Annexin A1 mimetic peptide controls the inflammatory and fibrotic effects of silica particles in mice

Background and Purpose Endogenous glucocorticoids are pro‐resolving mediators, an example of which is the endogenous glucocorticoid‐regulated protein annexin A 1 ( A NX A 1). Because silicosis is an occupational lung disease characterized by unabated inflammation and fibrosis, in this study we tested the therapeutic properties of the N ‐terminal A NX A 1‐derived peptide annexin 1‐(2‐26) ( A c2‐26) on experimental silicosis. Experimental Approach Swiss‐ W ebster mice were administered silica particles intranasally and were subsequently treated with intranasal peptide A c2‐26 (200 μg per mouse) or dexamethasone (25 μg per mouse) for 7 days, starting 6 h post‐challenge. A c2‐26 abolished the leukocyte infiltration, collagen deposition, granuloma formation and generation of pro‐inflammatory cytokines evoked by silica; these variables were only partially inhibited by dexamethasone. Key Results A clear exacerbation of the silica‐induced pathological changes was observed in A NX A 1 knockout mice as compared with their wild‐type ( WT ) littermate controls. Incubation of lung fibroblasts from WT mice with A c2‐26 in vitro reduced IL ‐13 or TGF ‐β‐induced production of CCL 2 (MCP‐1) and collagen, but this peptide did not affect the production of CCL2 (MCP‐1) by stimulated fibroblasts from formyl peptide receptor type 1 (FPR1) knockout mice. Ac2‐26 also inhibited the production of CCL 2 ( MCP ‐1) from fibroblasts of F PR2 knockout mice. Conclusions and Implications Collectively, our findings reveal novel protective properties of the A NX A 1 derived peptide A c2‐26 on the inflammatory and fibrotic responses induced by silica, and suggest that A NX A 1 mimetic agents might be a promising strategy as innovative anti‐fibrotic approaches for the treatment of silicosis.