Conference: 2012 International PHA Conference and Scientific Sessions
Release Date: 06.22.2012
Presentation Type: Abstracts
BACKGROUND: Pulmonary fibrosis is a relentlessly progressive disorder leading to respiratory failure. Endothelin-1 (ET-1), a potent vasoconstrictor and inducer of fibrocyte and smooth muscle cell proliferation, is implicated in pulmonary arterial hypertension (PAH) pathogenesis but its full role in pulmonary fibrosis pathobiology and treatment is still under investigation. We tested the effect of the highly specific endothelin receptor A (ETA) inhibitor sitaxentan (UK-372882 AKA PF 1228305-00, provided by Global Pfizer) in the bleomycin mouse lung fibrosis model.
METHODS: Bleomycin sulfate (2mg/kg) or saline was injected intratracheally (it) to 8 week-old C57/Bl6 male mice following anesthesia with intraperitoneal ketamine/xylazine. Sitaxentan (15 mg/kg/day) was added to the drinking water starting on day -1 (8 animals/group). Fourteen days after the it injection, lung compliance was measured using a small animal ventilator (Flexivent, Scireq, Ontario, Canada) and mice were subsequently sacrificed by exsanguination under deep anesthesia. Bronchoalveolar lavage fluid (BALF) was obtained and lung tissue was formalin-fixed or snap frozen in liquid N2. Total cell numbers in BALF were quantified by hemocytometer, while total BALF protein content was measured with the bicintronic acid reaction. Sample means were compared by ANOVA and Dunnet’s (*) or Newman-Keuls’ (#) post-hoc tests to 0.05 significance level.
RESULTS: Bleomycin induced lung injury, evidenced as reduced lung compliance (left), as well as BALF pleocytosis (right) and increased total protein levels. Sitaxentan administration was associated with significantly reduced total cell count in BALF, while lung compliance deterioration was prevented. Conversely, BALF total protein levels were not reduced in the sitaxentan-treated mice.
CONCLUSIONS: In our bleomycin mouse model, sitaxentan preserves lung function and reduces airspace inflammation 14 days post bleomycin administration, without affecting vascular permeability. ETA-specific inhibition may be a promising approach to the treatment of pulmonary fibrotic disorders (supported by an Investigator-Initiated Research grant from Pfizer Hellas).