Baboolal Hemanth A, Ichinose Fumito, Ullrich Roman, Kawai Noriko, Bloch Kenneth D, Zapol Warren M
Department of Anesthesia and Critical Care, Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Anesthesiology. 2002 Nov;97(5):1227-33. doi: 10.1097/00000542-200211000-00028.
Sepsis and endotoxemia attenuate hypoxic pulmonary vasoconstriction (HPV), thereby impairing systemic oxygenation. Reactive oxygen species (ROS) are implicated in the pathogenesis of sepsis-induced lung injury. The authors investigated whether treatment with scavengers of ROS prevents impairment of HPV in mice challenged with endotoxin.
The pulmonary vasoconstrictor response to left mainstem bronchus occlusion (LMBO) was studied in anesthetized mice 22 h after an intraperitoneal challenge with saline solution or 10 mg/kg Escherichia coli endotoxin. In some mice, challenge with saline solution or endotoxin was followed after 1 h with intraperitoneal or intratracheal administration of the ROS scavengers N-acetylcysteine or EUK-8. Myeloperoxidase activity and nitric oxide synthase-2 gene expression were measured in lung tissues.
The LMBO increased left pulmonary vascular resistance by 106 +/- 24% in saline-challenged control mice but by only 23 +/- 12% (P < 0.05) in endotoxin-challenged mice. Intraperitoneal administration of N-acetylcysteine or EUK-8 1 h after endotoxin challenge attenuated the endotoxin-induced impairment of HPV (58 +/- 6% and 68 +/- 10%, respectively; both P< 0.05 endotoxin-challenged mice). Intratracheal administration of ROS scavengers 1 h after endotoxin challenge was equally effective but required lower doses than systemic treatment. Administration of the ROS scavengers 22 h after endotoxin challenge did not restore HPV.
Administration of N-acetylcysteine or EUK-8 1 h after endotoxin challenge in mice prevented the impairment of HPV after LMBO. Early therapy with ROS scavengers, either systemically or by inhalation, may provide a means to preserve HPV in sepsis-associated acute lung injury.
脓毒症和内毒素血症会减弱低氧性肺血管收缩（HPV），从而损害全身氧合作用。活性氧（ROS）与脓毒症诱导的肺损伤发病机制有关。作者研究了用ROS清除剂治疗是否能预防内毒素攻击小鼠时HPV受损。
在腹腔注射生理盐水或10mg/kg大肠杆菌内毒素22小时后，对麻醉小鼠的左主支气管闭塞（LMBO）引起的肺血管收缩反应进行研究。在一些小鼠中，腹腔或气管内注射ROS清除剂N-乙酰半胱氨酸或EUK-8，1小时后再用生理盐水或内毒素攻击。测量肺组织中的髓过氧化物酶活性和一氧化氮合酶-2基因表达。
在生理盐水攻击的对照小鼠中，LMBO使左肺血管阻力增加了106±24%，而在内毒素攻击的小鼠中仅增加了23±12%（P<0.05）。内毒素攻击1小时后腹腔注射N-乙酰半胱氨酸或EUK-8可减轻内毒素诱导的HPV损伤（分别为58±6%和68±10%；内毒素攻击小鼠两者均P<0.05）。内毒素攻击1小时后气管内注射ROS清除剂同样有效，但所需剂量低于全身治疗。内毒素攻击22小时后给予ROS清除剂不能恢复HPV。
小鼠内毒素攻击1小时后给予N-乙酰半胱氨酸或EUK-8可预防LMBO后HPV受损。早期用ROS清除剂进行全身或吸入治疗，可能为脓毒症相关急性肺损伤中保留HPV提供一种方法。
