CXCR2 antagonism as a promising therapeutic approach for pulmonary fibrosis therapy.

Abstract

Pulmonary inflammation is a central feature of several chronic lung diseases. The chemokine receptor CXCR2 plays a key role in regulating recruitment and activation of leukocytes and other cell types involved in acute and chronic inflammation of the lungs. In this study, we evaluated and compared the anti-inflammatory effects of four CXCR2 antagonists - DF2755A, AZD-5069, SX-682, and SCH527123 - in a murine model of bleomycin-induced lung injury. C57BL/6 mice received intranasal bleomycin and were treated once a day with known active doses of the antagonists by oral gavage. Following disease induction through bleomycin inoculation on day 0, animals were either treated at days 0-2 and then evaluated at day 2 (focus on the early inflammatory response) or treated from days 0-16 (preventive schedule) or from days 8-16 (therapeutic schedule) and then evaluated at day 16 (focus on fibrosis). We assessed inflammatory responses in bronchoalveolar lavage fluid (BALF) and lung tissue by analyzing total and differential leukocyte counts, cytokine levels, myeloperoxidase (MPO) activity, BALF protein content, and lung histopathology. All compounds displayed anti-inflammatory effects (day 2), with DF2755A and AZD-5069 standing out for their greater efficacy in reducing early neutrophils influx. Importantly, DF2755A and SX-682 were particularly effective in mitigating fibrosis and chronic inflammatory changes when administered in both preventive and therapeutic schedules, even at later stages of disease progression. These findings underscore the potential of CXCR2 antagonism, especially with DF2755A, as a promising strategy to limit inflammation and fibrosis in experimental lung injury.