Raveh Yehuda, Ichinose Fumito, Orbach Pini, Bloch Kenneth D, Zapol Warren M
Department of Anesthesia, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Anesthesiology. 2002 Apr;96(4):926-33. doi: 10.1097/00000542-200204000-00021.
Sepsis is associated with an impaired pulmonary vasodilator response to inhaled nitric oxide (NO). A combination of NO and other inflammatory mediators appears to be responsible for endotoxin-induced pulmonary vascular hyporesponsiveness to inhaled NO. The authors investigated whether scavengers of reactive oxygen species could preserve inhaled NO responsiveness in endotoxin-challenged mice.
The vasorelaxation to inhaled NO was studied in isolated, perfused, and ventilated lungs obtained from mice 16 h after an intraperitoneal challenge with saline or 50 mg/kg Escherichia coli lipopolysaccharide. In some mice, challenge with saline or lipopolysaccharide was followed by intraperitoneal administration of N-acetylcysteine, dimethylthiourea, EUK-8, or polyethylene glycol-conjugated catalase.
The pulmonary vasodilator response of U46619-preconstricted isolated lungs to ventilation with 0.4, 4, and 40 ppm inhaled NO in lipopolysaccharide-challenged mice was reduced to 32, 43, and 60%, respectively, of that observed in saline-challenged mice (P < 0.0001). Responsiveness to inhaled NO was partially preserved in lipopolysaccharide-challenged mice treated with a single dose of N-acetylcysteine (150 or 500 mg/kg) or 20 U/g polyethylene glycol-conjugated catalase (all P < 0.05 vs. lipopolysaccharide alone). Responsiveness to inhaled NO was fully preserved by treatment with either dimethylthiourea, EUK-8, two doses of N-acetylcysteine (150 mg/kg administered 3.5 h apart), or 100 U/g polyethylene glycol-conjugated catalase (all P < 0.01 vs. lipopolysaccharide alone).
When administered to mice concurrently with lipopolysaccharide challenge, reactive oxygen species scavengers prevent impairment of pulmonary vasodilation to inhaled NO. Therapy with scavengers of reactive oxygen species may provide a means to preserve pulmonary vasodilation to inhaled NO in sepsis-associated acute lung injury.
脓毒症与肺血管对吸入一氧化氮（NO）的舒张反应受损有关。NO与其他炎症介质的联合作用似乎是内毒素诱导的肺血管对吸入NO反应性降低的原因。作者研究了活性氧清除剂是否能在受到内毒素攻击的小鼠中保留吸入NO的反应性。
在腹腔注射生理盐水或50mg/kg大肠杆菌脂多糖16小时后，从小鼠获取离体、灌注和通气的肺，研究其对吸入NO的血管舒张作用。在一些小鼠中，腹腔注射生理盐水或脂多糖后，再腹腔注射N-乙酰半胱氨酸、二甲基硫脲、EUK-8或聚乙二醇结合的过氧化氢酶。
在受到脂多糖攻击的小鼠中，U46619预收缩的离体肺对吸入0.4、4和40ppm NO通气的肺血管舒张反应分别降至生理盐水攻击小鼠中观察到反应的32%、43%和60%（P<0.0001）。用单剂量N-乙酰半胱氨酸（150或500mg/kg）或20U/g聚乙二醇结合的过氧化氢酶处理的脂多糖攻击小鼠中，对吸入NO的反应性部分得以保留（与单独使用脂多糖相比，所有P<0.05）。用二甲基硫脲、EUK-8、两剂N-乙酰半胱氨酸（间隔3.5小时给予150mg/kg）或100U/g聚乙二醇结合的过氧化氢酶处理可完全保留对吸入NO的反应性（与单独使用脂多糖相比，所有P<0.01）。
当与脂多糖攻击同时给予小鼠时，活性氧清除剂可防止肺血管对吸入NO的舒张功能受损。活性氧清除剂治疗可能为脓毒症相关急性肺损伤中保留肺血管对吸入NO的舒张功能提供一种方法。
