Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of
plasminogen activators, thereby playing a major role in fibrinolysis. Whereas hyperfibrinolysis is common in
alcoholic cirrhosis, hypofibrinolysis (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 ALD has been unclear. The role of
PAI-1 was therefore investigated in models of early (steatosis), intermediate (
inflammation/
necrosis) and late (
fibrosis) stages of
alcoholic liver disease. For example, hepatic steatosis caused by both acute and chronic
ethanol was blunted by inhibiting
PAI-1 activation. This effect of inhibiting
PAI-1 appears to be mediated, at least in part, by an increase in
very low-density lipoprotein (VLDL) synthesis in the absence of
PAI-1. The results from that study also indicated that
PAI-1 plays a critical role in both acute and chronic hepatic
inflammation. Lastly, knocking out
PAI-1 potently protected against experimental hepatic
fibrosis; the mechanism of this protective effect appears to be mediated predominantly by extracellular matrix (ECM) resolution by matrix
metalloproteases, which are indirectly inhibited by
PAI-1. In summary, targeting
PAI-1 protects against all three stages of ALD in model systems. The mechanisms by which
PAI-1 contributes to these disease stages appear to not only involve the 'classical' function of
PAI-1 (i.e. in mediating fibrinolysis), but also other functions of this
protein. These data support a role of
PAI-1 in the initiation and progression of ALD, and suggest that
PAI-1 may be a useful target for clinical
therapy to halt or blunt
disease progression.