The Role and Regulation of TIMP-1 in Lung Inflammation

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DESCRIPTION (provided by applicant): Idiopathic Pulmonary Fibrosis (IPF) is a lethal pulmonary disorder characterized by persistent inflammation in response to injury. The accumulation of inflammatory cells in the injured lung is accomplished, in part, through a dynamic interaction between matrix metalloproteinases (MMP) and their inhibitors. Expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) is markedly elevated in the lungs of patients with inflammatory lung diseases. Increased secretion of TIMP-1 may function to regulate the inflammatory response to lung injury. In this proposal we will use the well established bleomycin lung injury model to examine the role and regulation of TIMP-1 in the neutrophilic response of the injured lung. Our studies demonstrate a marked and durable increase in TIMP-1 expression by inflammatory leukocytes and lung mesenchymal cells in the bleomycin injured lung. Using TIMP-1 null mutation mice, we find that TIMP-1 deficiency provokes enhanced neutrophil accumulation in the injured lungs. Our work in progress indicates that activation of the cell surface molecule CD4O on cultured lung fibroblasts selectively induces TIMP-1 production that is post-transcriptionally regulated. Aim 1 is to characterize the role of TIMP-1 in neutrophil emigration from the vascular to the alveolar compartments of the injured lung. Studies are designed using mice chimeric for TIMP-1 deficiency in either hematopoietic or lung structural cells to define the contribution of inflammatory and structural cell-derived TIMP-1 to governing neutrophil emigration. Chimeric mice that possess both TIMP-1 deficient and wild type neutrophils will be constructed to evaluate the role of neutrophil-derived TIMP-1 in modulating neutrophil emigration in vivo. Studies are proposed to compare the expression profiles of inflammatory response genes of bleomycin injured TIMP-1 deficient and wild type lungs by DNA microarray strategies. Aim 2 is to characterize the molecular mechanisms of CD4O mediated TIMP-1 and MMP expression in lung fibroblasts. Studies are proposed to define if CD4O induces TIMP-1 translation by usage of alternative 5' transcription start sites, increased transcript translocation or increased translational efficiency.