Acute renal failure remains a significant contributor to morbidity and mortality in patients with multi-system disease, with a 54% mortality rate reported in patients under 30 years of age. Acute renal failure afflicts patients of all ages, including 8-23% of newborns admitted to the neonatal intensive care unit. Care for patients with acute renal failure remains supportive without specific interventions available to speed restitution of renal function and morbidity and mortality statistics have not improved over the past two decades. Ischemia reperfusion injury (IRI) plays a major pathogenic role in acute renal failure resulting from a wide range of etiologies. The hypothesis of the present application is that the inflammatory response, which involves complex interactions between leukocytes and resident tissue cells, plays an important contributory role in renal (IRI) both in the acute phase of injury and in the subsequent healing phase. Published studies from other laboratories relevant to this hypothesis have providing conflicting results. This hypothesis will be approached using a murine model of renal IRI.
Specific Aim 1 will define this model in terms of the time course for accumulation and tissue distribution of inflammatory neutrophils, macrophages and lymphocytes, areas of tissue injury, and biochemical measures of tissue inflammation and organ dysfunction. These studies will focus on local (renal effects) of reperfusion as well as remote systemic effects (plasma, lung and liver). The pathogenic significance of sequestered neutrophils will be investigated in neutropenic animals.
Aim 2 will determine the expression of E-Selectin and P-Selectin in kidney, lung and liver in wild-type mice, and will determine the potential contribution of the Selectin family of cell adhesion molecules (CAMs) in the kidney reperfusion syndrome in mice selectively deficient in each member of the Selectin family.
Aim 3 will determine the specific sites of augmented expression of CD54 (an important ligand for CD18 integrins), and will assess the contributions of CD18 integrins in the kidney reperfusion syndrome using blocking monoclonal antibodies and mice selectively deficient in each member of this family of CAMs.
