THE ROLE OF INTERLEUKIN,TUMOR NECROSIS FACTOR-ALPHA AND PROTEINASES IN THE DEVELOPMENT OF ACUTE LUNG INJURY IN SHEEP

本实验研究了细胞因子合成酶抑制剂JTE-607对内毒素诱导的绵羊慢性肺淋巴瘘肺功能障碍的影响。JTE-607(10 mg/kg)不能预防静脉注射内毒素(1µg/kg)所致的早期肺高压、循环白细胞减少、低氧血症和晚期通透性水肿增加等功能障碍。内毒素血症引起血清肿瘤坏死因子-α浓度显著升高(Yoshie et al.J Biochem 100：531,1986)，但JTE-607不能抑制升高的肿瘤坏死因子水平。由于分泌型白蛋白水解酶抑制剂(SLPI)是一种12 KDa丝氨酸抗蛋白水解酶，生理性地存在于上呼吸道上皮表面，显著增加肺上皮衬里和肺淋巴I…中谷胱甘肽的水平为了研究重组半尺寸SLPI(1/2SLPI；TEI-7361)对清醒绵羊肺泡灌洗液(BALF)和肺淋巴中谷胱甘肽(GALF)水平的影响。清醒绵羊静脉注射TEI-7361 15 mg/kg，对BALF、肺淋巴和血清中谷胱甘肽水平无明显影响。因此，1/2SLPI似乎不具有增加肺上皮细胞衬里层谷胱甘肽水平的能力。高原肺水肿(HAPE)是一种非心源性肺水肿，是一种典型的疾病，如急性肺损伤，发生在日本阿尔卑斯山。HAPE的发病机制尚不清楚。本文观察了7例HAPE患者早期BALF中ILS、TNF-α和P-选择素的水平及其与肺血流动力学的关系。IL-1β、IL-6、IL-8、TNF-α等促炎细胞因子显著升高，而IL-10、P-选择素未见明显升高。然而，恢复时BALF中未检测到这些值或处于较低水平。IL-6和TNF-α水平的升高与驾驶压力有关。促炎症细胞因子在HAPE的发生发展中起着重要作用，但作用是短暂的。此外，肺动脉高压与促炎细胞因子的变化有关。另一方面，在HAPE早期，我们检测了BALF中与通透性增加相关的一种新的趋化因子--血管内皮生长因子(VEGF)的水平，其值有所增加，但我们还需要进一步的研究来了解VEGF在HAPE中的作用。较少

We investigated effects of JTE-607, a synthetase inhibitor of cytokines, especially tumor necrosis factor-alpha (TNF-alpha), interleukin (IL) -1 and IL-6, on endotoxin-induced lung dysfunction in awake sheep with chronic lung lymph fistula. The pretreatment of JTE-607 (10mg/kg) did not prevent the dysfunctions induced by intravenous infustion of E.coli endotoxin (1 mug/kg) including pulmonary hypertension, circulating leukocyte depletion and hypoxemia during the early phase, and increased permeability edema during the late phase. The endotoxemia led to a significant increase in the serum concentration of TNF-alpha which was measured by bioassay (Yoshie et al.J Biochem 100 : 531,1986), but JTE-607 did not suppress the increased TNF levels.Since secretary leukoprotease inhibitor (SLPI), which is a 12KDa serine antiproteasae and physiologically exist in the epithelial surface of upper airways significantly increases the levles of glutathione of lung epithelial lining layr and lung lymph i … More n sheep (Gillissen et al.J Appl Physiol 75 : 825,1993), we tried the effects of recombinant half-sized SLPI (1/2 SLPI ; TEI-7361) on the levels of glutathione in bronchoalveolar lavage fluid (BALF) and lung lymph in awake sheep. Intravenous administration of TEI-7361 of 15mg/kg into awake sheep did not change the glutathione levels in BALF,lung lymph and serum. Therefore, it seems that 1/2 SLPI does not have the ability to increase the levels of glutathione of lung epithelial lining layr.High altitude pulmonary edema (HAPE) is a non cardiogenic pulmonary edema, a typical disorder as acute lung injury, occurs in the Japan Alps. The pathogenesis of HAPE is unclear. We investigated the levels of ILs, TNF-alpha and P-selectin in BALF performed at early period of 7 patients with HAPE and the relations between these values and pulmonary hemodynamics. The proinflammatory cytokines such as IL-1 beta, IL-6, IL-8 and TNF-alpha were remarkably increased, but IL-10 and P-selection did not increase. However, these values were not detected or within low levels in BALF at recovery. The increased levels of IL-6 and TNF-alpha were related to driving pressure. The proinflammatory cytokines play an important role of the development of HAPE,although the role is transient. Furthermore, pulmonary hypertension is related to the changes of proinflammatory cytokines. On the other hand, we measured the levels of vascular endothelial growth factor (VEGF), a new chemotactic factor related to increasing permeability, in BALF at its early period of HAPE.The values were increased, but we need further studies to see the role of VEGF in HAPE. Less