Wang D, Wei J, Hsu K, Jau J, Lieu M W, Chao T J, Chen H I
Department of Medical Research, Cheng Hsin General Hospital, Taipei, Republic of China.
J Biomed Sci. 1999 Jan;6(1):28-35. doi: 10.1007/BF02256421.
Endotoxin shock is characterized by systemic hypotension, hyporeactiveness to vasoconstrictors and acute lung edema. A nitric oxide synthase (NOS) inhibitor, NG-monomethyl-L-arginine (L-NMMA) has been shown to be effective in reversing acute lung injury. In the present study, we evaluated the effects of NOS blockade by different mechanisms on the endotoxin-induced changes. In anesthetized rats, lipopolysaccharide (LPS, Klebsiella pneumoniae) was administered intravenously in a dose of 10 mg/kg. LPS caused sustained systemic hypotension accompanied by an eightfold increase of exhaled NO during an observation period of 4 h. After the experiment, the lung weight was obtained and lung tissues were taken for the determination of mRNA expressions of inducible NOS (iNOS), interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha-(TNF-alpha). Histological examination of the lungs was also performed. In the control group injected with saline solution, mRNA expressions of iNOS, IL-1beta and TNF-alpha were absent. Four hours after LPS, the mRNA expressions of iNOS and IL-1beta were still significantly enhanced, but TNF-alpha was not discernibly expressed. LPS also caused a twofold increase in lung weight. Pathological examination revealed endothelial damage and interstitial edema. Various NOS inhibitors were given 1 h after LPS administration. These agents included Nomega-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg), a constitutive NOS and iNOS inhibitor; S, S'-1,4-phenylene-bis-(1,2-ethanedinyl) bis-isothiourea dihydrobromide (1,4-PBIT, 10 mg/kg), a relatively specific iNOS inhibitor, and dexamethasone (3 mg/kg), an inhibitor of iNOS expression. These NOS inhibitors all effectively reversed the systemic hypotension, reduced the exhaled NO concentration and prevented acute lung injury. The LPS-induced mRNA expressions of iNOS and IL-1beta were also significantly depressed by these NOS inhibitors. Our results suggest that NO production through the iNOS pathway is responsible for endotoxin-induced lung injury. Certain cytokines such as IL-1beta are possibly involved. These changes are minimized by NOS inhibitors through different mechanisms.
内毒素休克的特征为全身性低血压、对血管收缩剂反应性降低以及急性肺水肿。一氧化氮合酶（NOS）抑制剂N-单甲基-L-精氨酸（L-NMMA）已被证明可有效逆转急性肺损伤。在本研究中，我们评估了通过不同机制阻断NOS对内毒素诱导变化的影响。在麻醉大鼠中，静脉注射剂量为10 mg/kg的脂多糖（LPS，肺炎克雷伯菌）。LPS导致持续性全身性低血压，在4小时的观察期内呼出的NO增加了八倍。实验结束后，获取肺重量并取肺组织用于测定诱导型NOS（iNOS）、白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）的mRNA表达。还对肺进行了组织学检查。在注射生理盐水的对照组中，未检测到iNOS、IL-1β和TNF-α的mRNA表达。LPS注射4小时后，iNOS和IL-1β的mRNA表达仍显著增强，但未检测到TNF-α的表达。LPS还使肺重量增加了两倍。病理检查显示内皮损伤和间质水肿。在LPS给药1小时后给予各种NOS抑制剂。这些药物包括Nω-硝基-L-精氨酸甲酯（L-NAME，10 mg/kg），一种组成型NOS和iNOS抑制剂；S，S'-1,4-亚苯基-双-（1,2-乙二基）双异硫脲二氢溴化物（1,4-PBIT，10 mg/kg），一种相对特异性的iNOS抑制剂，以及地塞米松（3 mg/kg），一种iNOS表达抑制剂。这些NOS抑制剂均有效逆转了全身性低血压，降低了呼出的NO浓度并预防了急性肺损伤。这些NOS抑制剂还显著抑制了LPS诱导的iNOS和IL-1β的mRNA表达。我们的结果表明，通过iNOS途径产生的NO是内毒素诱导的肺损伤的原因。某些细胞因子如IL-1β可能参与其中。NOS抑制剂通过不同机制使这些变化最小化。
