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

败血性休克仍然是与高死亡率有关的严重疾病。我们研究了抗CD18或抗中细胞粘附分子1（1CAM-1）对小鼠中高剂量的脂多糖（LPS）诱导的急性致死性的影响。抗CD18或抗ICAM-1抗体的添加可阻止急性致死性。 LPS的体内作用需要白细胞与内皮通过粘附分子相互作用。接下来，我们检查了配体对L-和p-选择蛋白（硫化物）对内毒素休克的影响。用硫化物预处理可预防急性致死性和低血压，并降低血清TNF-α水平的升高。这些结果表明，选择蛋白在会议上与白细胞对LPS的反应性有关，硫化物干扰了细胞内信号传导途径，这会导致TNF-Alpha Gene激活。我们假设内毒素的体内作用需要Codinati与codinati相互作用……与leukoukococytes的互动相互作用。这些相互作用最终导致白细胞沿着静脉壁滚动，然后是牢固的附着和随后的白细胞迁移。 Hence, new molecules which inhibit interaction between leukocytes and the endothelium, thereby preventing subsequent leukocyte-mediated tissue injury and Inframmation, 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高血压。在这些模型中，抗MCAF/MCP-1抗体可防止疾病的严重程度。在肾小球肾炎模型中，抗体的施用可预防后期肾小球的蛋白尿和纤维化，在肺动脉高压模型中，抗体治疗阻止了肺中巨噬细胞的浸润，并导致肺中动脉增厚的抑制。这些结果表明，MCAF/MCP-1在慢性感染的发病机理中扮演角色。较少的

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)

Mukaida,N.,Ishikawa,Y.,and Matsushima,K.et al.: "Novel insight into molecular mechanism of endotoxin shock." J.Leukocyte Biol.59巻. 145-151 (1996)

Mukaida, N.、Ishikawa, Y. 和 Matsushima, K. 等人：“对内毒素休克分子机制的新见解。” J. Leukcyto Biol。 59. 145-151 (1996)

Yokoi,K.,Mukaida,N.,and Matsushima,K.et al.: "Prevention of endotoxin-induced acute respiratory distress syndrome(ARDS)-like lung injury in rabbits by a monoclonal antibody to IL-8." Lab.Invest.(印刷中).

Yokoi, K.、Mukaida, N. 和 Matsushima, K. 等人：“通过 IL-8 单克隆抗体预防兔子内毒素诱导的急性呼吸窘迫综合征 (ARDS) 样肺损伤”。投资。（新闻中）。