Gebauer P H, Turzo M, Lasitschka F, Weigand M A, Busch C J
Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany.
Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Pulm Circ. 2020 Dec 15;10(4):2045894020915831. doi: 10.1177/2045894020915831. eCollection 2020 Oct-Dec.
Endotoxemia impairs hypoxic pulmonary vasoconstriction which leads to systemic hypoxemia. This derogation is attributable to increased activity of nitric oxide synthase 2 and arginase metabolism. Gene expression analysis has shown increased expression of ornithine decarboxylase in lungs of endotoxemic mice, a downstream enzyme of arginase metabolism. The aim of this study was to investigate whether inhibition of ornithine decarboxylase increases hypoxic pulmonary vasoconstriction in lungs of endotoxemic mice. Mice received lipopolysaccharides or saline intraperitoneal, and hypoxic pulmonary vasoconstriction was measured using an isolated perfused mouse lung model. Additional mice with and without endotoxemia were pretreated with the ornithine decarboxylase-inhibitor difluoromethylornithine before examination of hypoxic pulmonary vasoconstriction. Hypoxic pulmonary vasoconstriction was defined as the difference of pulmonary arterial pressure between normoxic and hypoxic ventilation. In addition, lung tissue was analyzed using real-time quantitative polymerase chain reaction, Western blot and immunohistochemistry. Lipopolysaccharides caused an up-regulation of ornithine decarboxylase mRNA level (2.73 ± 0.19-fold increase, < 0.05) as well as ornithine decarboxylase protein level (4.05 ± 0.37-fold increase, < 0.05). Endotoxemia attenuated hypoxic pulmonary vasoconstriction when compared with untreated control mice (26.3 ± 9.7% vs. 67.0 ± 17.5%). Difluoromethylornithine (20, 100, 500 mg kg body weight intraperitoneal) restored hypoxic pulmonary vasoconstriction in lungs of endotoxemic mice in a dose-dependent way (25.8 ± 9.9%, 57.3 ± 17.2%, 62.3 ± 12.4%) and decreased hypoxic pulmonary vasoconstriction in control mice (53.6 ± 13.6%, 40.0 ± 14.9%, 35.9 ± 12.4%). These results show that endotoxemia induces ornithine decarboxylase expression and suggest that ornithine decarboxylase contributes to the endotoxemia-induced impairment of hypoxic pulmonary vasoconstriction. Inhibition of ornithine decarboxylase might be a target in the therapy of diseases with inflammation impaired hypoxic pulmonary vasoconstriction, like the sepsis-associated acute respiratory distress syndrome (ARDS).
内毒素血症会损害缺氧性肺血管收缩，进而导致全身性低氧血症。这种损害归因于一氧化氮合酶2和精氨酸酶代谢活性的增加。基因表达分析表明，内毒素血症小鼠肺中鸟氨酸脱羧酶（精氨酸酶代谢的下游酶）的表达增加。本研究的目的是调查抑制鸟氨酸脱羧酶是否会增加内毒素血症小鼠肺中的缺氧性肺血管收缩。小鼠腹腔注射脂多糖或生理盐水，使用离体灌注小鼠肺模型测量缺氧性肺血管收缩。在检查缺氧性肺血管收缩之前，对另外有或没有内毒素血症的小鼠用鸟氨酸脱羧酶抑制剂二氟甲基鸟氨酸进行预处理。缺氧性肺血管收缩定义为常氧通气和低氧通气之间肺动脉压的差值。此外，使用实时定量聚合酶链反应、蛋白质免疫印迹和免疫组织化学分析肺组织。脂多糖导致鸟氨酸脱羧酶mRNA水平上调（增加2.73±0.19倍，P<0.05）以及鸟氨酸脱羧酶蛋白水平上调（增加4.05±0.37倍，P<0.05）。与未处理的对照小鼠相比，内毒素血症减弱了缺氧性肺血管收缩（26.3±9.7%对67.0±17.5%）。二氟甲基鸟氨酸（腹腔注射20、100、500mg/kg体重）以剂量依赖性方式恢复内毒素血症小鼠肺中的缺氧性肺血管收缩（25.8±9.9%、57.3±17.2%、62.3±12.4%），并降低对照小鼠的缺氧性肺血管收缩（53.6±13.6%、40.0±14.9%、35.9±12.4%）。这些结果表明，内毒素血症诱导鸟氨酸脱羧酶表达，并提示鸟氨酸脱羧酶促成了内毒素血症诱导的缺氧性肺血管收缩损害。抑制鸟氨酸脱羧酶可能是治疗炎症性缺氧性肺血管收缩受损疾病（如脓毒症相关急性呼吸窘迫综合征（ARDS））的一个靶点。
