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ABSTRACT: Immunity to type V collagen [col(V)] contributes to lung transplant rejection. Matrix metalloproteases (MMPs), which are induced by transplant-related ischemia-reperfusion injury (IRI), could expose col(V) and regulate local IRI-induced inflammation.
To test the hypothesis that MMPs induce col(V) exposure and inflammation, Wistar-Kyoto rats were treated with the MMP inhibitor, COL-3, before inducing lung IRI without transplantation, and in parallel studies, Wistar-Kyoto lung donor and recipients were treated with COL-3 pre- and postisograft lung transplantation.
Ischemia-reperfusion injury induced growth-related oncogene/CINC-1-dependent neutrophil influx, and up-regulated tumor necrosis factor-alpha. MMP2 and MMP9, induced at 4 and 24 hr after IRI, respectively, were associated with detection of antigenic col(V) in bronchoalveolar lavage and lung interstitium because of MMP-mediated matrix degradation. MMP-inhibitor treatment significantly reduced polymorphonuclear leukocytes, growth-related oncogene/CINC-1, and tumor necrosis factor-alpha; abrogated MMP-9 expression; and resulted in lower levels of antigenic col(V) in bronchoalveolar lavage. In the lung transplant model, inhibiting MMPs in the donor before lung harvest and in the recipient after lung transplantation resulted in improved oxygenation and diminished polymorphonuclear leukocyte influx into the isograft.
MMP inhibition may be a potential therapy to prevent release of antigenic col(V) and ameliorate IRI in the transplant recipient.
Transplantation 03/2008; 85(3):417-26. · 4.00 Impact Factor
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Shigetoshi Yoshida,
Takekazu Iwata,
Masako Chiyo,
Gerald N Smith,
Brian H Foresman, Elizabeth A Mickler,
Kathleen M Heidler,
Oscar W Cummings,
Takehiko Fujisawa,
David D Brand,
Andrew Baker,
David S Wilkes
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ABSTRACT: Upregulation of matrix metalloproteinases (MMPs) has been associated with chronic lung allograft rejection known as bronchiolitis obliterans syndrome. It has been suggested that MMP inhibition could prevent the rejection response. However, the effect of MMP inhibition on lung allograft rejection has not been reported.
Utilizing a rat model of lung transplantation, tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) were overexpressed by gene therapy in F344 rat lung allografts prior to transplantation into WKY recipient rats. Separately, WKY rats that received F344 lung allografts were treated systemically with COL-3, a global MMP inhibitor.
TIMP-1 and TIMP-2 had differential effects on delayed type hypersensitivity (DTH) responses to donor antigens and type V collagen, an autoantigen involved in the rejection response. Neither TIMP-1 or TIMP-2 affected the onset of rejection pathology. COL-3 suppressed DTH responses to donor antigens and type V collagen, abrogated local production of tumor necrosis factor-alpha, and interleukin-1beta. Although it did not prevent rejection pathology, COL-3 (30 mg/kg) induced intragraft B cell hyperplasia suggestive of posttransplant proliferative disorder (PTLD).
These data identify a complex role for MMPs and TIMPs in the immunopathogenesis of lung allograft rejection, and indicate their effects are not limited to matrix remodeling.
Transplantation 04/2007; 83(6):799-808. · 4.00 Impact Factor
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ABSTRACT: To determine if intraarticular (IA) injection of hyaluronan (HA) into the canine knee after anterior cruciate ligament transection (ACLT) alters the progression of osteoarthritis (OA) and the perception of pain in this model.
OA was induced in 30 adult dogs of mixed breed by ACLT. The dogs were divided into 3 groups and given 5 weekly IA injections into the unstable knee during Weeks 1-5 and 13-17. The prophylactic treatment group received HA in the first series and saline during the second series. The therapeutic group received saline in the first series and HA in the second series. The control group received saline during both injection series. The progression of joint damage of OA was evaluated by arthroscopy 12 weeks after ACLT and by gross examination 32 weeks after ACLT. Histologic and biochemical changes of OA were evaluated. Loading of the unstable limb during gait was determined by force-plate analysis before surgery, after each series of injections, and the week before euthanasia.
Arthroscopic examination 12 weeks after ACLT revealed OA changes in the cruciate-deficient knees. Chondropathy scores ranged from 0 to 8 (possible range 0-65). The mean chondropathy score was 2.5 +/- 1.3 (mean +/- SD) for the controls, 2.5 +/- 2.5 for the therapeutic group, and 2.1 +/- 1.3 for the prophylactic group. At the termination of the experiment 32 weeks after ACLT, the gross chondropathy scores were 14.0 +/- 5.2 for controls, 17.6 +/- 6.8 for the therapeutic group, and 13.3 +/- 5.0 for the prophylactic group. There were no significant differences among the means of the gross scores, the histologic scores, or biochemical composition of articular cartilage. The peak vertical ground reaction force (VGRF) generated by the unstable limb was reduced by ~60% after ACLT, and slowly increased to ~75% of the baseline value over the 32 weeks after ACLT. HA injection had no effect on the VGRF or on the pathologic changes of OA.
Intraarticular HA injection did not alter the progression of OA in the cruciate-deficient canine knee or alter the loading of the unstable limb.
The Journal of Rheumatology 03/2005; 32(2):325-34. · 3.69 Impact Factor
