The objective of this project is to improve the survival of marrow transplant patients reducing the incidence and severity of multiorgan failure which follows cytoreductive therapy. PROJECT A is a series of prospective physiologic studies in patients at risk for liver, renal and cardiopulmonary failure in which the following will be addressed: 1) the role of cytokines, coagulant proteins, and endothelins in liver injury (venocclusive disease), 2) mechanisms responsible for renal sodium retention following obstruction of liver blood flow, 3) the etiology of renal failure and the role of endothelins, prostaglandins, and cytokines in producing renal vasoconstriction, and 4) the effects of cytoreductive therapy on the lungs and the role of cytokines in non-infectious pneumonia. PROJECT B includes clinical trials of pharmacologic agents for prophylaxis and treatment of liver, renal and pulmonary failures in transplant patients. The major thrust is modulation of inflammatory mediators with pentoxifylline and the aminosteroid U74500A, alone or in combination with other modalities such as GM-CSF. Studies include: 1) randomized, placebo- controlled trials of oral pentoxifylline for renal insufficiency and intravenous pentoxifylline for non-infectious pneumonia, 2) a pilot study of the aminosteroid U75400A for pneumonia, 3) prophylactic study of oral pentoxifylline to prevent or ameliorate organ toxicity, and 4) use of other modalities such as prostaglandin E1 and tissue plasminogen activator to prevent and treat venocclusive disease of the liver. PROJECT C includes in vitro experiments which will characterize potentially useful agents for preventing tissue injury mediated by inflammatory cytokines. Different cell culture systems will be used to study: 1) the effects of pentoxifylline and its metabolites and other agents which down regulate TNFalpha (such as ciprofloxacin and dexamethasone) and the interactions of these drugs with GM-CSF, 2) the effect of pentoxifylline on TNF signal transduction, and 3) the effect of pentoxifylline on T-cell activation. These in vitro experiments are preliminary to phase I studies of these drugs in human marrow graft recipients.
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