Our application is focused on the concern that purification and protein modification of stroma free hemoglobin (SFH) will not prevent toxicity in animals or humans. We will examine the hypothesis that SFH will cause prolonged systemic and intrarenal vasoconstriction persisting after the oxyhemoglobin is metabolized. We also will examine the hypothesis that both unmodified and modified preparations of SFH have the potential to cause acute renal failure (ARF) in two distinct settings: a. We hypothesize that SFH will exacerbate renal injury when administered shortly after established renal failure has been caused by a period of renal ischemia. b. We hypothesize that the SFH will cause """"""""de novo"""""""" ARF (in the absence of established renal injury) when administered in large, """"""""therapeutic"""""""" doses following hemorrhagic shock.
Our specific aims are: 1. To examine and compare the mechanisms of vasoconstriction induced by unmodified and modified SFH. We will examine the mechanism by which oxyhemoglobin inhibits nitric oxide mediated vasorelaxation to determine whether protein modification is likely to reduce this cause of vasoconstriction associated with unmodified SFH We will examine the role of endothelin release in SFH-associated vasoconstriction. 2. To test the hypothesis that SFH will induce neutrophil mediated endothelial injury. We will examine the effects of unmodified and modified forms of SFH and its metabolite hemin on neutrophil-endothelial cell adhesion and neutrophil-induced endothelial injury. The pathogenetic mechanisms involved in the SFH induced neutrophil-adhesion interactions will be elucidated. 3. To examine and compare the extent to which unmodified and modified SFH exacerbates underlying established ischemic renal injury. 4. To examine the extent to which unmodified and modified SFH cause de novo ARF after the administration of large amounts of SFH to hypovolemic animals. We will examine our hypothesis that renal failure will be induced days after the administration of SFH to hypotensive rats resulting from the combined effects of a) prolonged intrarenal vasoconstriction b) the accumulation of toxic metabolites (hemin and free iron) in the renal parenchyma and c) neutrophil-induced endothelial injury.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-S (M1))
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Boston Medical Center
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Lieberthal, Wilfred; Fuhro, Robert; Alam, Hasan et al. (2002) Comparison of the effects of a 50% exchange-transfusion with albumin, hetastarch, and modified hemoglobin solutions. Shock 17:61-9
Bergin, E; Levine, J S; Koh, J S et al. (2000) Mouse proximal tubular cell-cell adhesion inhibits apoptosis by a cadherin-dependent mechanism. Am J Physiol Renal Physiol 278:F758-68
Lieberthal, W; Fuhro, R; Freedman, J E et al. (1999) O-raffinose cross-linking markedly reduces systemic and renal vasoconstrictor effects of unmodified human hemoglobin. J Pharmacol Exp Ther 288:1278-87
Iglesias, J; Abernethy, V E; Wang, Z et al. (1999) Albumin is a major serum survival factor for renal tubular cells and macrophages through scavenging of ROS. Am J Physiol 277:F711-22
Zoeller, R A; Lake, A C; Nagan, N et al. (1999) Plasmalogens as endogenous antioxidants: somatic cell mutants reveal the importance of the vinyl ether. Biochem J 338 ( Pt 3):769-76
Lieberthal, W; Menza, S A; Levine, J S (1998) Graded ATP depletion can cause necrosis or apoptosis of cultured mouse proximal tubular cells. Am J Physiol 274:F315-27
Koh, J S; Lieberthal, W; Heydrick, S et al. (1998) Lysophosphatidic acid is a major serum noncytokine survival factor for murine macrophages which acts via the phosphatidylinositol 3-kinase signaling pathway. J Clin Invest 102:716-27
Lieberthal, W; Triaca, V; Koh, J S et al. (1998) Role of superoxide in apoptosis induced by growth factor withdrawal. Am J Physiol 275:F691-702
Lieberthal, W; Koh, J S; Levine, J S (1998) Necrosis and apoptosis in acute renal failure. Semin Nephrol 18:505-18
Lieberthal, W; McKenney, J B; Kiefer, C R et al. (1997) Beta1 integrin-mediated adhesion between renal tubular cells after anoxic injury. J Am Soc Nephrol 8:175-83

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