Tissue Inhibitor of Metalloproteinase-1 Moderates Airway Re-Epithelialization by Regulating Matrilysin Activity

Abstract

Obliterative bronchiolitis (OB) is the histopathological finding in chronic lung allograft rejection. Mounting evidence suggests that epithelial damage drives the development of airway fibrosis in OB. Tissue inhibitor of metalloproteinase (TIMP)-1 expression increases in lung allografts and is associated with the onset of allograft rejection. Furthermore, in a mouse model of OB, airway obliteration is reduced in TIMP-1-deficient mice. Matrilysin (matrix metallproteinase-7) is essential for airway epithelial repair and is required for the re-epithelialization of airway wounds by facilitating cell migration; therefore, the goal of this study was to determine whether TIMP-1 inhibits re-epithelialization through matrilysin. We found that TIMP-1 and matrilysin co-localized in the epithelium of human lungs with OB and both co-localized and co-immunoprecipitated in wounded primary airway epithelial cultures. TIMP-1-deficient cultures migrated faster, and epithelial cells spread to a greater extent compared with wild-type cultures. TIMP-1 also inhibited matrilysin-mediated cell migration and spreading in vitro. In vivo, TIMP-1 deficiency enhanced airway re-epithelialization after naphthalene injury. Furthermore, TIMP-1 and matrilysin co-localized in airway epithelial cells adjacent to the wound edge. Our data demonstrate that TIMP-1 interacts with matrix metalloproteinases and regulates matrilysin activity during airway epithelial repair. Furthermore, we speculate that TIMP-1 overexpression restricts airway re-epithelialization by inhibiting matrilysin activity, contributing to a stereotypic injury response that promotes airway fibrosis via bronchiole airway epithelial damage and obliteration. Bronchiolitis obliterans syndrome (BOS) is the manifestation of chronic lung rejection and limits the 5-year survival after lung transplant to less than 50%.1 In comparison, transplantations of other solid organs, such as the heart, pancreas, liver, and kidneys, have 5-year survival rates exceeding 70%.2 Obliterative bronchiolitis (OB) is the histopathological equivalent of BOS and is characterized by small airway fibrosis that contributes to progressive respiratory failure and death.3 Although the pathogenesis of OB is poorly understood, evidence suggests that the primary immunological target in the lung allograft is the airway epithelium. 4 -7 Moreover, aberrant airway re-epithelialization is apparently sufficient for the progression of fibrosis during the allograft rejection process. -13The airway epithelium is an important barrier in the innate defenses of the lung.14 After lung transplantation, persistent allo-dependent (eg, acute rejection) and alloindependent (eg, infection, ischemia) pressures on the airway epithelium necessitate rapid re-epithelialization to prevent further damage that can contribute to inflammation and fibrosis.3 Disturbances in the epithelial barrier are quickly repaired through coordinated processes by which epithelial cells bordering the injury quickly spread over the denuded basement membrane. [15][...

Obliterative Airway Remodeling

“…TIMP-2 inhibits MMPs and, thus, increases collagen accumulation, decreases reepithelialization of the airways, and facilitates epithelial-mesenchymal transition. 26,27 Although the present study found that BMP-2 was elevated in remodeling of the bronchioli, others have previously demonstrated its involvement in smooth muscle cell proliferation in pulmonary hypertension.…”

Matrilysin (Matrix Metalloproteinase-7) Regulates Anti-Inflammatory and Antifibrotic Pulmonary Dendritic Cells That Express CD103 (αEβ7-Integrin)

“…Wounds in air-liquid interface cultures of Mmp7 Ϫ/Ϫ cells close more slowly than in wild-type cultures, 39 recapitulating the defects in airway re-epithelialization observed in Mmp7 Ϫ/Ϫ mice in vivo. 9,10 Wild-type and Mmp7…”

3-D nasal cultures: Systems toxicological assessment of a candidate modified-risk tobacco product

“…Normally, TIMP1 is constitutively expressed at low levels in airway epithelium (Chen et al, 2008). In various wound healing and disease models, the expression of TIMP1 in epithelial cells increases during regeneration (Chen et al, 2008). Moreover, the role of VEGFA in tissue repair is linked to increased compensatory growth during repair processes (Marwick et al, 2006).…”

“…Normally, TIMP1 is constitutively expressed at low levels in airway epithelium (Chen et al, 2008). In various wound healing and disease models, the expression of TIMP1 in epithelial cells increases during regeneration (Chen et al, 2008).…”