Yamashita T, Kawashima S, Ohashi Y, Ozaki M, Ueyama T, Ishida T, Inoue N, Hirata K, Akita H, Yokoyama M
First Department of Internal Medicine, Kobe University School of Medicine, Kobe, Japan.
Circulation. 2000 Feb 29;101(8):931-7. doi: 10.1161/01.cir.101.8.931.
Nitric oxide (NO) plays a central role in the pathogenesis of septic shock. However, the role of the NO produced by endothelial NO synthase (eNOS) in septic shock is still unclear. We examined the effect of chronic eNOS overexpression and the role of eNOS-derived NO in lipopolysaccharide (LPS)-induced septic shock using eNOS transgenic (Tg) mice.
LPS was intraperitoneally injected into Tg and control mice. No differences existed in the peak plasma nitrate and nitrate levels induced by LPS between the 2 genotypes. In LPS-treated control mice, blood pressure progressively declined and reached 60% of basal levels (from 97+/-3 to 59+/-3 mm Hg) 24 hours after LPS injection. In contrast, the blood pressure of LPS-treated Tg mice fell only 15% from basal levels (from 84+/-4 to 71+/-4 mm Hg) after the first 6 hours and, thereafter, it remained at this level. LPS-induced increases in the expression of the mRNA of both vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 in the lungs were significantly lower in Tg mice than in control mice. LPS-induced pulmonary leukocyte infiltration and increases in lung water content were also significantly attenuated in Tg mice. Histological examination revealed that lung injury after LPS injection was milder in Tg mice. Furthermore, Tg mice exhibited enhanced survival from LPS-induced septic shock compared with control mice.
Chronic eNOS overexpression in the endothelium of mice resulted in resistance to LPS-induced hypotension, lung injury, and death. These effects are associated with the reduced vascular reactivity to NO and the reduced anti-inflammatory effects of NO.
一氧化氮（NO）在脓毒性休克的发病机制中起核心作用。然而，内皮型一氧化氮合酶（eNOS）产生的NO在脓毒性休克中的作用仍不清楚。我们使用eNOS转基因（Tg）小鼠研究了慢性eNOS过表达的影响以及eNOS衍生的NO在脂多糖（LPS）诱导的脓毒性休克中的作用。
将LPS腹腔注射到Tg小鼠和对照小鼠体内。两种基因型之间由LPS诱导的血浆硝酸盐和亚硝酸盐水平峰值没有差异。在LPS处理的对照小鼠中，血压逐渐下降，在注射LPS后24小时降至基础水平的60%（从97±3降至59±3 mmHg）。相比之下，LPS处理的Tg小鼠的血压在最初6小时后仅从基础水平下降了15%（从84±4降至71±4 mmHg），此后一直保持在这个水平。Tg小鼠肺中血管细胞黏附分子-1和细胞间黏附分子-1的mRNA表达因LPS诱导的增加明显低于对照小鼠。LPS诱导的肺白细胞浸润和肺含水量增加在Tg小鼠中也明显减轻。组织学检查显示，LPS注射后Tg小鼠的肺损伤较轻。此外，与对照小鼠相比，Tg小鼠在LPS诱导的脓毒性休克中的存活率更高。
小鼠内皮中慢性eNOS过表达导致对LPS诱导的低血压、肺损伤和死亡具有抵抗力。这些作用与血管对NO的反应性降低以及NO的抗炎作用降低有关。
