Role of the chemokine receptor CXCR2 in bleomycin-induced pulmonary inflammation and fibrosis

Russo, R.C. et al. (2009) Role of the chemokine receptor CXCR2 in bleomycin-induced pulmonary inflammation and fibrosis. American Journal of Respiratory Cell and Molecular Biology, 40(4), pp. 410-421. (doi: 10.1165/rcmb.2007-0364OC)

Abstract

Pulmonary fibrosis is characterized by chronic inflammation and excessive collagen deposition. Neutrophils are thought to be involved in the pathogenesis of lung fibrosis. We hypothesized that CXCR2-mediated neutrophil recruitment is essential for the cascade of events leading to bleomycin-incluced pulmonary fibrosis. CXCL1 / KC was detected as early as 6 hours after bleomycin instillation and returned to basal levels after Day 8. Neutrophils were detected in bronchoalveolar lavage and interstitium from 12 hours and peaked at Day 8 after instillation. Treatment with the CXCR2 receptor antagonist, DF2162, reduced airway neutrophil transmigration but led to an increase of neutrophils in lung parenchyma. There was a significant reduction in IL-13, IL-10, CCL5/RANTES, and active transforming growth factor (TGF)-beta(1) levels, but not on IFN-gamma and total TGF-beta(1), and enhanced granulocyte macrophage-colony-stimulating factor production in DF2162-treated animals. Notably, treatment with the CXCR2 antagonist led to an improvement of the lung pathology and reduced Collagen deposition. Using a therapeutic schedule, DF2162 administered from Days 8 to 16 after bleomycin reduced pulmonary fibrosis and levels of active TGF-beta(1) and IL-13. DF2162 treatment reduced bleomycin-incluced expression of von Willebrand Factor, a marker of angiogenesis, in the lung. In vitro, DF2162 reduced the angiogenic activity of IL-8 on human umbilical vein endothelial cells. In conclusion, we show that CXCR2 plays an important role in mediating fibrosis after bleomycin instillation. The compound blocks angiogenesis and the production of pro-angiogenic cytokines, and decreases IL-8-induced endothelial cell activation. An effect on neutrophils does not appear to account for the major effects of the blockade of CXCR2 in the system.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Guabiraba Brito, Dr Rodrigo
• Authors: Russo, R.C., Guabiraba Brito, R., Garcia, C.C., Barcelos, L.S., Roffe, E., Souza, A.L.S., Amaral, F.A., Cisalpino, D., Cassali, G.D., Doni, A., Bertini, R., and Teixeira, M.M.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: American Journal of Respiratory Cell and Molecular Biology
• ISSN: 1044-1549