title: Pulmonary antifibrotic mechanisms aspirin-triggered lipoxin A(4) synthetic analog.
abstract: No successful therapies are available for pulmonary fibrosis, indicating the need for new treatments. Lipoxins and their 15-epimers, aspirin-triggered lipoxins (ATL), present potent antiinflammatory and proresolution effects (Martins et al., J Immunol 2009;182:5374-5381). We show that ATLa, an ATL synthetic analog, therapeutically reversed a well-established pulmonary fibrotic process induced by bleomycin (BLM) in mice. We investigated the mechanisms involved in its effect and found that systemic treatment with ATLa 1 week after BLM instillation considerably reversed the inflammatory response, total collagen and collagen type 1 deposition, vascular endothelial growth factor, and transforming growth factor (TGF)-β expression in the lung and restored surfactant protein C expression levels. ATLa also inhibited BLM-induced apoptosis and cellular accumulation in bronchoalveolar lavage fluid and in the lung parenchyma as evaluated by light microscopy and flow cytometry (Ly6G(+), F4/80(+), CD11c(+), CD4(+), and B220(+) cells) assays. Moreover, ATLa inhibited the lung production of IL-1β, IL-17, TNF-α, and TGF-β induced by BLM-challenged mice. ATLa restored the balance of inducible nitric oxide synthase-positive and arginase-positive cells in the lungs, suggesting a prevalence of M2 versus M1 macrophages. Together, these effects improved pulmonary mechanics because ATLa treatment brought to normal levels lung resistance and elastance, which were clearly altered at 7 days after BLM challenge. Our findings support ATLa as a promising therapeutic agent to treat lung fibrosis.
authors.affiliation: 1 Instituto de Ciências Biomédicas and.
authors.forename: Rafael F
authors.initials: RF
authors.lastname: Guilherme
authors.forename: Debora G
authors.initials: DG
authors.lastname: Xisto
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: Célio G
authors.initials: CG
authors.lastname: Freire-de-Lima
authors.forename: Patricia R M
authors.initials: PR
authors.lastname: Rocco
authors.forename: Josiane S
authors.initials: JS
authors.lastname: Neves
authors.forename: Iolanda M
authors.initials: IM
authors.lastname: Fierro
authors.forename: Claudio
authors.initials: C
authors.lastname: Canetti
authors.forename: Claudia F
authors.initials: CF
authors.lastname: Benjamim
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism; D001241:Aspirin / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D001761:Bleomycin / Q000633:toxicity; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D036341:Intercellular Signaling Peptides and Proteins; D044045:Lipoxins / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D037721:Pulmonary Surfactant-Associated Protein C; D015656:Respiratory Mechanics / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C489638:16-(4-fluoro)phenoxylipoxin A4 methyl ester; D015415:Biomarkers; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D044045:Lipoxins; D010455:Peptides; D037721:Pulmonary Surfactant-Associated Protein C; C489680:Sftpc protein, mouse; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D001761:Bleomycin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D001119:Arginase; D001241:Aspirin