Melatonin Alleviates Acute Exacerbation Of COPD Induced By Influenza Virus Infection By Inhibiting M1 Macrophage Polarization And Apoptosis

Influenza News: Chronic obstructive pulmonary disease (COPD) is a complex respiratory condition characterized by persistent airflow limitation and often associated with acute exacerbations triggered by various factors, including respiratory infections. Among these infections, influenza A viruses (IAV) stand out as significant contributors to COPD exacerbations, posing substantial challenges to patient management and healthcare systems globally. In this comprehensive exploration, we delve into the intricate relationship between IAV infection, COPD exacerbations, and the potential therapeutic role of melatonin in mitigating these effects.
 
Understanding the Impact of Influenza Virus Infection in COPD
Influenza viruses, particularly types A and B, are well-known culprits in seasonal respiratory epidemics, affecting millions worldwide each year. For individuals with underlying respiratory conditions like COPD, influenza infections can lead to acute exacerbations characterized by worsened symptoms, increased respiratory distress, and heightened risk of complications. Among the various subtypes, influenza A/H3N2 has been particularly associated with severe outcomes in COPD patients, necessitating a deeper understanding of its pathogenic mechanisms and therapeutic interventions.
 
Macrophage Polarization: A Key Player in COPD Pathogenesis
Central to the immune response in COPD are pulmonary macrophages, versatile immune cells that can adopt different activation states or phenotypes based on environmental cues. In COPD, chronic exposure to cigarette smoke induces a skewed polarization of macrophages, notably into pro-inflammatory M1 phenotype and pro-proliferative M2 phenotype. This dysregulated polarization contributes significantly to airway inflammation, tissue damage, and the overall pathogenesis of COPD exacerbations.
 
Melatonin: Unveiling Its Therapeutic Potential in COPD and Influenza Infections
Melatonin, primarily known for its role in regulating circadian rhythms and sleep-wake cycles, has garnered increasing attention for its diverse physiological functions, including anti-inflammatory and antioxidant properties. Studies have also highlighted melatonin's ability to modulate immune responses, inhibit viral replication, and protect against respiratory infections such as influenza viruses and coronaviruses.
 
A recent study conducted by scientists from the First Affiliated Hospital of Anhui Medical University, Hefei-China that is covered in this Influenza News report found that melatonin alleviates acute exacerbation of COPD induced by influenza virus infection by inhibiting M1 macrophage polarization and apoptosis.
 
Experimental Insights into Melatonin's Protective Effects
In experimental models using COPD mice exposed to cigarette smoke and subsequently infected with IAV, researchers observed significant improvements in lung function, reduced inflammation, and mitigated lung damage following melatonin administration. These beneficial effects were attributed to melatonin's ability to modulate macrophage polarization, particularly by inhibiting the pro-inflammatory M1 phenotype while preserving the anti-inflammatory M2 phenotype.
 
The study demonstrated that IAV/H3N2 infection deteriorated lung function (reduced FEV20,50/FVC), exacerbated lung damages in COPD mice with higher dual polarization of AMs (alveolar macrophages). Melatonin therapy improved airflow limitation and lung damages of AECOPD (acute exacerbation of chronic obstructive pulmonary disease) mice by decreasing IAV nucleoprotein (IAV-NP) protein levels and the M1 polarization of pulmonary macrophages. Furthermore, in CSE-stimulated Raw264.7 cells, IAV infection further promoted the dual polarization of macrophages accompanied with decreased MT1 expression. Melatonin decreased STAT1 phosphorylation, the levels of M1 markers and IAV-NP via MTs reflected by the addition of luzindole. Recombinant IL-1β attenuated the inhibitory effects of melatonin on IAV infection and STAT1-driven M1 polarization, while its converting enzyme inhibitor VX765 potentiated the inhibitory effects of melatonin on them. Moreover, melatonin inhibited IAV infection-induced apoptosis by suppressing IL-1β/STAT1 signaling via MTs.
 
Melatonin-Macrophage Interactions: Mechanistic Underpinnings
The protective effects of melatonin on macrophage polarization were found to be mediated through its interaction with melatonin receptors (MTs). By binding to MTs, melatonin exerted regulatory control over key signaling pathways involved in macrophage activation, such as STAT1/STAT6 signaling, which play crucial roles in orchestrating M1 and M2 phenotypes, respectively.
 
Interleukin-1β (IL-1β) and Apoptosis: Connecting the Dots
Further insights into the molecular mechanisms revealed that interleukin-1β (IL-1β), a potent pro-inflammatory cytokine, played a pivotal role in mediating macrophage polarization and apoptosis in response to IAV infection. Melatonin's anti-apoptotic effects were linked to its ability to suppress IL-1β-mediated signaling pathways, particularly STAT1-driven responses, thereby preventing excessive inflammation and tissue damage.
 
Clinical Implications and Future Directions
The findings from preclinical studies highlight the therapeutic potential of melatonin in managing COPD exacerbations induced by respiratory infections, especially IAV. Translating these insights into clinical practice could offer novel strategies for improving patient outcomes, reducing healthcare burdens, and enhancing the overall management of COPD patients, particularly during influenza seasons or viral outbreaks.
 
Challenges and Opportunities in Melatonin-Based Therapies
Despite promising results, several challenges remain in harnessing melatonin's full therapeutic potential in COPD and viral infections. These include optimizing dosing regimens, elucidating optimal timing of melatonin administration, addressing potential interactions with existing COPD medications, and conducting rigorous clinical trials to validate efficacy and safety profiles in diverse patient populations.
 
Conclusion: Towards Personalized Interventions for COPD and Viral Exacerbations
These findings suggested that melatonin inhibited IAV infection, improved lung function and lung damages of acute exacerbation of chronic obstructive pulmonary disease via suppressing IL-1β/STAT1-driven macrophage M1 polarization and apoptosis in a MTs-dependent manner. Melatonin may be considered as a potential therapeutic agent for influenza virus infection-induced acute exacerbation of chronic obstructive pulmonary disease
 
In conclusion, the interplay between melatonin, influenza virus infections, and COPD exacerbations unveils a multifaceted landscape of immune regulation, inflammation modulation, and tissue protection. Melatonin emerges as a promising candidate for personalized interventions aimed at mitigating respiratory infections, preserving lung function, and improving overall outcomes in COPD patients. Continued research efforts, interdisciplinary collaborations, and translational studies will be pivotal in unlocking the full therapeutic potential of melatonin in respiratory medicine.
 
The study findings were published in the peer reviewed journal: Respiratory Research.
https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-024-02815-0
 
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