title: Annexin A1 mimetic peptide controls the inflammatory and fibrotic effects of silica particles in mice.
abstract: OBJECTIVE
  Endogenous glucocorticoids are pro-resolving mediators, an example of which is the endogenous glucocorticoid-regulated protein annexin A1 (ANXA1). 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 ANXA1-derived peptide annexin 1-(2-26) (Ac2-26) on experimental silicosis.
  
  
  METHODS
  Swiss-Webster mice were administered silica particles intranasally and were subsequently treated with intranasal peptide Ac2-26 (200 μg per mouse) or dexamethasone (25 μg per mouse) for 7 days, starting 6 h post-challenge. Ac2-26 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.
  
  
  RESULTS
  A clear exacerbation of the silica-induced pathological changes was observed in ANXA1 knockout mice as compared with their wild-type (WT) littermate controls. Incubation of lung fibroblasts from WT mice with Ac2-26 in vitro reduced IL-13 or TGF-β-induced production of CCL2 (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 CCL2 (MCP-1) from fibroblasts of FPR2 knockout mice.
  
  
  CONCLUSIONS
  Collectively, our findings reveal novel protective properties of the ANXA1 derived peptide Ac2-26 on the inflammatory and fibrotic responses induced by silica, and suggest that ANXA1 mimetic agents might be a promising strategy as innovative anti-fibrotic approaches for the treatment of silicosis.
authors: Laboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
authors: P G
authors: PG
authors: Trentin
authors: Laboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
authors: T P T
authors: TP
authors: Ferreira
authors: Laboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
authors: A C S
authors: AC
authors: Arantes
authors: Laboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
authors: B T
authors: BT
authors: Ciambarella
authors: Laboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
authors: R S B
authors: RS
authors: Cordeiro
authors: Department of Biochemical Pharmacology, The William Harvey Research Institute, Queen Mary University of London, London, UK.
authors: R J
authors: RJ
authors: Flower
authors: Department of Biochemical Pharmacology, The William Harvey Research Institute, Queen Mary University of London, London, UK.
authors: M
authors: M
authors: Perretti
authors: Laboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
authors: M A
authors: MA
authors: Martins
authors: Laboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
authors: P M R
authors: PM
authors: Silva
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000235:genetics / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000494:pharmacology*; D012822:Silicon Dioxide / Q000633:toxicity*; D012829:Silicosis / Q000188:drug therapy* / Q000473:pathology
chemical_list: D017305:Annexin A1; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D010455:Peptides; C096153:annexin A1 peptide (2-26); C573274:annexin A1, mouse; D012822:Silicon Dioxide; D003907:Dexamethasone