Exercise Hormone Irisin Restores Lung Autophagy in COPD-Like Disease Model

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a leading cause of hospitalization and disease progression in COPD patients. Cigarette smoke and bacterial infection, particularly from organisms triggering LPS-mediated inflammation, are the most common drivers. Despite existing therapies, a significant proportion of patients respond poorly to corticosteroids, underscoring the need for novel therapeutic strategies. This study investigated irisin — an exercise-induced hormone-like myokine — as a potential regulator of lung autophagy disrupted by combined CSE and LPS exposure.

The research team built both in vivo and in vitro autophagy-deficient models. In mice, a 30-day protocol combined cigarette smoke exposure (twice daily) with intratracheal LPS instillation on days 1, 14, and 28. Six groups were studied, including wild-type and ATG5-knockout animals, with or without irisin pretreatment (0.5 µg/g body weight intraperitoneally). In vitro, mouse alveolar macrophages (MH-S cells) were exposed to 2% CSE and LPS (10 µg/ml), and autophagic flux was visualized using the Ad-mCherry-GFP-LC3B dual-fluorescence adenoviral system and transmission electron microscopy. Inflammatory cytokine levels were measured by ELISA in bronchoalveolar lavage fluid and cell supernatants.

CSE+LPS treatment caused significant lung pathology including alveolar wall thinning, septal disruption, alveolar space expansion, bullae formation, and increased inflammatory cell infiltration — hallmarks of emphysema. Western blotting confirmed elevated LC3-II and P62, indicating autophagosome accumulation with impaired clearance (blocked autophagic flux). Irisin treatment reversed these findings: it significantly reduced P62 accumulation, promoted LC3-I to LC3-II conversion, increased autophagosome-lysosome fusion, and reduced IL-1β, IL-6, and TNF-α levels. Mechanistically, irisin increased phosphorylation of AMPK and upregulated Beclin1, a key autophagy initiation protein. These effects were abolished by the AMPK inhibitor Compound C and by ATG5 siRNA knockdown in cells, and by ATG5 genetic knockout in mice, confirming the pathway dependence.

The study also found that CSE+LPS reduced endogenous irisin expression in lung tissue, and that exogenous irisin supplementation compensated for this deficit, suggesting a potential feedback loop where exercise-induced irisin may naturally protect against smoke- and infection-driven lung damage. Lung injury scores and mean linear intercept measurements confirmed that irisin-treated animals had significantly less emphysematous remodeling.

These findings position irisin as a promising therapeutic candidate for AECOPD, acting through restoration of protective autophagy rather than simple anti-inflammatory suppression. The ATG5-KO experiments elegantly confirm that irisin's anti-inflammatory effects are downstream of — and dependent upon — its pro-autophagic function. Limitations include the use of a short-duration animal model that may not fully capture chronic COPD, small group sizes (n=5 per group), and the lack of human tissue or clinical data. The translational pathway from exogenous irisin administration to clinical therapy also remains to be established.