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The Study to Clarify The Pathophysiology of Endotoxin-induced Lung Injury -Especially The Role of Tumor Necrosis Factor-

阐明内毒素引起的肺损伤的病理生理学的研究-特别是肿瘤坏死因子的作用-

基本信息

批准号：
02807079
负责人：
KUBO Keishi
金额：
$ 1.79万
依托单位：
Shinshu University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1990
资助国家：
日本
起止时间：
1990 至 1991
项目状态：
已结题

项目摘要

In the present project we performed the two main studies to clarify the pathophysiology of endotoxin-induced lung injury using awake sheep with chronic lung lymph fistula. First study is to see the pathophysiology of TNF (tumor necrosis factor)-induced lung injury. After infusion of recombinant human TNF (r-hTNF) produced the almost same lung injuries as endotoxin-induced lung injury which we have reported^<1)>, such as the early pulmonary hypertension, transient leukopenia, decreased PaO_2 and the increased permeability pulmonary edema during the late phase. Pretreatment of selective thromboxane synthetase inhibitor, OKY-046, inhibited the early pulmonary hypertension induced by TNF, though other lung injuries did not change. Furthermore, the appearance of lung injuries induced by TNF occurred earlier 0.5-1hr than that induced by endotoxin. Secondly we examined the effects of recombinant human superoxide dismutase (r-hSOD) on endotoxin-induced lung injury to see the role of superoxide anion (O_2^-). Treatment of r-h SOD suppressed lung injuries as mentioned above, but the degree of inhibition was approximately half.These results suggest that the mechanism of endotoxin-induced lung injury in awake sheep is complicated. O_2^- has an important role in this injury. However, we need to study the role of other oxygan radicals than O_2^- and some chemical mediators such as proteases. TNF infusion resulted in the same lung injury as that caused by endotoxin. Recently, intravascular macrophages (M*) are thought to have a central role in the development of endotoxin-induced lung injury. M* releases several mediators when stimulated by endotoxemia, and these mediators lead to lung injury. We need further studies to see whether TNF is crucial among these mediators.( ^<1)> Kubo and Kobayashi : Am Rev Respir Dis 132 : 494, 1985)

在本项目中，我们进行了两项主要研究，以阐明内毒素诱导的肺损伤的病理生理学，使用清醒的绵羊慢性肺淋巴瘘。第一项研究是了解肿瘤坏死因子（TNF）诱导的肺损伤的病理生理学。重组人肿瘤坏死因子（r-hTNF）可引起与内毒素性肺损伤相似的肺损伤，如早期肺动脉高压、一过性白细胞减少、PaO_2降低和晚期肺水肿。预先给予选择性血栓素合成酶抑制剂OKY-046可抑制TNF诱导的早期肺动脉高压，但对其他肺损伤无明显影响。TNF诱导的肺损伤比内毒素诱导的肺损伤早0.5 - 1小时出现。其次，我们研究了重组人超氧化物歧化酶（r-hSOD）对内毒素诱导的肺损伤的影响，以观察超氧阴离子（O_2 ^-）的作用。用r-h SOD处理后，上述肺损伤均得到抑制，但抑制程度约为对照组的一半，提示内毒素致清醒绵羊肺损伤的机制是复杂的。O_2 ^-在此损伤中起重要作用。然而，除O_2 ^-外的其他氧自由基以及蛋白酶等化学介质的作用还有待进一步研究。TNF输注可引起与内毒素相同的肺损伤。最近，血管内巨噬细胞（M *）被认为在内毒素诱导的肺损伤的发展中具有中心作用。当受到内毒素血症刺激时，M * 释放几种介质，这些介质导致肺损伤。我们需要进一步的研究来确定TNF在这些介质中是否是至关重要的。（^<1）> Kubo和小林：Am Rev Respir Dis 132：494，1985）