Acute Renal Failure (ARF) occurs late in the course and is a major cause of death in patients with acute edematous lung injury (ARDS). The mechanism by which the kidney is damaged in ARDS in unknown. However, the usual causes of ARF (for example, hypotension, hypovolemia or aminoglycoside) do not adequately account for ARF. Alternative mechanisms need to be considered. Endotoxin (ETX) and cytokines, which are increased in the blood of patients with ARDS, are important mediators of cell injury. The prime target of ETX/cytokine attack are endothelial cells. Recent evidence suggests that the endothelium may be important modulator of glomerular and tubular function. Moreover, endothelial injury occurs in both ischemia/reperfusion and neutrophil mediated ARF. The present Hypothesis is that compared to the lung, the kidney is relatively resistant to ETX, cytokines, and neutrophils unless a preceding or superimposed ischemia/reperfusion insult has also occurred. Renal endothelial control of glomerular and tubular function is altered in ARDS. This defect in endothelial regulation of target function results in the initiation and maintenance of ARD. No single mechanism adequately accounts for endothelial injury. Rather, it is a combination of extra- and intra-renal factors which interact to cause endothelial injury. These include circulating factors such as ETX, cytokines and neutrophils as well as intra-renal events such a as ischemia/reperfusion.
The Specific Aims are 1) to determine effects of endothelial cell activation on mesangial cell and tubular epithelial cell function; 2) to determine whether endothelial cell injury modifies endothelial cell function; 3) to determine consequences of endothelial cell injury on glomerular and tubular cell function; and 4) to work with other projects to compare kidneys to lungs with regard to mechanisms of organ injury as well as responses to pharmacological interventions (IL, receptor antagonist, Zileuton, SOD, Lip-PGE). The Methods to be used include isolated kidney perfusion as well as co- incubations of endothelial cells with mesangial cells, proximal epithelial cells or inner medullary collecting duct cell. This co- incubation technique allows cell-cell interaction to be determined as well as for the manipulation of one cell type but not the other. Endothelial cells will be stimulated with known agonists and target cell functions under endothelial control will be identified. Models of endothelial cell injury will be developed and the effect of endothelial injury on endothelial function and endothelial control of target function will be ascertained. Target cell functions to be measured include cell viability, endothelia production, endothelia receptor expression, PLC, cAMP, CGMP and sodium transport. The Significance of these studies is t improve understanding of mechanisms of kidney injury in ARDS. This new information may be relevant to the design of therapeutic modalities to prevent ARF in ARDS or sepsis. These would include anti-ETX or anti-cytokine antibodies.
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