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Tissue Inhibitor of Metalloproteinase-1 Deficiency Abrogates Obliterative Airway Disease after Heterotopic Tracheal Transplantation

Sections of Pulmonary and Critical Care Medicine, Fred Hutchinson Cancer Research Center, and Departments of Medicine and Surgery, University of Washington School of Medicine, Seattle, Washington

Correspondence and requests for reprints should be addressed to David K. Madtes, M.D., Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, D3-190, P.O. Box 19024, Seattle, WA 98109-1024. E-mail: dmadtes{at}fhcrc.org

Obliterative bronchiolitis (OB) is a major cause of allograft dysfunction after lung transplantation and is thought to result from immunologically mediated airway epithelial destruction and luminal fibrosis. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been implicated in the regulation of lung inflammation, airway epithelial repair, and extracellular matrix remodeling and therefore may participate in the pathogenesis of OB. The goals of this study were to determine the expression profiles of MMPs and TIMPs and the role of TIMP-1 in the development of airway obliteration using the murine heterotopic tracheal transplant model of OB. We demonstrate the selective induction of MMP-3, MMP-9, MMP-12, and TIMP-1 in a temporally restricted manner in tracheal allografts compared with isografts. In contrast, the expression of MMP-7, TIMP-2, and TIMP-3 was decreased in allografts relative to isografts during the period of graft rejection. TIMP-1 protein localized to epithelial, mesenchymal, and inflammatory cells in the tracheal grafts in a temporally and spatially restricted manner. Using TIMP-1–deficient mice, we demonstrate that the absence of TIMP-1 in the donor trachea or the allograft recipient reduced luminal obliteration and increased re-epithelialization in the allograft compared with wild-type control at 28 d after transplantation. Our findings provide direct evidence that TIMP-1 contributes to the development of airway fibrosis in the heterotopic tracheal transplant model, and suggest a potential role for this proteinase inhibitor in the pathogenesis of OB in patients with lung transplant.

Key Words: heterotopic tracheal transplant • matrix metalloproteinase • obliterative bronchiolitis • tissue inhibitor of metalloproteinase

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