ATLa, an Aspirin-Triggered Lipoxin A4 Synthetic Analog, Prevents the Inflammatory and Fibrotic Effects of Bleomycin-Induced Pulmonary Fibrosis
Open Access
- 1 May 2009
- journal article
- Published by The American Association of Immunologists
- Vol. 182 (9), 5374-5381
- https://doi.org/10.4049/jimmunol.0802259
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 (α-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.Keywords
This publication has 64 references indexed in Scilit:
- A Novel Mechanism for CCR4 in the Regulation of Macrophage Activation in Bleomycin-Induced Pulmonary FibrosisThe American Journal of Pathology, 2008
- What Differentiates Normal Lung Repair and Fibrosis?: Inflammation, Resolution of Repair, and FibrosisProceedings of the American Thoracic Society, 2008
- Escape from the Matrix: Multiple Mechanisms for Fibroblast Activation in Pulmonary FibrosisProceedings of the American Thoracic Society, 2008
- Cellular and molecular mechanisms of fibrosisThe Journal of Pathology, 2007
- Cysteinyl-leukotriene 1 receptor antagonist attenuates bleomycin-induced pulmonary fibrosis in miceLife Sciences, 2007
- Infectious disease, the innate immune response, and fibrosisJCI Insight, 2007
- Common and unique mechanisms regulate fibrosis in various fibroproliferative diseasesJCI Insight, 2007
- Soluble TNF Mediates the Transition from Pulmonary Inflammation to FibrosisPLOS ONE, 2006
- Endogenous Anti-inflammatory Mediators from Arachidonate in Human NeutrophilsBiochemical and Biophysical Research Communications, 2002
- A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry, 1976