Antagonistic Regulation of Pro-Inflammatory AnnexinA2 and Anti-Inflammatory AnnexinA1 in the Pathogenesis of Idiopathic Pulmonary Fibrosis.

Idiopathic Pulmonary Fibrosis (IPF) is a progressive and often fatal lung disease marked by excessive fibroblast proliferation and collagen deposition, leading to respiratory failure. The precise mechanisms underlying IPF remain poorly understood, but inflammation and dysregulation of cellular pathways are known to play key roles in disease progression. This study hypothesizes that pro-inflammatory Annexin A2 (ANXA2) and anti-inflammatory Annexin A1 (ANXA1) are reciprocally regulated, contributing to the pathogenesis of IPF. Our study aimed to investigate the expression patterns and functional roles of ANXA1 and ANXA2 in IPF, focusing on their potential as soluble biomarkers and upstream regulators of cytokine imbalances in the fibrotic microenvironment. Using in vitro, in vivo, and IPF patient samples, we found that ANXA2 expression significantly increased in fibrotic tissues, correlating with increased pro-inflammatory cytokines, while ANXA1 levels were markedly reduced. These findings were also reflected in serum samples from both PF mice and IPF patients. Treatment with butyrate, an anti-inflammatory short-chain fatty acid, showed a therapeutic effect by upregulating ANXA1, downregulating ANXA2, and reducing epithelial-mesenchymal transition (EMT) in pulmonary fibrosis in vitro and in vivo model systems. This shift in expression of ANXA1 and ANXA2 was accompanied by decreased collagen deposition, oxidative stress, and increased expression of epithelial markers in the bleomycin model, underscoring butyrate’s potential to counter fibrosis. Overall, the reciprocal regulation of ANXA1 and ANXA2 plays a significant role in PF pathogenesis, and butyrate modulation of this axis suggests a promising therapeutic approach for IPF.