Role of the Plasminogen Activation System in Liver Injury and Repair: Knowns and Known Unknowns

The plasminogen activation system (PAS) is primarily responsible for the degradation of fibrin clots as well as extracellular matrix remodeling. Many components of the PAS are produced by the liver, and the expression of these proteins is altered during liver disease. Liver is a primary site for the synthesis of proteins in the PAS, including plasminogen, tPA (tissue-type plasminogen activator), and uPA (urokinase-type plasminogen activator), as well as several modulators of plasmin activation. Clinical studies have shown that liver injury profoundly changes levels of PAS components and fibrinolytic activity in plasma. Likewise, there is strong experimental evidence to suggest that components of the PAS play an important role in determining the severity of hepatic injury and, paradoxically, also contribute to repair and regeneration of the injured liver. Here, we review the dynamic connections between the PAS and liver injury/disease, including changes in PAS expression and function accompanying liver disease in patients and mechanism-centered studies in animal models. We focus on established models of acute hepatic injury, chronic liver disease, and repair/regeneration, and review the effect of gain or loss of function of PAS components on the liver. The review seeks to cover not only field-driving discoveries but also spotlights unexplained dichotomies, challenges with interpretation, and the need for further exploration of mechanisms using leading-edge tools. Critical gaps in our understanding of how the PAS contributes to liver pathophysiology, and vice versa, are identified, and future directions are considered.