Alcoholic liver disease and the potential role of plasminogen activator inhibitor-1 and fibrin metabolism

Abstract

Plasminogen activator inhibitor-1 (PAI-1) is a major player in fibrinolysis due to its classical role of inhibiting plasminogen activators. Although increased fibrinolysis is common in alcoholic cirrhosis, decreased fibrinolysis (driven mostly by elevated levels of PAI-1) is common during the development of alcoholic liver disease (ALD). However, whether or not PAI-1 plays a causal role in the development of early ALD was unclear. Recent studies in experimental models have suggested that PAI-1 may contribute to the development of early (steatosis), intermediate (steatohepatitis) and late (fibrosis) stages of ALD. For example, fatty liver owing to both acute and chronic ethanol was blunted by the genetic inhibition of PAI-1. This effect of targeting PAI-1 appears to be mediated, at least in part, by an increase in very low-density lipoprotein (VLDL) synthesis in the genetic absence of this acute phase protein. Results from a two-hit model employing ethanol and lipopolysaccharide administration suggest that PAI-1 plays a critical role in hepatic inflammation, most likely due to its ability to cause fibrin accumulation, which subsequently sensitizes the liver to ensuing damaging insults. Lastly, the role of PAI-1 in hepatic fibrosis is less clear and appears that PAI-1 may serve a dual role in this pathological change, both protective (enhancing regeneration) and damaging (blocking matrix degradation). In summary, results from these studies suggest that PAI-1 may play multiple roles in the various stages of ALD, both protective and damaging. The latter effect is mediated by its influence on steatosis (i.e. decreasing VLDL synthesis), inflammation (i.e. impairing fibrinolysis) and fibrosis (i.e. blunting matrix degradation), whereas the former is mediated by maintaining hepatocyte division after an injury.

Figure 1

Schematic representation of the role of plasminogen activator inhibitor-1 (PAI-1) in fibrin(ogen) metabolism in vivo. Cross-linked fibrin deposition is initiated by activation of the coagulation cascade via thrombin. PAI-1 inhibits the activity of the plasminogen activators (uPA and tPA), blocking the activation of plasminogen to plasmin and thereby blunting degradation of fibrin matrices (fibrinolysis). The balance between fibrin deposition and degradation determines whether fibrin accumulates in vivo. uPA, urokinase plasminogen activator; tPA, tissue plasminogen activator; FDP, fibrin degradation product

Figure 2

Potential mechanisms by which fibrin(ogen) contributes to hepatic inflammation caused by ethanol. Chronic ethanol increases hepatic fibrin extracellular matrix (ECM) deposition. This effect could contribute to alcohol-induced inflammation via one or more of the following mechanisms: (1) slowing blood flow in the liver (hemostasis), thereby increasing hypoxia; (2) stimulating platelets via integrin α_IIbβ₃ activation; (3) stimulating inflammatory cells via integrin α_Mβ₂ activation; and (4) directly stimulating endothelial cells via integrin α_vβ₃ activation. uPA, urokinase plasminogen activator; tPA, tissue plasminogen activator; FDP, fibrin degradation product; PAI-1, plasminogen activator inhibitor-1; SECs, stimulated endothelial cells

Figure 3

Proposed mechanisms by which plasminogen activator inhibitor-1 (PAI-1) inhibition protects against hepatic fibrosis. PAI-1 is a potent inhibitor of tPA and uPA, which convert plasminogen to plasmin. Plasmin can directly degrade extracellular matrix (ECM) components (e.g. fibrin, fibronectin, laminin, proteoglycan and type IV collagen). Plasmin can also indirectly degrade ECM via activation of MMPs (e.g. MMP-3). uPA, urokinase plasminogen activator; tPA, tissue plasminogen activator; MMP, matrix metalloproteinase