Effects of Nitric Oxide Synthase Inhibitors on Systemic Hypotension, Cytokines and Inducible Nitric Oxide Synthase Expression and Lung Injury following Endotoxin Administration in Rats
Effects of Nitric Oxide Synthase Inhibitors on Systemic Hypotension, Cytokines and Inducible Nitric Oxide Synthase Expression and Lung Injury following Endotoxin Administration in Rats
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DOI：
10.1159/000025368
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发表时间：
1999-02
影响因子：
11
通讯作者：
David Wang;Jeng Wei;K. Hsu;Jin-Chi Jau;M. Lieu;Tai-Jong Chao;Hsing-I Chen
中科院分区：
文献类型：
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作者：
David Wang;Jeng Wei;K. Hsu;Jin-Chi Jau;M. Lieu;Tai-Jong Chao;Hsing-I Chen
内毒素休克的特征是全身性低血压、对血管收缩药的低反应性和急性肺水肿。一氧化氮合酶抑制剂L精氨酸具有逆转急性肺损伤的作用。在本研究中，我们评估了通过不同机制阻断一氧化氮合酶对内毒素诱导的改变的影响。麻醉大鼠静脉注射脂多糖(内毒素，肺炎克雷伯菌)10 mg/kg。实验结束后取肺组织，测定诱导型一氧化氮合酶(INOS)、白介素1β(IL-1β)和肿瘤坏死因子-α-(α)的基因表达。同时进行肺组织学检查。生理盐水对照组未见诱导型一氧化氮合酶、IL-1β和肿瘤坏死因子-α的表达。内毒素诱导后4h，诱导型一氧化氮合酶和IL-1β的表达仍显著增强，但未见肿瘤坏死因子-α的表达。脂多糖还导致肺重量增加了两倍。病理检查示内皮细胞损伤，间质水肿。内毒素注射后1h给予不同的一氧化氮合酶抑制剂。这些药物包括原生型一氧化氮合酶和诱导型一氧化氮合酶抑制剂N-ω-硝基-L-精氨酸甲酯(L，10 mg/kg)，相对特异的诱导型一氧化氮合酶抑制剂S，S‘-1，4-苯基-二(1，2-乙二基)二氢异硫脲(1，4-PBIT，10 mg/kg)和诱导型一氧化氮合酶表达抑制剂地塞米松(3 mg/kg)。这些一氧化氮合酶抑制剂均能有效逆转全身低血压，降低呼出的NO浓度，预防急性肺损伤。内毒素诱导的诱导型一氧化氮合酶和IL-1β的表达也被这些一氧化氮合酶抑制剂显著抑制。我们的结果提示，通过iNOS途径产生的NO与内毒素诱导的肺损伤有关。某些细胞因子，如IL-1β可能参与了这一过程。一氧化氮合酶抑制剂通过不同的机制使这些变化最小化。
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-1β (IL-1β) and tumor necrosis factor-α-(TNF-α). Histological examination of the lungs was also performed. In the control group injected with saline solution, mRNA expressions of iNOS, IL-1β and TNF-α were absent. Four hours after LPS, the mRNA expressions of iNOS and IL-1β were still significantly enhanced, but TNF-α 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 Nω-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-1β 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-1β are possibly involved. These changes are minimized by NOS inhibitors through different mechanisms.