Role of the Chemokine Receptor CXCR2 in Bleomycin-Induced Pulmonary Inflammation and Fibrosis

• Published in: American journal of respiratory cell and molecular biology Vol. 40; no. 4; pp. 410 - 421
• Main Authors: Russo, Remo C, Guabiraba, Rodrigo, Garcia, Cristiana C, Barcelos, Luciola S, Roffe, Ester, Souza, Adriano L. S, Amaral, Flavio A, Cisalpino, Daniel, Cassali, Geovanni D, Doni, Andrea, Bertini, Riccardo, Teixeira, Mauro M
• Format: Journal Article
• Language: English
• Published: United States Am Thoracic Soc 01.04.2009; American Thoracic Society
• Subjects: Animals; Benzeneacetamides - administration & dosage; Benzeneacetamides - pharmacology; Bleomycin; Bronchoalveolar Lavage Fluid; Cell Movement - drug effects; Chemokines - biosynthesis; Dose-Response Relationship, Drug; Humans; Immunology; Kinetics; Life Sciences; Male; Mesylates - administration & dosage; Mesylates - pharmacology; Mice; Mice, Inbred C57BL; Microbiology and Parasitology; Neovascularization, Pathologic - metabolism; Neutrophils - cytology; Neutrophils - drug effects; Pneumonia - chemically induced; Pneumonia - complications; Pneumonia - metabolism; Pneumonia - pathology; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - complications; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Receptors, Interleukin-8B - antagonists & inhibitors; Receptors, Interleukin-8B - metabolism; Time Factors; bleomycin; fibrosis; neutrophil; angiogenesis; CXCR2
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2007-0364OC

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-induced 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-induced 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.