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

白细胞介素、肿瘤坏死因子-α和蛋白酶在绵羊急性肺损伤发生过程中的作用

• 批准号: 08457179
• 负责人: KUBO Keishi
• 金额: $ 1.34万
• 依托单位: SHINSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457179/
• 关键词: Endotoxin-induced lung injury; Acute lung injury; Interleukin; Tumor necrosis factor; Proteinase; Sheep; VEGF,VPF; 蛋白分解酵素阻害剤; 気道上皮液; グルタチオン

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

我们研究了JTE-607，一种细胞因子，特别是肿瘤坏死因子-α（TNF-α），白细胞介素（IL）-1和IL-6的合成酶抑制剂，对清醒绵羊慢性肺淋巴瘘内毒素诱导的肺功能障碍的影响。JTE-607（10 mg/kg）预处理不能预防静脉注射大肠杆菌内毒素（1 μ g/kg）引起的功能障碍，包括早期的肺动脉高压、循环白细胞减少和低氧血症，以及晚期的通透性增加水肿。内毒素血症导致TNF-α的血清浓度显著增加，通过生物测定法测量（Yoshie等人，J Biochem 100：531，1986），但JTE-607不能抑制TNF水平的增加。其是一种12 KDa丝氨酸抗蛋白酶，生理上存在于上呼吸道上皮表面，肺上皮衬里层和肺淋巴液谷胱甘肽含量 ...更多信息 在绵羊中（Gillissen等，J Appl Physiol 75：825，1993），我们试验了重组半大小SLPI（1/2 SLPI ; TEI-7361）对清醒绵羊的支气管肺泡灌洗液（BALF）和肺淋巴中谷胱甘肽水平的影响。清醒绵羊静脉注射TEI-7361 15 mg/kg后，BALF、肺淋巴液和血清中谷胱甘肽水平无明显变化。因此，1/2SLPI似乎不具有增加肺上皮衬里层谷胱甘肽水平的能力。高原肺水肿（High altitude pulmonary edema，HAPE）是发生在日本阿尔卑斯山区的一种非心源性肺水肿，是一种典型的急性肺损伤。HAPE的发病机制尚不清楚。本文观察了7例HAPE患者早期BALF中IL、TNF-α和P-选择素的水平及其与肺血流动力学的关系。促炎细胞因子如IL-1 β、IL-6、IL-8和TNF-α显著增加，但IL-10和P-选择素没有增加。然而，在恢复期BALF中未检测到这些值或处于低水平。IL-6和TNF-α水平的升高与驾驶压力有关。促炎细胞因子在HAPE的发生发展中起重要作用，但这种作用是短暂的。此外，肺动脉高压与促炎细胞因子的变化有关。另一方面，我们检测了HAPE早期BALF中血管内皮生长因子（VEGF）的水平，这是一种新的与通透性增加相关的趋化因子，其值升高，但VEGF在HAPE中的作用还有待进一步研究。少

项目成果

Kubo, K.et al: "Inflammatory cytokines in the BAL fluid and pulmonary hemodynamics in high-altitude pulmonary edema" Respir Physiol. (In press).

Kubo, K.等人：“BAL 液中的炎症细胞因子和高原肺水肿中的肺血流动力学”Respir Physiol。

Kubo, K.et al.: "Inflammatory cytokines in the BAL fluid and pulmonary hemodynamics in high-altitude pulmonary edema." Respir Physiol. (in press). (1998)

Kubo, K.等人：“BAL 液中的炎症细胞因子和高原肺水肿中的肺血流动力学。”

Hanaoka, M.et al: "Effect of post-treatment with granulocyte colony-stimulating factor on endotoxin-induced lung injury in sheep" Exp Lung Res. 24. 15-25 (1998)

Hanaoka, M.等人：“粒细胞集落刺激因子后处理对绵羊内毒素引起的肺损伤的影响”Exp Lung Res。

Droma, Y.et al.: "Acute hypoxic pulmonary vascular response does not accompany plasma endothelin-1 elevation in subjects susceptible to high altitude pulmonary edema." Intern Medicine. 35. 257-260 (1996)

Droma, Y.等人：“在易患高原肺水肿的受试者中，急性缺氧性肺血管反应并不伴随血浆内皮素-1 升高。”

Hanaoka,M.et al: "Association of high-altitude pulmonary edema with the major histocompatibility complex" Circulation. (in press).

Hanaoka,M.et al：“高原肺水肿与主要组织相容性复合体的关联”循环。