ATLa, an aspirin-triggered lipoxin A4 synthetic analog, prevents the inflammatory and fibrotic effects of bleomycin-induced pulmonary fibrosis.

Abstract

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 (alpha-actin immunohistochemistry). Interestingly, ATLa posttreatment (4 days after BLM) showed similar inhibitory effects on inflammation and matrix deposition, besides the TGF-beta 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.

• Authors: Vanessa Martins, Samuel S Valença, Francisco A Farias-Filho, Raphael Molinaro, Rafael L Simões, Tatiana P T Ferreira, Patrícia M R e Silva, Cory M Hogaboam, Steven L Kunkel, Iolanda M Fierro, Claudio Canetti, Claudia F Benjamim
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 182 Issue 9 Pg. 5374-81 (May 01 2009) ISSN: 1550-6606 [Electronic] United States
• PMID: 19380784 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 16-(4-fluorophenoxy)lipoxin A4
• Anti-Inflammatory Agents, Non-Steroidal
• Antifibrinolytic Agents
• Lipoxins
• lipoxin A4
• Bleomycin
• Aspirin

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (therapeutic use)
• Antifibrinolytic Agents (therapeutic use)
• Aspirin (pharmacology)
• Bleomycin (antagonists & inhibitors, toxicity)
• Immunity, Innate (drug effects, immunology)
• Lipoxins (therapeutic use)
• Mice
• Mice, Inbred C57BL
• Pulmonary Fibrosis (chemically induced, mortality, physiopathology, prevention & control)
• Respiratory Function Tests
• Survival Analysis