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Supplementary Material for: Highly Selective Endothelin-1 Receptor A Inhibition Prevents Bleomycin-Induced Pulmonary Inflammation and Fibrosis in Mice
<p><b><i>Background:</i></b> Pulmonary fibrosis is a chronic disease,
which progressively leads to respiratory failure and ultimately death.
Endothelin-1 (ET-1), a vasoconstrictor secreted by endothelial cells,
promotes vasoconstriction by activation of its receptors A and B. <b><i>Objectives:</i></b>
We addressed the role of highly selective ET-1 receptor A (ETA)
inhibition in the pathogenesis of experimental pulmonary fibrosis by
bleomycin (BLM). <b><i>Methods:</i></b> BLM sulfate (2 U/mL) or saline was intratracheally administered to C57/Bl6 mice (4 groups; <i>n</i>
= 5-11/group). Pretreatment with the highly selective ETA receptor
inhibitor sitaxentan (15 mg/kg/day) was started 1 day prior to BLM
injection and continued for the duration of the experiment. Lung
mechanics were assessed prior to sacrifice at days 7, 14, and 21 after
BLM, followed by procurement of bronchoalveolar lavage fluid (BALF),
blood, and lung tissue samples. <b><i>Results:</i></b> Time-dependent
effects of BLM exposure included decreased static compliance and
increased lung elastance, airspace inflammation and microvascular
permeability, histological acute lung injury and fibrosis, and lung
collagen deposition. Pretreatment with highly selective ETA receptor
inhibitor had no adverse effect on control mice but improved lung
mechanics and lung injury score in addition to decreasing BALF
pleocytosis, protein content, and collagen deposition in BLM-treated
mice. Mortality from BLM reached 40% and occurred primarily during the
inflammatory stage of the model but was abrogated by sitaxentan
pretreatment. <b><i>Conclusions:</i></b> We conclude that in our
BLM-induced pulmonary fibrosis model, prophylactic highly selective ETA
inhibition improves survival, preserves lung function, attenuates lung
injury, and reduces collagen deposition.</p