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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063994-02
Application #
6621887
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Reynolds, Herbert Y
Project Start
2002-04-01
Project End
2006-02-28
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
2
Fiscal Year
2003
Total Cost
$346,000
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Chen, Peter; McGuire, John K; Hackman, Robert C et al. (2008) Tissue inhibitor of metalloproteinase-1 moderates airway re-epithelialization by regulating matrilysin activity. Am J Pathol 172:1256-70
Wang, Yi; Rosen, Henry; Madtes, David K et al. (2007) Myeloperoxidase inactivates TIMP-1 by oxidizing its N-terminal cysteine residue: an oxidative mechanism for regulating proteolysis during inflammation. J Biol Chem 282:31826-34
Chen, Peter; Farivar, Alexander S; Mulligan, Michael S et al. (2006) Tissue inhibitor of metalloproteinase-1 deficiency abrogates obliterative airway disease after heterotopic tracheal transplantation. Am J Respir Cell Mol Biol 34:464-72
Kim, Kyoung-Hee; Burkhart, Kristin; Chen, Peter et al. (2005) Tissue inhibitor of metalloproteinase-1 deficiency amplifies acute lung injury in bleomycin-exposed mice. Am J Respir Cell Mol Biol 33:271-9
Gharib, Sina A; Luchtel, Daniel L; Madtes, David K et al. (2005) Global gene annotation analysis and transcriptional profiling identify key biological modules in hypoxic pulmonary hypertension. Physiol Genomics 22:14-23