Molecular analysis of inflammation and immune response

感染性休克仍然是一种与高死亡率相关的严重疾病。我们研究了抗 CD18 或抗细胞间粘附分子 1 (1CAM-1) 对单次给予高剂量脂多糖 (LPS) 诱导的小鼠急性致死的影响。添加抗 CD18 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细胞相互作用。接下来，我们检查了 L-和 P-选择素的配体硫脑苷脂对内毒素休克的影响。硫脑苷脂预处理可预防急性死亡和低血压，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 的反应性方面发挥着至关重要的作用，而硫苷脂会干扰导致 TNF-α 基因激活的细胞内信号传导途径。我们假设内毒素的体内作用需要白细胞与内皮细胞的协调相互作用。这些相互作用最终导致白细胞沿着小静脉壁滚动，随后是白细胞的牢固附着和随后的迁移。因此，抑制白细胞与内皮相互作用的新分子，从而阻止随后的白细胞介导的组织损伤和炎症，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小球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 抗体可阻止疾病进展的严重程度。在肾小球肾炎模型中，施用抗体可防止后期蛋白尿和肾小球纤维化，并抑制肾衰竭。在肺动脉高压模型中，抗体治疗阻止了巨噬细胞在肺部的浸润，并抑制了肺部小动脉的增厚。这些结果表明MCAF/MCP-1在慢性炎症的发病机制中发挥着重要作用。较少的

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