Inhibition of obliterative airway disease development in murine tracheal allografts by matrix metalloproteinase-9 deficiency.
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.
Fernández
Félix G
FG
Department of Surgery, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Campbell
Lacey G
LG
Liu
Wei
W
Shipley
J Michael
JM
Itohara
Shigeyoshi
S
Patterson
G Alexander
GA
Senior
Robert M
RM
Mohanakumar
T
T
Jaramillo
Andrés
A
D000402:Airway Obstruction / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D001989:Bronchiolitis Obliterans / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D004318:Doxycycline / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000172:deficiency / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013997:Time Factors; D014132:Trachea / Q000201:enzymology / Q000276:immunology / Q000637:transplantation*; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline