Inhibition of obliterative airway disease development in murine tracheal allografts by matrix metalloproteinase-9 deficiency

Félix G. Fernández, Lacey G. Campbell, Wei Liu, J. Michael Shipley, Shigeyoshi Itohara, G. Alexander Patterson, Robert M. Senior, T. Mohanakumar, Andres Jaramillo

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39 Scopus citations

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.

Original languageEnglish
Pages (from-to)671-683
Number of pages13
JournalAmerican Journal of Transplantation
Volume5
Issue number4 I
DOIs
StatePublished - Apr 2005

Keywords

  • Bronchiolitis obliterans syndrome
  • Cytokines
  • MMP-2
  • MMP-9
  • Obliterative airway disease
  • T cells

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