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Inhibition of Obliterative Airway Disease Development in Murine Tracheal Allografts by Matrix Metalloproteinase‐9 Deficiency
Author(s) -
Fernández Félix G.,
Campbell Lacey G.,
Liu Wei,
Shipley J. Michael,
Itohara Shigeyoshi,
Patterson G. Alexander,
Senior Robert M.,
Mohanakumar T.,
Jaramillo Andrés
Publication year - 2005
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2005.00751.x
Subject(s) - medicine , matrix metalloproteinase , chemokine , transplantation , immunology , lung transplantation , cytokine , copd , lung , respiratory disease , pathology , inflammation
This study was designed to define the roles of matrix metalloproteinase (MMP)‐2 and MMP‐9 in obliterative airway disease (OAD) in heterotopic murine tracheal allografts, considered a suitable animal model for chronic lung allograft rejection. BALB/c tracheal allografts were transplanted into MMP‐2‐deficient (−/−) and MMP‐9−/− mice. Also, wild‐type recipients were treated with doxycycline, a nonspecific MMP inhibitor. After 10, 20 and 30 days, allografts were analyzed for OAD development, intragraft levels of MMP‐2 and MMP‐9 and the frequency and cytokine/chemokine production profile of alloreactive T cells. Allografts transplanted into wild‐type mice developed OAD lesions within 30 days. These allografts revealed significant upregulation of both MMP‐2 and MMP‐9. Allografts transplanted into MMP‐9−/− and doxycycline‐treated recipients did not develop OAD. In contrast, allografts transplanted into MMP‐2−/− mice developed OAD lesions with normal kinetics. Interestingly, MMP‐9−/− recipients showed an enhanced T cell alloreactivity associated with an abnormal profile of cytokine/chemokine production. The enhanced T cell alloreactivity in MMP‐9−/− mice was mediated by enhanced dendritic cell stimulatory capacity as well as enhanced T cell responsive capacity. These results suggest that MMP‐9 plays an important role in the pathogenesis of OAD and may represent a target for the therapeutic intervention of chronic lung allograft rejection.