Oxygen radicals and matrix metalloproteinases mediate reperfusion liver injury.
Many pathological processes involve the breakdown and remodeling of the extracellular matrix, which is mediated by the family of important enzymes known as matrix metalloproteinases (MMPs). One such process is warm ischemia/reperfusion (I/R) injury, the most important cause of dysfunction of liver allografts. We monitored protein expression of MMP-9 by Western blotting in rat liver after I/R. We also monitored changes in total MMP activity in the serum before and after I/R. Ischemia was induced by clamping the common hepatic artery and portal vein for 40 minutes and reperfusing for 90 minutes. Blood samples collected before ischemia and after reperfusion were analyzed for AST, hydroxyl radical, and tumor necrosis factor (TNFalpha). This protocol resulted in a high level of MMP-9 expression in liver tissue. Total MMP activity in serum was also significantly increased. Levels of AST, hydroxyl radicals, and TNF alpha were concomitantly increased. Ilomastat, an MMP inhibitor, attenuated the I/R-induced liver injury. After administration of the oxygen radical scavenger N-acetylcysteine (NAC), total MMP activity was suppressed, and liver injury was again attenuated. These results indicated that reperfusion liver injury induced an increase in MMP-9 protein expression and in serum MMP activity. The protective effects of an MMP inhibitor and NAC indicate that oxygen radical production is involved in MMP expression and liver injury associated with I/R.
Chen
C-F
CF
Division of Gastroenterology, Department of Internal Medicine, Cheng Hsin General Hospital, Ming Chuan University, Taipei, Taiwan.
Leu
F J
FJ
Chen
H I
HI
Wang
D
D
D000111:Acetylcysteine / Q000097:blood; D000818:Animals; D006499:Hepatic Artery; D006861:Hydrogen Peroxide / Q000097:blood*; D007511:Ischemia / Q000097:blood*; D008102:Liver Circulation; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D020782:Matrix Metalloproteinases / Q000097:blood*; D011169:Portal Vein; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9; D000111:Acetylcysteine