Molecular analysis of inflammation and immune response

炎症和免疫反应的分子分析

• 批准号: 08457104
• 负责人: MATSUSHIMA Kouji
• 金额: $ 4.74万
• 依托单位: University of Tokyo
• 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-08457104/
• 关键词: endotoxin shock; CD18; ICAM-1; selectin; sulfatide; adhesion molecule; chemokine; inflammation; エンドトキシンショック; Sulfatide; エンドトキシン; 腫瘍壊死因子; インテグリン; インターロイキン8(IL8); 単球走化活性化因子

Septic shock remains a serious disorder associated with high mortality. We studied the effects of an anti-CD18 or an anti-intercellular adhesion molecule 1 (1CAM-1) on acute lethality induced by a single administration of a high dose of lipopolysaccharide (LPS) in mice. Addition of anti-CD18 or an anti-ICAM-1 antibody prevented acute lethality. Thus in vivo action of LPS requires the interaction of leukocytes with the endothelium through adhesion molecules. Next, we examined the effects of a ligand for L- and P-selectins, sulfatide, on endotoxin shock. Pretreatment with sulfatide prevented acute lethality and hypotension, with a concomitant reduction in the increase in serum TNF-alpha levels. These results suggest that selectin is critically involved in conferring the responsiveness of leukocytes to LPS and that sulfatide interferes with the intracellular signaling pathway which leads to TNF-alpha gene activation.We postulate that the in vivo action of endotoxins requires the coodinati … More ve interaction of leukocytes with the endothelium. These interactions eventually result in leukocyte rolling along the venular wall, followed by the firm attachment and subsequent transmigration of leukocytes. Hence, new molecules which inhibit interaction between leukocytes and the endothelium, thereby preventing subsequent leukocyte-mediated tissue injury and inflammation, can be a new target to prevent septic shock.On the other hand, in order to investigate the role of MCAF/MCP-1 chronic inflammation, we established rat models of crescent glomerulonephritis and monocrotaline-induced pulmonary hypertension. In these models, anti-MCAF/MCP-1 antibodies prevented severity of the diseases progression. In glomerulonephritis models, administration of the antibodies prevented proteinuria and fibrosis of the glomeruli in later phase, and inhibited the renal failure. In pulmonary hypertension models, antibody treatment prevented the infiltration of the macrophage in the lung and resulted in inhibition of the thickening of the arterioles in the lung. These results suggested that MCAF/MCP-1 plays seesntail role in the pathogenesis of the chronic inflammation. Less

脓毒性休克仍然是一种严重的疾病，死亡率高。我们研究了抗CD 18或抗细胞间粘附分子1（ICAM-1）对单次给予高剂量脂多糖（LPS）诱导的小鼠急性致死性的影响。添加抗CD 18或抗ICAM-1抗体可防止急性致死。因此，LPS的体内作用需要白细胞通过粘附分子与内皮相互作用。接下来，我们研究了L-和P-选择素的配体硫苷脂对内毒素休克的影响。用硫苷脂预处理可预防急性致死性和低血压，同时降低血清TNF-α水平的升高。这些结果表明，选择素在赋予白细胞对LPS的反应性中起关键作用，硫苷脂干扰导致TNF-α基因激活的细胞内信号通路。 ...更多信息 白细胞与内皮细胞的相互作用。这些相互作用最终导致白细胞沿着小静脉壁沿着，随后是白细胞的牢固附着和随后的迁移。因此，新的分子，抑制白细胞和内皮细胞之间的相互作用，从而防止随后的白细胞介导的组织损伤和炎症，可能是一个新的目标，以防止脓毒性休克。另一方面，为了研究MCAF/MCP-1慢性炎症的作用，我们建立了大鼠模型的新月形肾小球肾炎和野百合碱诱导的肺动脉高压。在这些模型中，抗MCAF/MCP-1抗体阻止了疾病进展的严重程度。在肾小球肾炎模型中，抗体的施用防止了后期的蛋白尿和肾小球纤维化，并抑制了肾衰竭。在肺动脉高压模型中，抗体处理防止了巨噬细胞在肺中的浸润，并导致肺中小动脉增厚的抑制。提示MCAF/MCP-1在慢性炎症的发病机制中起重要作用。少

项目成果

Harada,A.,Mukaida,N.,and Matsushima,K.: "Use of blocking antibodies as probes for in vivo functions of chemokines.In A Companion to Methods in Enzymology,vol.10.Sozzani,S.(ed.)" Academic Press,New York,NY,U.S.A., pp.166-174 (1996)

Harada, A.、Mukaida, N. 和 Matsushima, K.：“使用封闭抗体作为趋化因子体内功能的探针。酶学方法指南，第 10 卷。Sozzani, S.（编辑）

Harada,A.,Mukaida,N.,and Matsushima,K.: "The role of chemokines in ischemia and reperfusion injury.In Chemokines in Diseases.A.Koch and R.M.Strieter(eds.)." R.G.Landers Company,Austin,Texas,USA,pp.179-193 (1996)

Harada, A.、Mukaida, N. 和 Matsushima, K.：“趋化因子在缺血和再灌注损伤中的作用。疾病中的趋化因子。A.Koch 和 R.M.Strieter（编辑）”。

Shono,T.,Ono,and Matsushima,K.,et al.: "Involvement of the transcription factor NF-κB in tubular morphogenesis of human microvascular endothelial cells by oxidative stress." Mol.Cell.Biol.16巻. 4231-4239 (1996)

Shono, T.、Ono 和 Matsushima, K. 等人：“转录因子 NF-κB 通过氧化应激参与人微血管内皮细胞的管状形态发生”，Mol.Cell.Biol.Vol.16。 - 4239 (1996)

Tsuji, H., Harada, A., Mukaida, N., Nakanuma, Y., Bluethmann, H., Kaneko, s., Yamakawa, K., Nakamura, S.I., Kobayashi, K.I., and Matsushima, K.: "Essential requirement of TNF-TNFR but not FasL-Fas system for intrahepatic granuloma formation and hepatocell

Tsuji, H.、Harada, A.、Mukaida, N.、Nakanum, Y.、Bluethmann, H.、Kaneko, s.、Yamakawa, K.、Nakamura, S.I.、Kobayashi, K.I. 和 Matsushima, K.：“

Shono, T., et al.: "Involvement of the transcription factor NF-kB in tubular morphogenesis of human microvascular endothelial cells by oxidative stress." Mol.Cell.Biol.16. 4231-4239 (1996)

Shono, T. 等人：“转录因子 NF-kB 通过氧化应激参与人微血管内皮细胞的管状形态发生。”