Inhibition of Obliterative Airway Disease Development in Murine Tracheal Allografts by Matrix Metalloproteinase-9 Deficiency |
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Authors: | Félix G Fernández Lacey G Campbell Wei Liu J Michael Shipley Shigeyoshi Itohara G Alexander Patterson Robert M Senior T Mohanakumar Andrés Jaramillo |
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Institution: | Departments of Surgery;, Internal Medicine;, Cell Biology &Physiology;and Pathology &Immunology, Washington University School of Medicine, Saint Louis, MO 63110;and Laboratory for Behavioral Genetics, Brain Science Institute, Riken, Saitama 351-0198, Japan |
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Abstract: | 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. |
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Keywords: | Bronchiolitis obliterans syndrome cytokines MMP-2 MMP-9 obliterative airway disease T cells |
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