Acute alcohol-induced liver injury

Abstract

Alcohol consumption is customary in most cultures and alcohol abuse is common worldwide. For example, more than 50% of Americans consume alcohol, with an estimated 23.1% of Americans participating in heavy and/or binge drinking at least once a month. A safe and effective therapy for alcoholic liver disease (ALD) in humans is still elusive, despite significant advances in our understanding of how the disease is initiated and progresses. It is now clear that acute alcohol binges not only can be acutely toxic to the liver, but also can contribute to the chronicity of ALD. Potential mechanisms by which acute alcohol causes damage include steatosis, dysregulated immunity and inflammation, and altered gut permeability. Recent interest in modeling acute alcohol exposure has yielded new insights into potential mechanisms of acute injury, which also may well be relevant for chronic ALD. Recent work by this group on the role of PAI-1 and fibrin metabolism in mediating acute alcohol-induced liver damage serve as an example of possible new targets that may be useful for alcohol abuse, be it acute or chronic.

Keywords: acute; alcohol; hepatic; inflammation; steatosis.

Figure 1

Effects of LPS and ethanol on PAI-1 and fibrinolysis. Activation of the coagulation cascade by LPS via thrombin results in accumulation of cross-linked fibrin. Cross-linked fibrin is degraded by plasmin. PAI-1 blocks fibrinolysis by inhibiting the plasminogen activators uPA and tPA and therefore the activation of plasmin. Both ethanol and LPS can modulate signaling downstream of the coagulation cascade, increasing fibrin deposition. Ethanol may also blunt fibrin degradation by altering signaling downstream of TNFα. LPS can have similar effects on fibrinolysis by stimulating release of TNFα.

Figure 2

Chronic ethanol increases hepatic fibrin(ogen) deposition. Representative photomicrographs (40×) depicting immunofluorescent detection of fibrin(ogen) ECM are shown. Liver tissue is from mice fed either control diet or enteral ethanol diet for 4 weeks.

Figure 3

Inhibition of Integrin α_vβ₃ protects against enhanced LPS-induced liver injury caused by ethanol pre-exposure. Representative photomicrographs (100×; insets 400×) of hematoxylin and eosin staining are shown in upper panel. Circulating ALT levels and neutrophil migration (determined by CAE staining) are in the lower left and right panels, respectively. Animals were exposed to alcohol (6 g/kg i.g.) for 3 days, followed by LPS administration (10 mg/kg; i.p) 24 h after last dose of ethanol and were sacrificed 24 h after ethanol administration. Some animals received CycloRGDfV (3 mg/kg i.p.) 1 h prior to LPS.