Weimann J, Bloch K D, Takata M, Steudel W, Zapol W M
Department of Anesthesia and Critical Care Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Anesthesiology. 1999 Dec;91(6):1744-53. doi: 10.1097/00000542-199912000-00028.
In animal models, endotoxin (lipopolysaccharide) challenge impairs the pulmonary vasodilator response to inhaled nitric oxide (NO). This impairment is prevented by treatment with inhibitors of NO synthase 2 (NOS2), including glucocorticoids and L-arginine analogs. However, because these inhibitors are not specific for NOS2, the role of this enzyme in the impairment of NO responsiveness by lipopolysaccharide remains incompletely defined.
To investigate the role of NOS2 in the development of lipopolysaccharide-induced impairment of NO responsiveness, the authors measured the vasodilator response to inhalation of 0.4, 4, and 40 ppm NO in isolated, perfused, and ventilated lungs obtained from lipopolysaccharide-pretreated (50 mg/kg intraperitoneally 16 h before lung perfusion) and untreated wild-type and NOS2-deficient mice. The authors also evaluated the effects of breathing NO for 16 h on pulmonary vascular responsiveness during subsequent ventilation with NO.
In wild-type mice, lipopolysaccharide challenge impaired the pulmonary vasodilator response to 0.4 and 4 ppm NO (reduced 79% and 45%, respectively, P < 0.001), but not to 40 ppm. In contrast, lipopolysaccharide administration did not impair the vasodilator response to inhaled NO in NOS2-deficient mice. Breathing 20 ppm NO for 16 h decreased the vasodilator response to subsequent ventilation with NO in lipopolysaccharide-pretreated NOS2-deficient mice, but not in lipopolysaccharide-pretreated wild-type, untreated NOS2-deficient or untreated wild-type mice.
In response to endotoxin challenge, NO, either endogenously produced by NOS2 in wild-type mice or added to the air inhaled by NOS2-deficient mice, is necessary to impair vascular responsiveness to inhaled NO. Prolonged NO breathing, without endotoxin, does not impair vasodilation in response to subsequent NO inhalation. These results suggest that NO, plus other lipopolysaccharide-induced products, are necessary to impair responsiveness to inhaled NO in a murine sepsis model.
在动物模型中，内毒素（脂多糖）刺激会损害肺血管对吸入一氧化氮（NO）的舒张反应。一氧化氮合酶2（NOS2）抑制剂（包括糖皮质激素和L-精氨酸类似物）的治疗可预防这种损害。然而，由于这些抑制剂对NOS2不具有特异性，该酶在脂多糖导致的NO反应性损害中的作用仍未完全明确。
为了研究NOS2在脂多糖诱导的NO反应性损害发展中的作用，作者测量了从脂多糖预处理（肺灌注前16小时腹腔注射50mg/kg）和未处理的野生型及NOS2缺陷型小鼠获得的离体、灌注和通气肺对吸入0.4、4和40ppm NO的舒张反应。作者还评估了呼吸NO 16小时对随后用NO通气期间肺血管反应性的影响。
在野生型小鼠中，脂多糖刺激损害了肺对0.4和4ppm NO的舒张反应（分别降低79%和45%，P<0.001），但对40ppm NO无损害。相比之下，给予脂多糖并未损害NOS2缺陷型小鼠对吸入NO的舒张反应。在脂多糖预处理的NOS2缺陷型小鼠中，呼吸20ppm NO 16小时会降低随后用NO通气时的舒张反应，但在脂多糖预处理的野生型、未处理的NOS2缺陷型或未处理的野生型小鼠中则不会。
对内毒素刺激的反应中，野生型小鼠中由NOS2内源性产生的NO或添加到NOS2缺陷型小鼠吸入空气中的NO，对于损害血管对吸入NO的反应性是必要的。无内毒素时，长时间呼吸NO不会损害随后吸入NO时的血管舒张。这些结果表明，在小鼠脓毒症模型中，NO加上其他脂多糖诱导的产物对于损害对吸入NO的反应性是必要的。
