bLf restore the physiological internalization of Transferrin (Tf) Receptor 1, the molecular gate for Tf-bound iron uptake. The involvement of astrocytic antioxidant response in Tat-mediated neurotoxicity was evaluated in co-cultures of U373-Tat with human neuronal SH-SY5Y cells. The results show that the Holo-bLf exacerbates Tat-induced excitotoxicity on SH-SY5Y, which is directly dependent on System-Xc− upregulation, thus highlighting the mechanistic role of iron in the biological activities of the glycoprotein.
... Aerosolized lactoferrin has been shown to be a promising treatment option, based on studies in a CF mouse model. Aerosolized bovine lactoferrin reduced the bacterial load in the lung, as well as decreased the infiltrating neutrophils [182]; these studies further indicate that lactoferrin is a potent anti-Pseudomonas effector. P. aeruginosa, however, is not without its own defense against lactoferrin. ...
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators, a new series of therapeutics that correct and potentiate some classes of mutations of the CFTR, have provided a great therapeutic advantage to people with cystic fibrosis (pwCF). The main hindrances of the present CFTR modulators are related to their limitations in reducing chronic lung bacterial infection and inflammation, the main causes of pulmonary tissue damage and progressive respiratory insufficiency,
particularly in adults with CF. Here, the most debated issues of the pulmonary bacterial infection and inflammatory processes in pwCF are revisited. Special attention is given to the mechanisms favoring the bacterial infection of pwCF, the progressive adaptation of Pseudomonas aeruginosa and its interplay with Staphylococcus aureus, the cross-talk among bacteria, the bronchial epithelial cells
and the phagocytes of the host immune defenses. The most recent findings of the effect of CFTR modulators on bacterial infection and the inflammatory process are also presented to provide critical hints towards the identification of relevant therapeutic targets to overcome the respiratory pathologyof pwCF.
Keywords: cystic fibrosis; airway epithelia; airway infection; airway inflammation; Pseudomonas aeruginosa; Staphylococcus aureus; CFTR modulators
... In a murine model of chronic lung infection induced by Pseudomonas aeruginosa, aerosolized bLF was able to reduce neutrophil recruitment and levels of pro-inflammatory interleukins and chemokines [164]. Similarly, in the CF model in mice deficient in CFTR and infected with P. aeruginosa, aerosolized bLF restricted infection by reducing pulmonary bacterial load, inflammation and iron dysbalance [165]. An in vitro study in the A549 human bronchial cell line showed an antiinvasive effect of bLF on Pseudomonas aeruginosa and Burkholderia cenocepacia, two important opportunistic respiratory pathogens in patients with CF [166]. ...
Lactoferrin (LF) is a multifunctional iron-binding glycoprotein that exhibits a variety of properties, such as immunomodulatory, anti-inflammatory, antimicrobial, and anticancer, that can be used to treat numerous diseases. Lung diseases continue to be the leading cause of death and disability worldwide. Many of the therapies currently used to treat these diseases have limited efficacy or are associated with side effects. Therefore, there is a constant pursuit for new drugs and therapies, and LF is frequently considered a therapeutic agent and/or adjunct to drug-based therapies for the treatment of lung diseases. This article focuses on a review of the existing and most up-to-date literature on the contribution of the beneficial effects of LF on the treatment of lung diseases, including asthma, viral infections, cystic fibrosis, or lung cancer, among others. Although in vitro and in vivo studies indicate significant potency of LF in the treatment of the listed diseases, only in the case of respiratory tract infections do human studies seem to confirm them by demonstrating the effectiveness of LF in reducing episodes of illness and shortening the recovery period. For lung cancer, COVID-19 and sepsis, the reports are conflicting, and for other diseases, there is a paucity of human studies conclusively confirming the beneficial effects of LF.
... With a timekill assay, the bactericidal effect of Lf in combination with hypothiocyanite at 24 h has been demonstrated not only for P. aeruginosa strains but also on sputum [108]. It has also been demonstrated that treating aerosolized bLf for seven days in a CF chronic lung infection in a mouse model effectively reduced the infection by P. aeruginosa when both pulmonary bacterial growth and infiltrated leukocytes were evaluated [109]. Bovine Lf was able to inhibit the efficiency of invasion of P. aeruginosa and Burkholderia cenocepacia on human lung epithelial A549 cells [110]. ...
The emergence of multidrug-resistant bacterial strains with respect to commercially available antimicrobial drugs has marked a watershed in treatment therapies to fight pathogens and has stimulated research on alternative remedies. Proteins of the innate immune system of mammals have been highlighted as potentially yielding possible treatment options for infections. Lactoferrin (Lf) is one of these proteins; interestingly, no resistance to it has been found. Lf is a conserved cationic nonheme glycoprotein that is abundant in milk and is also present in low quantities in mucosal secretions. Moreover, Lf is produced and secreted by the secondary granules of neutrophils at infection sites. Lf is a molecule of approximately 80 kDa that displays multiple functions, such as antimicrobial, anti-viral, anti-inflammatory, and anticancer actions. Lf can synergize with antibiotics, increasing its potency against bacteria. Lactoferricins (Lfcins) are peptides resulting from the N-terminal end of Lf by proteolytic cleavage with pepsin. They exhibit several anti-bacterial effects similar to those of the parental glycoprotein. Synthetic analog peptides exhibiting potent antimicrobial properties have been designed. The aim of this review is to update understanding of the structure and effects of Lf and Lfcins as anti-bacterial compounds, focusing on the mechanisms of action in bacteria and the use of Lf in treatment of infections in patients, including those studies where no significant differences were found. Lf could be an excellent option for prevention and treatment of bacterial diseases, mainly in combined therapies with antibiotics or other antimicrobials.
... In recent years, our group has demonstrated the efficacy of bLf in reverting iron dysregulation in different inflamed/infected in vitro [51,67] and in vivo [68] models as well as in clinical trials [54]. Such an effect on iron homeostasis can be related to the ability of Lf to chelate free iron and downregulate pro-inflammatory cytokines, such as IL-1β and IL-6, thus boosting anti-oxidant and anti-inflammatory host response to viral infection. ...
SARS-CoV-2 causes COVID-19, a predominantly pulmonary disease characterized by a burst of pro-inflammatory cytokines and an increase in free iron. The viral glycoprotein Spike mediates fusion to the host cell membrane, but its role as a virulence factor is largely unknown. Recently , the antiviral activity of lactoferrin against SARS-CoV-2 was demonstrated in vitro and shown to occur via binding to cell surface receptors, and its putative interaction with Spike was suggested by in silico analyses. We investigated the anti-SARS-CoV-2 activity of bovine and human lactofer-rins in epithelial and macrophagic cells using a Spike-decorated pseudovirus. Lactoferrin inhibited pseudoviral fusion and counteracted the deleterious effects of Spike on iron and inflammatory ho-meostasis by restoring basal levels of iron-handling proteins and of proinflammatory cytokines IL-1β and IL-6. Using pull-down assays, we experimentally proved for the first time that lactoferrin binds to Spike, immediately suggesting a mechanism for the observed effects. The contribution of transferrin receptor 1 to Spike-mediated cell fusion was also experimentally demonstrated. In silico analyses showed that lactoferrin interacts with transferrin receptor 1, suggesting a multifaceted mechanism of action for lactoferrin. Our results give hope for the use of bovine lactoferrin, already available as a nutraceutical, as an adjuvant to standard therapies in COVID-19.
... Neutrophils were shown to be the key source of lactoferrin in the blood plasma after degranulation owing to its elevated production during most inflammatory reactions and certain viral infections, some scholars recognize lactoferrin as an acute-phase protein [14,15]. The association between its exposure and physiological or adverse impact on body functions, though, is still not well characterized [16] .This phenomenon recalls the interactions which have been observed between lactoferrin and other important immunological factors [17]. As pointed out by [17], several investigators have noted the joint presence of lactoferrin and lysozyme in milk,specific granules of polimorphonucleates, tears and tubotympanum mucus. ...
... The association between its exposure and physiological or adverse impact on body functions, though, is still not well characterized [16] .This phenomenon recalls the interactions which have been observed between lactoferrin and other important immunological factors [17]. As pointed out by [17], several investigators have noted the joint presence of lactoferrin and lysozyme in milk,specific granules of polimorphonucleates, tears and tubotympanum mucus. And in in vitro tests a synergy between lactoferrin and lysozyme was shown towards various bacteria [18]. ...
... Recently, in addition to the well-characterized activities, bLf has been found to be a physiological orchestrator of iron and inflammatory homeostasis through its ability in modulating the expression of the major iron proteins, such as ferroportin (Fpn), transferrin receptor 1 (TfR1) and ferritin (Ftn), both in in vitro and in vivo studies as well as in clinical trials (Cutone et al. , 2019Rosa et al. 2017;Lepanto et al. 2018). ...
Beyond the absolute and indisputable relevance and efficacy of anti-SARS-CoV-2 vaccines, the rapid transmission, the severity of infection, the absence of the protection on immunocompromised patients, the propagation of variants, the onset of infection and/or disease in vaccinated subjects and the lack of availability of worldwide vaccination require additional antiviral treatments. Since 1987, lactoferrin (Lf) is well-known to possess an antiviral activity related to its physico-chemical properties and to its ability to bind to both heparan sulfate proteoglycans (HSPGs) of host cells and/or surface components of viral particles. In the present review, we summarize in vitro and in vivo studies concerning the efficacy of Lf against DNA, RNA, enveloped and non-enveloped viruses. Recent studies have revealed that the in vitro antiviral activity of Lf is also extendable to SARS-CoV-2. In vivo, Lf oral administration in early stage of SARS-CoV-2 infection counteracts COVID-19 pathogenesis. In particular, the effect of Lf on SARS-CoV-2 entry, inflammatory homeostasis, iron dysregulation, iron-proteins synthesis, reactive oxygen formation, oxidative stress, gut-lung axis regulation as well as on RNA negativization, and coagulation/fibrinolysis balance will be critically reviewed. Moreover, the molecular mechanisms underneath, including the Lf binding to HSPGs and spike glycoprotein, will be disclosed and discussed. Taken together, present data not only support the application of the oral administration of Lf alone in asymptomatic COVID-19 patients or as adjuvant of standard of care practice in symptomatic ones but also constitute the basis for enriching the limited literature on Lf effectiveness for COVID-19 treatment.
... As described above, this leads to the increased release of intracellular iron stores and dietary uptake of iron to counter inflammation-induced anemia. More passively, Lf directly binds free iron, thereby limiting the iron-dependent inflammatory processes in tissues [33]. ...
The association of hyperinflammation and hyperferritinemia with adverse outcomes in SARS-CoV-2-infected patients suggests an integral role for iron homeostasis in pathogenesis, a commonly described symptom of respiratory viral infections. This dysregulated iron homeostasis results in viral-induced lung injury, often lasting long after the acute viral infection; however, much remains to be understood mechanistically. Lactoferrin is a multipurpose glycoprotein with key immunomodulatory, antimicrobial, and antiviral functions, which can be found in various secreted fluids, but is most abundantly characterized in milk from all mammalian species. Lactoferrin is found at its highest concentrations in primate colostrum; however, the abundant availability of bovine-dairy-derived lactoferrin (bLf) has led to the use of bLf as a functional food. The recent research has demonstrated the potential value of bovine lactoferrin as a therapeutic adjuvant against SARS-CoV-2, and herein this research is reviewed and the potential mechanisms of therapeutic targeting are considered.
