ABROGATION OF OBLITERATIVE AIRWAY DISEASE IN MURINE TRACHEAL ALLOGRAFTS BY INHIBITION OF MATRIX METALLOPROTEINASES-2 AND -9.

1.1
#8
ABROGATION OF OBLITERATIVE AIRWAY DISEASE IN MURINE TRACHEAL ALLOGRAFTS BY INHIBITION OF MATRIX METALLOPROTEINASES-2 AND -9.
Felix G. Fernandez , Lacey G. Campbell , Chan Chen , Robert M. Senior , Shigeyoshi Itohara , T. Mohanakumar and Andres Jaramillo . St. Louis MO, Washington University School of Medicine, Department of Surgery ; St. Louis MO, Washington University School of Medicine, Department of Cell Biology & Physiology and Wako Japan, Brain Science Institute .

Introduction: Obliterative airway disease (OAD) development after heterotopic tracheal transplantation in mice is a suitable model for the study of bronchiolitis obliterans syndrome (BOS, chronic lung allograft rejection). The goal of this study was to determine whether matrix metalloproteinase (MMP)-2 and MMP-9 play a role in the pathogenesis of OAD.
Methods: BALB/c tracheal allografts were transplanted into MMP-2-/- (C57BL/6) and MMP-9-/- (129/SvEv) mice. Then, OAD development and intra-graft levels of MMP-2 and MMP-9 mRNA and enzymatic activities were determined at 20 and 30 days after transplantation. Proliferative responses (MLR) were determined in allograft recipients after 20 days.
Results: Allografts transplanted into C57BL/6 and 129/SvEv mice showed fibrotic obliteration, inflammatory infiltrates, and loss of the epithelium by day 30. Rejected allografts revealed significant up-regulation of MMP-2 and, to a lesser extent, MMP-9. In contrast, allografts transplanted into MMP-2-/- and MMP-9-/- mice did not show any evidence of OAD. In addition, treatment of C57BL/6 recipients with an inhibitor of MMP enzymatic activity, doxycycline, inhibited OAD lesions in the allografts. Interestingly, MMP-2-/- recipients showed significantly higher proliferative alloresponse as compared to C57BL/6 recipients. This was not accompanied by a significant up-regulation of either IL-4 or IFN-γ production. Parallel experiments in human patients showed a significant up-regulation of MMP-2 but not MMP-9 during acute lung allograft rejection (a significant risk factor for BOS).
Conclusion: These data indicate that MMP-2 and MMP-9 play important roles in the pathogenesis of OAD.