Biological roles and substrates of plasmin in the mouse

The plasminogen activation system is an intricate system of serine proteases, protease inhibitors and protease receptors, whose ultimate function is to govern the conversion of the abundant plasma protease zymogen plasrninogen (Plg) to the active protease ptasmin. Plasmin has a broad substrate specificity, and has been implicated in the activation of latent growth factors and procollagenases, degradation of extracellular matrix and fibrin clearance. To elucidate the biological and biochemical roles of Pig, we generated Pig-deficient (Plg-/-) mice. Plg-/- mice were born, survived to adulthood, and reproduced. However, the mice developed a plethora of progressive and ultimately fatal pathologies, that demonstrated a pivotal role of Pig in physiologic cell migration and tissue remodeling. These included spontaneous ulcerated lesions of epithelial surfaces of the gastrointestinal, reproductive and respiratory tracts, the comea and the conjunctiva. Lesions also developed in the liver, lung, adrenals, pancreas, ovaries and other organs. Pig-/- mice presented delayed and aberrant skin and corneal wound healing after injury, as a consequence of impaired keratinocyte migration. In experimental pathological settings, Pig-/-mice displayed accelerated atherosclerosis, but demonstrated delayed dissemination of metastatic tumors, and were resistant to excitotoxic neuronal degeneration. Loss of fibrinogen rescued Pig-/- mice from all spontaneous pathologies and corrected wound healing times, indicating that fibrinolysis is the essential, non-redundant physiological function of the plasminogen activation system.