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Pulmonary antifibrotic mechanisms aspirin-triggered lipoxin A(4) synthetic analog.

Guilherme RF, Xisto DG, Kunkel SL, Freire-de-Lima CG, Rocco PR, Neves JS, Fierro IM, Canetti C, Benjamim CF.

Am J Respir Cell Mol Biol. 2013 Dec;49(6):1029-37.

Instituto de Ciências Biomédicas and.




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)-{Beta} 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-1{Beta}, IL-17, TNF-{Alpha}, and TGF-{Beta} 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.

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Pulmonary Anti-fibrotic Mechanisms of ATLa, An Aspirin-Triggered Lipoxin A4 Synthetic Analog