ESPE Abstracts

Background and Purpose: Nutritional obesity is a significant health issue worldwide, and severe obesity can lead to obesity hypoventilation syndrome (OHS). However, previous studies have mainly focused on changes of mechanical respiratory function without in-depth study on damage of lung epithelial cells. This study investigates the molecular mechanism underlying obese hypoventilation.

Methods: C57BL/6 mice were used to construct a high-fat diet (HFD)-induced obesity model. Metabolic cage indicators, blood gas analysis, and lung function tests were conducted to assess respiratory parameters. Proteomics and molecular biology methods, RT-qPCR, Western blot, immunohistochemistry and electron microscopy were used. The adeno-associated virus (AAV9) expressing a complement 3 (C3) loss-of-function mutant was employed to explore the role of C3 in obesity hypoventilation as the antagonist. Further cell culture of bronchial epithelia was performed with recombinant human C3 (Rh-C3), palmitic acid (PA), or both.

Results: There was a significant negative correlation between body weight and respiratory function in obese mice, elevated hydrogencarbonate levels confirmed the presence of obesity hypoventilation. Electron microscopy showed pyroptosis primarily in type 1 alveolar epithelial cells and bronchial epithelial cells in obese mice, while there was no abvious apoptosis, necrosis nor autophagy. The proteomics results suggested significant reduction in complement C3 in obese mice, consistent with the significant downregulation of complement C3 by PCR and westernblot, which was negatively correlated with pyroptosis-related proteins Caspase-8 and GSDME in both obese mice and AAV9-shRNA-C3 administrated mice. In cell culture experiment, Rh-C3 treatment inhibited PA-induced pyroptosis. Complement factor B had the consistent trend with C3 in vitro and vivo experiments, which indicating a synergistic role in cell protection.

Conclusion: Complement C3 plays a crucial role in protecting lung tissue cells by inhibiting Caspase-8/GSDME-related pyroptosis, in which complement factor B appears to have the synergistic effect. These findings provide new targets for the therapy of obesity hypoventilation syndrome.