Lung transplant ischemia reperfusion injury: metalloprotease inhibition down-regulates exposure of type V collagen, growth-related oncogene-induced neutrophil chemotaxis, and tumor necrosis factor-alpha expression.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
MMP inhibition may be a potential therapy to prevent release of antigenic col(V) and ameliorate IRI in the transplant recipient.
Iwata
Takekazu
T
Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Chiyo
Masako
M
Yoshida
Shigetoshi
S
Smith
Gerald N
GN
Mickler
Elizabeth A
EA
Presson
Robert
R
Fisher
Amanda J
AJ
Brand
David D
DD
Cummings
Oscar W
OW
Wilkes
David S
DS
D000818:Animals; D002634:Chemotaxis, Leukocyte; D024062:Collagen Type V / Q000378:metabolism*; D015536:Down-Regulation; D016040:Lung Transplantation; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology*; D015513:Oncogene Proteins / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D024062:Collagen Type V; D015513:Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D045726:Metalloproteases