| Research Abstract |
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
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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
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