Lung toxicity following high dose chemotherapy (HDC) and bone marrow transplantation (BMT) or hematopoietic stem cell support develops in up to 70% of patients, with the most severe form of toxicity, termed idiopathic pneumonia syndrome (IPS), accounting for up to 40% of non-graft versus host disease related deaths. We have described a lung toxicity syndrome that occurs following HDC and autologous bone marrow transplant (autoBMT) that we termed delayed pulmonary toxicity syndrome (DPTS). DPTS may be an early form of IPS, is a risk factor for increased mortality, and manifests as an interstitial pneumonitis no sooner than 4 to 6 weeks following autoBMT (mean onset 11 weeks). To begin to better understand its pathogenesis, we developed a novel HDCIautoBMT mouse model of lung toxicity that shows remarkable similarity to the human condition. Based on clinical and bronchoalveolar lavage studies of patients undergoing HDC/autoBMT and our mouse model, we hypothesize three specific mechanisms the development of DPTS. First, HDC induces an intense oxidative stress resulting in both lung tissue injury and increases in monocyte chemo attractant protein-1 (MCP-1). Second, in response primarily to MCP-1 (and MIP-1a), pulmonary inflammatory cells are recruited into the lung, which possess antigen presenting cells (APC) features and may further stimulate a T cell lymphocyte response. Finally, fibroblast growth factors, like FGF-2, initiate a lung repair and fibrotic response. We plan to test these hypotheses by utilizing mouse strains that 1) overexpress and under express (knockout) antioxidant enzymes, 2) overexpress MCP-1, and 3) are deficient in CCR2. Additional studies designed to characterize the pulmonary inflammatory cells, determine their activation status, and their ability to stimulate T cells will be performed. Finally, we plan to identify BALF growth factors responsible for the development of restrictive lung. This proposal should provide new insights into the pathophysiology of lung injury following autologous bone marrow transplant and provide the basis for future clinical studies to prevent or treat this serious pulmonary complication.
