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

在本项目中，我们对患有慢性肺淋巴瘘的清醒羊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。首先研究TNF（肿瘤坏死因子）诱导肺损伤的病理生理。重组人TNF （r-hTNF）输注后的肺损伤与我们报道的内毒素所致肺损伤几乎相同，如早期肺动脉高压，短暂性白细胞减少，PaO_2降低，晚期通透性肺水肿增加。选择性血栓素合成酶抑制剂OKY-046预处理可抑制TNF诱导的早期肺动脉高压，但其他肺损伤无变化。此外，TNF诱导的肺损伤出现时间比内毒素诱导的早0.5-1hr。其次，研究了重组人超氧化物歧化酶（r-hSOD）对内毒素所致肺损伤的影响，探讨了超氧化物阴离子（O_2^-）的作用。处理r-h SOD可抑制上述肺损伤，但抑制程度约为一半。上述结果提示，内毒素致醒羊肺损伤的机制是复杂的。O_2^-在这种损伤中起重要作用。然而，我们需要研究除O_2^-外的其他氧自由基和一些化学介质如蛋白酶的作用。TNF输注引起的肺损伤与内毒素引起的肺损伤相同。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起着核心作用。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在这些介质中是否至关重要。（^<1） [b] Kubo and Kobayashi: Am Rev . doi: jjjjjj]

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)