E-Mail karger@karger.com Basic Science Investigation Respiration 2018;95:122–136 DOI: 10.1159/000481201 Highly Selective Endothelin-1 Receptor A Inhibition Prevents Bleomycin-Induced Pulmonary Inflammation and Fibrosis in Mice Nikolaos Manitsopoulos a Ioanna Nikitopoulou a Nikolaos A. Maniatis a, c Christina Magkou d Anastasia Kotanidou a, b Stylianos E. Orfanos a, c a GP Livanos and M Simou Laboratories, 1st Department of Critical Care Medicine & Pulmonary Services, Evangelismos Hospital, University of Athens Medical School, b 1st Department of Critical Care Medicine & Pulmonary Services, Evangelismos Hospital, University of Athens Medical School, c 2nd Department of Critical Care, “Attikon” Hospital, University of Athens Medical School, and d Department of Pathology, Evangelismos Hospital, Athens, Greece 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 colla- gen deposition in BLM-treated mice. Mortality from BLM reached 40% and occurred primarily during the inflamma- tory stage of the model but was abrogated by sitaxentan pretreatment. Conclusions: We conclude that in our BLM- induced pulmonary fibrosis model, prophylactic highly se- lective ETA inhibition improves survival, preserves lung func- tion, attenuates lung injury, and reduces collagen deposi- tion. © 2017 S. Karger AG, Basel Introduction Idiopathic pulmonary fibrosis (IPF), a chronic and progressive scarring process of the lung [1], is associated with a poor prognosis, with the majority of patients dying of respiratory failure within 2–4 years from diagnosis [2, 3]. The pathogenesis of IPF is not fully understood. The Keywords Inflammation · Fibrosis · Bleomycin · Endothelin-1 · Sitaxentan · Lung function Abstract Background: Pulmonary fibrosis is a chronic disease, which progressively leads to respiratory failure and ultimately death. Endothelin-1 (ET-1), a vasoconstrictor secreted by en- dothelial cells, promotes vasoconstriction by activation of its receptors A and B. Objectives: We addressed the role of highly selective ET-1 receptor A (ETA) inhibition in the patho- genesis of experimental pulmonary fibrosis by bleomycin (BLM). Methods: BLM sulfate (2 U/mL) or saline was intratra- cheally administered to C57/Bl6 mice (4 groups; n = 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 ex- periment. 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. Results: Time-dependent effects of BLM exposure included decreased static compliance and increased lung elastance, airspace inflammation and microvascular perme- ability, histological acute lung injury and fibrosis, and lung Received: February 16, 2017 Accepted after revision: August 30, 2017 Published online: November 9, 2017 Dr. Stylianos E. Orfanos 2nd Department of Critical Care, Attikon University Hospital 1, Rimini Street Haidari Athens 12462 (Greece) E-Mail stylianosorfanosuoa @ gmail.com © 2017 S. Karger AG, Basel www.karger.com/res N. Manitsopoulos and I. Nikitopoulou contributed equally to this work.