Molecular analysis of inflammation and immune response

感染性休克仍然是一种严重的疾病，与高死亡率有关。我们研究了抗CD18或抗细胞间黏附分子1(1CAM-1)对单次注射高剂量脂多糖(LPS)所致小鼠急性死亡的影响。加入抗CD18或抗ICAM-1抗体可防止急性死亡。因此，内毒素在体内的作用需要白细胞通过黏附分子与内皮细胞相互作用。接下来，我们研究了L-选择素和P-选择素的配体硫脂对内毒素休克的影响。硫脂预治疗可预防急性死亡和低血压，同时降低血清肿瘤坏死因子-α水平的升高。这些结果表明，选择素在增强白细胞对内毒素的反应性中起重要作用，而硫脂干扰了导致肿瘤坏死因子-α基因激活的细胞内信号通路。我们推测，内毒素的体内作用需要Coodinati…更多的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静脉壁滚动，随后白细胞牢固附着和随后的移行。因此，抑制白细胞与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的新分子，可以成为预防感染性休克的新靶点。另一方面，为了研究MCAF/MCP-1慢性炎症的作用，我们建立了新月体肾炎和野百合碱诱导的肺动脉高压的大鼠模型。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，给予抗体可防止晚期蛋白尿和肾小球纤维化，并抑制肾功能衰竭。在肺动脉高压模型中，抗体治疗阻止了巨噬细胞在肺内的渗透，并抑制了肺内小动脉的增厚。提示MCAF/MCP-1在慢性炎症的发病机制中起重要作用。较少

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