IPS is a rapidly progressive and often lethal complication of allogeneic bone marrow transplants (BMT) that somehow results from a combination of x- irradiation therapy, chemotherapy, and BMT rescue leading to a prominent and destructive inflammatory response. MMPs are a family of enzymes that as a group can degrade essentially all components of the extracellular matrix. They also modulate inflammation by activating latent tumor necrosis factor-alpha (TNFalpha) and perhaps other cytokines. MMPs are normally expressed only during periods of active remodeling, such as tissue involution and would repair, however, abnormal proteinase expression during exuberant or chronic inflammation leads to unwanted and excessive tissue destruction. Their preliminary data suggest that a unique and prominent pattern of MMPs is expressed in lung from patients with IPS, and they propose that these proteinases contribute significantly to uncontrolled inflammation and tissue destruction resulting in breathlessness, poor gas exchange, and diffuse pulmonary infiltrates characteristics of IPS. In addition, they hypothesize and present evidence that the marked influx of activated T lymphocytes and the interaction of these cells with macrophages and resident fibroblasts is a critical event leading to induction of MMPs and cytokines, notably latent TNFalpha, which interact to maintain and likely aggravate the inflammatory response leading to continued tissue destruction. To address these mechanistically linked hypotheses, they propose to investigate the following specific aims: 1) to delineate the temporal and spatial patterns and identify the cell sources of MMP expression in lungs of patients with IPS using immunohistochemistry and in situ hybridization techniques with lung samples obtained at different times post-BMT; 2) characterize the induction of MMPs by activated T lymphocytes and T lymphocytes from patients with IPS; 3) determine which MMP(s) can activate membrane-bound pro-TNFalpha and which enzyme performs this function in vivo; and 4) develop a murine model of post- BMT IPS and use MMP hydroxymate inhibitors and knock-out mice to determine directly the contribution of specific MMPs to the development of IPS.
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