Infiltration of leukocytes potentiates peritonitis, renal ischemia-reperfusion injury, a major cause of acute renal failure, and other acute inflammatory conditions. Likewise, leukocyte infiltration is a key initiating step during chronic inflammation in lupus nephritis, resulting in progressive deterioration of kidney function, and in various other autoimmune diseases. Studies in experimental models have shown that modulating leukocyte recruitment is beneficial and decreases the severity or the pathogenesis of such diseases in animals. The leukocytic 2 integrin CD11b/CD18 (a.k.a. Mac-1, aMb2) is central to various functions of these cells. Conventional approaches using antibodies and ligand mimics to block binding of CD11b/CD18 to its ligands (anti-adhesion therapy), which showed marked reduction in leukocyte infiltration in animal models, failed in treating inflammatory/autoimmune diseases in several clinical trials. Here, we propose an innovative approach for treating inflammatory disease by activating, not blocking, integrin CD11b/CD18 using small molecules. We propose that CD11b/CD18 activation with small molecules would prevent leukocyte migration to the site of inflammation, a premise that is based on published literature going back 15 years that also provides in vivo support for this hypothesis. However, our approach is novel and is distinguished by our ability to activate integrins using novel small molecule agonists of CD11b/CD18 that can be systemically delivered and are easy to modify and improve upon in the future. The preliminary data presented in this proposal suggests that integrin-specific small molecule mediated activation of CD11b/CD18 reduces leukocyte infiltration and inflammation and can be an effective, pharamacologically useful methodology to treat a variety of inflammatory and autoimmune diseases. We have also made an unexpected discovery that activation of CD11b/CD18 by these compounds suppresses secretion of pro-inflammatory cytokines and other factors, although the nature of intracellular pathways modulating this anti-inflammatory effect is currently not known. This suggests that the novel CD11b/CD18 agonists represent a new class of anti-inflammatory agents that reduce inflammatory injury by decreasing leukocyte migration and by directly suppressing the proinflammatory function of leukocytes. The overall goal of this proposal is to fully characterize the molecular and the cellular basis for the function of our newly discovered CD11b/CD18 agonists in vitro and in vivo and to explore their therapeutic potential in vivo. Our proposed studies would open up new avenues for the development of therapeutically useful anti-inflammatory agents and strategies in the future, including ones that lead to progressive deterioration of kidney function and acute renal failure.
The studies proposed will test the effectiveness of our newly discovered compounds as novel anti- inflammatory agents using various models of human kidney disease. We believe that the proposed studies will also identify novel mechanisms for treating inflammatory diseases in humans.
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