GP Livanos and M Simou Laboratories, 1st Department of Critical Care Medicine & Pulmonary Services, Evangelismos Hospital, University of Athens Medical School, Athens, Greece.
Respiration. 2018;95(2):122-136. doi: 10.1159/000481201. Epub 2017 Nov 9.
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.
We addressed the role of highly selective ET-1 receptor A (ETA) inhibition in the pathogenesis of experimental pulmonary fibrosis by bleomycin (BLM).
BLM sulfate (2 U/mL) or saline was intratracheally 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 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.
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.
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.
肺纤维化是一种慢性疾病，可导致呼吸衰竭，最终导致死亡。内皮素-1（ET-1）是内皮细胞分泌的一种血管收缩剂，通过激活其受体 A 和 B 促进血管收缩。
我们通过博来霉素（BLM）探讨了高度选择性 ET-1 受体 A（ETA）抑制在实验性肺纤维化发病机制中的作用。
BLM 硫酸盐（2 U/mL）或生理盐水通过气管内给药至 C57/Bl6 小鼠（4 组；n = 5-11/组）。在 BLM 注射前 1 天开始用高度选择性 ETA 受体抑制剂西他生坦（15 mg/kg/天）预处理，并在实验过程中持续进行。在 BLM 后第 7、14 和 21 天牺牲前评估肺力学，随后采集支气管肺泡灌洗液（BALF）、血液和肺组织样本。
BLM 暴露的时间依赖性效应包括静态顺应性降低和肺弹性增加、气腔炎症和微血管通透性增加、组织学急性肺损伤和纤维化以及肺胶原沉积。高度选择性 ETA 受体抑制剂预处理对对照小鼠没有不良影响，但可改善肺力学和肺损伤评分，同时减少 BLM 处理小鼠的 BALF 白细胞增多、蛋白含量和胶原沉积。BLM 导致的死亡率达到 40%，主要发生在模型的炎症期，但通过西他生坦预处理可消除。
我们得出结论，在我们的 BLM 诱导的肺纤维化模型中，预防性高度选择性 ETA 抑制可提高存活率、保护肺功能、减轻肺损伤和减少胶原沉积。
