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Annexin A1 mimetic peptide controls the inflammatory and fibrotic effects of silica particles in mice
Author(s) -
Trentin P G,
Ferreira T P T,
Arantes A C S,
Ciambarella B T,
Cordeiro R S B,
Flower R J,
Perretti M,
Martins M A,
Silva P M R
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13109
Subject(s) - silicosis , annexin a1 , formyl peptide receptor , chemistry , inflammation , knockout mouse , fibrosis , pulmonary fibrosis , peptide , endocrinology , annexin , chemokine , nasal administration , medicine , immunology , receptor , chemotaxis , in vitro , biochemistry , pathology
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.