MECHANISMS OF POST BONE MARROW TRANSPLANTATION LUNG INJ

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The idiopathic pneumonia syndrome (LPs), a form of diffuse lung Injury not associated with a definable Infectious etiology, affects about one In six patients undergoing bone marrow transplantation (BMT) with a mortality in excess of 70%. These patients have frequently been excluded from other studies of acute lung injury and have not been subjected to recently developed prospective analyses of patterns of organ failure and reversal. The foundation of our studies will be the development of a large clinical database and specimen bank in patients undergoing BMT to allow better risk stratification for the development of IPS and multiple organ failure. Although the mechanisms of lung injury in such patients are likely heterogeneous, we propose that the processes of cellular activation/damage and in vivo lipid peroxidation occurring during the intense conditioning regimens prior to BMT predisposes patients for the subsequent development of organ injury. We propose to monitor these processes in patients undergoing BMT by employing gas chromatography/mass spectrometry to precisely quantify enzymatic metabolites of eicosanoid mediators In plasma, urine and bronchoalveolar lavage fluid as indices of in vivo cell activation. We will assess in vivo oxidant stress by measuring a recently described class of compounds, the isoprostanes, that derive from free radical-mediated peroxidation of arachidonic acid containing membrane phospholipids. We will concomitantly assess antioxidant defense by measuring reduced and oxidized glutathione. About half of the patients, those undergoing autologous BMT, will receive pharmacological doses of dimethylsulfoxide (DMSO), an agent that acts as a free radical scavenger and can suppress cytokine gene expression in whole blood. We hypothesize that DMSO, by suppressing donor cell activation ex vivo and decreasing oxidant stress in vivo, confers protection to autologous BMT recipients. Biochemical data, including measurement of IL-8 and TNF-alpha from these patients, will be compared with those undergoing allogeneic transplants. Finally, we propose to examine the effects of conditioning radiation and chemotherapy and marrow engraftment on the regulation of the synthesis of chemotactic lipids and cytokines in alveolar macrophages by examining their function ex vivo. These studies, combining clinical and biochemical information, will provide the scientific data to guide development of pharmacological strategies aimed at preventing and treating lung injury after bone marrow transplantation.