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

¹ Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, and ² Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil; ³ Istituto Clinico Humanitas (ICH), IRCCS, Department of Immunology and Inflammation, Rozzano, Milan, Italy; and ⁴ Department of Preclinical Pharmacology, Dompé pha.r.ma s.p.a., L'Aquila, Italy

Correspondence and requests for reprints should be addressed to Mauro M. Teixeira, M.D., Ph.D., Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, CEP 30882-650–Pampulha, Belo Horizonte, MG, Brazil. E-mail: mmtex{at}icb.ufmg.br

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)-β₁ levels, but not on IFN- and total TGF-β_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-β₁ 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.

Key Words: CXCR2 • neutrophil • angiogenesis • bleomycin • fibrosis

CLINICAL RELEVANCE These findings may assist in the development of new therapies for lung fibrosis and broaden our understanding of the biology of neutrophils, CXCR2, and mechanisms of lung fibrosis.