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

Remo C. Russo, Rodrigo Guabiraba, Cristiana C. Garcia, Lucíola S. Barcelos, Ester Roffê, Adriano L S Souza, Flávio A. Amaral, Daniel Cisalpino, Geovanni D. Cassali, Andrea Doni, Riccardo Bertini, Mauro M. Teixeira

Research output: Contribution to journalArticlepeer-review

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 leadingto 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)-β 1 levels, but not on IFN-γ 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 therapeu- ticschedule, DF2162 administered fromDays8to16afterbleomycin reduced pulmonary fibrosis and levels of active TGF-β 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-angio-genic 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.

Original languageEnglish
Pages (from-to)410-421
Number of pages12
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume40
Issue number4
DOIs
Publication statusPublished - Apr 1 2009

Keywords

  • Angiogenesis
  • Bleomycin
  • CXCR2
  • Fibrosis
  • Neutrophil

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Fingerprint

Dive into the research topics of 'Role of the chemokine receptor CXCR2 in bleomycin-induced pulmonary inflammation and fibrosis'. Together they form a unique fingerprint.

Cite this