Ischemia/Reperfusion Injury
Injury induced by ischemia and reperfusion results from (1) oxygen
deprivation during the ischemic period and (2) cytotoxic events during reperfusion.
[240]
[248]
[249]
[250]
Following brief periods of ischemia, reperfusion
is the main cause of cellular injury. Reperfusion stimulates the production of highly
reactive molecules (superoxide, hydrogen peroxide, hydroxyl radicals), which can
induce apoptosis or necrosis. As the ischemic period lengthens, oxygen deprivation
causes an increasing proportion of the ischemia/reperfusion injury.
Role of Xanthine Dehydrogenase/Xanthine Oxidase
The highest specific activities of xanthine dehydrogenase/xanthine
oxidase (XDH/XO) in humans occur in the liver and intestines.[251]
In healthy tissue, XDH catalyzes the rate-limiting step in nucleic acid degradation.
XDH uses nicotinamide adenine dinucleotide (rather than O2
) as the electron
acceptor and therefore does not produce oxygen radicals. Ischemic conditions, however,
transform XDH to XO, which is a significant generator of reactive radicals. During
reperfusion, XO-derived oxidants stimulate the production and release of leukotriene
B4
and platelet-activating factor, which promote neutrophil adherence
and migration. These neutrophils can damage the microvascular circulation by releasing
proteases and physically disrupting the endothelial barrier. Pretreatment with allopurinol,
an inhibitor of xanthine oxidase, markedly decreases reperfusion-induced increases
in microvascular permeability and epithelial cell necrosis.[252]
[253]
A pathologically important result of hepatocellular damage—from
ischemia, orthotopic transplantation, acute hepatitis, cholestasis—is the release
of XO and other hepatocellular substances into the central circulation.[238]
[242]
[254]
[255]
[256]
[257]
[258]
[259]
Circulating XO binds to vascular endothelial
cells in various organs.[251]
[260]
[261]
[262]
The
endothelial cells produce superoxide, which reacts with nitric oxide (NO·)
to form peroxynitrite (OONO-
).[239]
[263]
Peroxynitrite is a reactive molecule that can further damage hepatic and extrahepatic
tissues. Experimental data suggest that various interventions may confer protection
against reperfusion injury, including (1) antioxidants; (2) oxygen radical scavengers,
such as superoxide dismutase and dimethyl sulfoxide; (3) inhibitors of XO; and (4)
inhibitors of leukocyte adherence and migration.[253]
[264]
[265]
[266]
Hepatic Injury During Transplantation
PRESERVATION INJURY.
Paradoxically, solutions used to preserve the liver can eventually
make the transplanted liver susceptible to injury. For example, storing livers in
the University of Wisconsin solution for more than 24 hours increases the likelihood
of microcirculatory disturbances, leukocyte and platelet adhesion, and a systemic
inflammatory response after graft implantation. Over time this "preservation" method
exhausts the hepatic supply of antioxidants, contributing to the excessive production
of reactive molecules on reperfusion of the transplanted liver.[252]
The pathogenesis of ischemia and reperfusion injury is complex.
[267]
[268]
[269]
[270]
It involves (1) activated Kupffer cells[271]
[272]
; (2) formation of xanthine oxidase[259]
[273]
; (3) production of reactive oxygen and nitrogen
species, including superoxide, nitric oxide, peroxynitrite, and hydroxyl radicals;
(4) release of proinflammatory cytokines[274]
; and
(5) endothelial cell destruction.[275]
[276]
[277]
[278]
Hypothermic
preservation solutions can induce apoptotic changes in endothelial cells, which may
later cause their destruction. Improvements in graft survival may be achieved by
downregulating Kupffer cells with calcium channel blockers, pentoxifylline, or gadolinium.
Similarly, flushing grafts after storage with Carolina rinse solution (antioxidants,
adenosine, calcium channel blocker, energy substrates, glycine, and pH 6.5) reduces
Kupffer cell activation and endothelial cell killing and improves graft survival.
[279]
