Idiopathic pneumonia syndrome (IPS) defines a clinical entity characterized by a subacute non-infectious lung injury following autologous bone marrow transplantation (ABMT) related treatment protocols. Successful therapeutic strategies for treating primary breast cancer utilizing induction chemotherapy followed by consolidation chemotherapy and ABMT have been severely limited by the subsequent development of IPS. In this project, they hypothesize that IPS is caused by a relative increase in extracellular oxidant species and a relative decrease of extracellular antioxidant enzymes and nonenzymatic compounds. To test the hypothesis that this major nonenzymatic extracellular antioxidant is depleted in these patients, they will characterize broncho-alveolar lavage (BAL) lung levels of reduced glutathione (GSH). The major extracellular antioxidant enzyme in the lung is extracellular superoxide dismutase (EC-SOD). Its gene expression is markedly down regulated by cytokines such as TNF-alpha and TGF-beta. They will test their hypothesis that the generation of these cytokines in vivo results in decreased EC-SOD expression. This will be accomplished by directly measuring BAL levels of specific cytokines throughout the treatment program and studying these cytokine effects on EC-SOD gene expression using pulmonary cells grown in cell culture, BAL alveolar macrophages, and by in situ hybridization in mouse models of IPS. To further test the critical role of EC-SOD in these processes, they will use both transgenic mice which overexpress EC-SOD in the lung and EC-SOD knock-out mice to specifically probe the role of EC-SOD in the protection from and development of IPS in their mouse model. Previously identified biomarkers which predict pulmonary toxicity (MCP-1, prothrombin fragment Fl.2, D-Dimer, and TGF- beta) will be evaluated for their sensitivity and specificity for predicting the development of IPS. This project has been designed to critically evaluate the role of extracellular oxidants and antioxidants in the development of IPS following high-dose chemotherapy with autologous bone marrow support. Analysis of data generated from this project can be used to identify patients at highest risk for developing pulmonary toxicity and to formulate novel pharmacologic strategies to protect against the development of IPS, thus, potentially allowing for more effective treatment programs for breast cancer patients.
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