) The objective of this proposal is to understand, in a clinical laboratory translational trial, the pathophysiology of lung injury associated with high-dose chemoradiotherapy followed by BMT. The observation that interstitial pneumonia syndrome (IPS) is associated with autologous and allogeneic transplantation suggests that multiple processes act in concert to initiate the process that leads to IPS. We have observed a striking and consistent elevation in serum iron levels and saturation of transferrin in patients undergoing BMT. These data suggest that a temporary state of iron-overload occurs, and that this is accompanied by the generation of iron-catalyzed reactive oxygen species (ROS). We hypothesize that these ROS cause lung damage after BMT either by causing direct damage to lung cells, or by activating an inflammatory cascade that contributes to lung injury. In order to test the hypothesis we propose the following specific aims: (1) To determine, in a clinical trial, if the thiol anti-oxidant/iron chelator captopril can prevent lung injury after high-dose chemotherapy/radiotherapy or chemotherapy alone in patients undergoing bone marrow transplantation (BMT). Measures of lung injury include (a) high-resolution CT-scans, (b) measures of lung function (FEV, FVC, DLCO, pulse oximetry). (2) To establish surrogate markers of oxidant-mediated lung injury in serum and DNA from peripheral blood white cells in patients undergoing BMT. We will measure (a) footprints of oxidant-mediated injury to (1) cellular DNA (8-hydroxyguanosine (8-OHDGI), and (2) cellular membranes and cytoplasm (a) aldehydes, lipid hydroperioxides and thiobarbituric acid reactive substances (TBARS) and (b) inflammatory mediators and growth factors, including TGF-P. Measures of iron will include a)serum free iron, (b) serum iron, (c) transferrin and (d) ferritin samples will be collected at various times during and after BMT. To accomplish these aims we have assembled a multidisciplinary team of investigators with experience in clinical BMT assessment of lung injury, the biology of inflammation and free radical biology. The results obtained from these studies will provide new information on the mechanisms of IPS after BMT and should have important implications for patient, who undergo BMT.
