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

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-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.

CD36, but not G2A, modulates efferocytosis, inflammation, and fibrosis following bleomycin-induced lung injury

“…4A ). KC (CXCL1) is a potent chemokine for neutrophils whose receptor was shown to be important for neutrophilic recruitment into the airways of bleomycin-treated mice ( 40 ). While the main source of this increased bronchoalveolar CXCL1 in CD36 Ϫ / Ϫ mice remains to be determined, it is possible that Delayed clearance of neutrophils in zymosan-treated G2A ؊ / ؊ mice Frasch et al reported that antibody-mediated G2A blockade or genetic deletion of G2A both signifi cantly delay the clearance of neutrophils in the murine zymosaninduced peritoneal infl ammation model ( 37,38 ).…”

Prolonged Exposure to Sphingosine 1–Phosphate Receptor-1 Agonists Exacerbates Vascular Leak, Fibrosis, and Mortality after Lung Injury

“…Most notable of these differences were alterations in leukocyte accumulation in the airspaces, although the importance of inflammatory cells in the development of lung fibrosis after injury is a matter of controversy. According to numerous publications, the fibrotic and inflammatory responses to bleomycin appear to be independent of each other (46,(60)(61)(62)(63)(64)(65)(66). Specifically, the systemic depletion of neutrophils or a genetic deficiency in T cells does not prevent the development of fibrosis in the bleomycin model (62,64,65).…”

Importance of CXC Chemokine Receptor 2 in Alveolar Neutrophil and Exudate Macrophage Recruitment in Response to Pneumococcal Lung Infection

“…The murine CXCR2 (mCXCR2) and its ligands, CXCL1 (keratinocyte-derived chemokine [KC]) and CXCL2/3 (macrophage inflammatory protein 2 [MIP-2]), functional homologues of human growth-related oncogenes (GRO␣, -␤, and -␥), have been identified as the primary chemokine receptor system mediating neutrophil recruitment in various models of acute and chronic inflammation, including Escherichia coli endotoxin-induced acute lung inflammation and injury (6,19,20,23). Both CXCR2 knockout (KO) mice as well as small-molecule inhibitors that interfere with CXCR2 receptor function have shown a role for neutrophils in mediating hyperoxic or ventilator-induced lung injury and in collagen deposition in bleomycin-induced fibrosis (23).…”

“…Both CXCR2 knockout (KO) mice as well as small-molecule inhibitors that interfere with CXCR2 receptor function have shown a role for neutrophils in mediating hyperoxic or ventilator-induced lung injury and in collagen deposition in bleomycin-induced fibrosis (23). Unlike in influenza virus pneumonia, where CXCR2 is required for neutrophil recruitment but not viral clearance, CXCR2 is important for neutrophil recruitment as well as pathogen elimination in Pseudomonas aeruginosa or Nocardia asteroides pneumonia (18,29).…”