PAD4 deficiency alleviates airway inflammation in a mouse model of COPD exacerbation

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Aims: Exacerbations of COPD (ECOPD), characterized by increased airway inflammation and excessive mucus production, negatively impact patient health and accelerate disease progression. Histone citrullination, facilitated by the enzyme peptidylarginine deiminase 4 (PAD4), plays a critical role in the formation of neutrophil extracellular traps (NETs), an overabundance of which is associated with ECOPD. Our study aims to determine whether the absence of PAD4 can help regulate airway inflammation in a mouse model of ECOPD. Methods: COPD was induced in wide-type (WT) and PAD4 knockout (KO) mice through chronic exposure to cigarette smoke (CS), followed by intratracheal administration of Pseudomonas aeruginosa lipopolysaccharide (LPS) to trigger exacerbation. ELISA, histochemistry/immunohistochemistry, immunofluorescence microscopy, and western blotting were performed to assess the effects of PAD4 deficiency in ECOPD mice. Results: PAD4 KO mice showed significantly lower levels of citrullinated histone 3 and reduced formation of NETs in the lungs after CS exposure and LPS challenge compared to WT mice. PAD4 deficiency also led to less airway leukocyte infiltration, reduced mucus-secreting goblet cell hyperplasia, and lower levels of proinflammatory cytokines (IL-6, CXCL1, TNF-α) and mucin MUC5AC in bronchoalveolar lavage fluid. Additionally, PAD4 KO mice exhibited improved lung function in the ECOPD model, indicated by less decline in FEV20/FVC and reductions in FRC/BW and TLC/BW. Conclusions: These data indicate that PAD4 deficiency may reduce the pulmonary formation of NETs and alleviate airway inflammation caused by CS and LPS exposure, providing potential therapeutic targets for the management of ECOPD.

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