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* Departamento de Farmacologia Básica e Clínica-Instituto de Ciências Biomédicas and
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil;
Departamento de Histologia e Embriologia and
Departamento de Farmacologia e Psicobiologia, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil;
¶ Laboratório de Inflamação, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; and
|| Department of Pathology, University of Michigan, Ann Arbor, MI 48109
Despite an increase in the knowledge of mechanisms and mediators involved in pulmonary fibrosis, there are no successful therapeutics available. Lipoxins (LX) and their 15-epimers, aspirin-triggered LX (ATL), are endogenously produced eicosanoids with potent anti-inflammatory and proresolution effects. To date, few studies have been performed regarding their effect on pulmonary fibrosis. In the present study, using C57BL/6 mice, we report that bleomycin (BLM)-induced lung fibrosis was prevented by the concomitant treatment with an ATL synthetic analog, ATLa, which reduced inflammation and matrix deposition. ATLa inhibited BLM-induced leukocyte accumulation and alveolar collapse as evaluated by histology and morphometrical analysis. Moreover, Sirius red staining and lung hydroxyproline content showed an increased collagen deposition in mice receiving BLM alone that was decreased upon treatment with the analog. These effects resulted in benefits to pulmonary mechanics, as ATLa brought to normal levels both lung resistance and compliance. Furthermore, the analog improved mouse survival, suggesting an important role for the LX pathway in the control of disease establishment and progression. One possible mechanism by which ATLa restrained fibrosis was suggested by the finding that BLM-induced myofibroblast accumulation/differentiation in the lung parenchyma was also reduced by both simultaneous and posttreatment with the analog (
-actin immunohistochemistry). Interestingly, ATLa posttreatment (4 days after BLM) showed similar inhibitory effects on inflammation and matrix deposition, besides the TGF-β level reduction in the lung, reinforcing an antifibrotic effect. In conclusion, our findings show that LX and ATL can be considered as promising therapeutic approaches to lung fibrotic diseases.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Conselho Nacional de Pesquisa, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro.
2 C.F.B. and C.C. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Claudia Farias Benjamim, Centro de Ciências da Saúde, Departamento de Farmacologia, Bloco J, Sala 26, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho, 373 Rio de Janeiro, Rio de Janeiro, Brazil. E-mail address: cbenjamim{at}farmaco.ufrj.br
4 Abbreviations used in this paper: BLM, bleomycin; ALX, lipoxin receptor; ATL, aspirin-triggered lipoxin; ATLa, 15-epi-16-(para-fluoro)-phenoxy-lipoxin A4; i.t., intratracheal; LX, lipoxin.
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