The Plasminogen Activator (PA) system
The Plasminogen Activator (PA) system is a general protease system where the pro-enzyme plasminogen is activated to plasmin by either of two physiological plasminogen activators (PAs): urokinase-type PA (uPA) or tissue-type PA (tPA). The PA system is controlled by inhibitors belonging to the Serpin family of inhibitors. PAI-1 and PAI-2 are PA-inhibitors and anti-plasmin inhibits plasmin (see figure). The primary function of the PA system is fibrinolysis, but this system is also implicated in various tissue remodeling processes such as inflammation, tumor growth, and angiogenesis. My journey with this system started in 1983 with cloning of cDNA for human tPA. We have worked on the role of PA system in ovulation as a model for physiological tissue remodeling. Later when we moved to pathological processes we found that plasminogen is an important regulator of rheumatoid arthritis, a key factor in eliminating infections, and has a protective role against development of periodontitis. Currently, we work mainly on the role of plasminogen in wound healing (see figure).
Wound healing is a complicated biological process that includes a cascade of tightly regulated events. Wound healing consists of partially overlapping inflammatory, proliferative and tissue remodeling phases. If the inflammatory phase is not properly activated or cannot be terminated, the healing process is arrested and the wounds become chronic, as in diabetes. Diabetic wounds with impaired healing are the most severe types of chronic wounds that every year affect millions of people. In fact, over 10 million patients are amputated every year due to diabetes-related foot ulcers. Amputation are also associated with a 5-year mortality that is comparable to the mortality in cancer. Even though wound healing has been studied for many years, the knowledge regarding the molecular mechanisms involved is still limited.
We have recently discovered that plasminogen is a pro-inflammatory regulator that that regulates the wound healing process. In fact, plasminogen-deficient mice can not heal tympanic membrane perforations. Using cutaneous wound healing models we have shown that plasminogen is transported by inflammatory cells to the wound site where plasminogen induces expression of cytokines and intracellular signaling events that potentiate the early inflammatory response leading to healing of wounds. In plasminogen-deficient mice, healing of cutaneous wound is severely impaired. In these mice, debridement is inefficient, the inflammatory phase cannot resolve and granulation tissue is not remodeled leading to persistent inflammation and formation of chronic wounds.
Supplementation of plasminogen-deficient mice with human plasminogen activates the healing process including wound debridement, which is followed by resolution of inflammation and completion of the entire wound healing process. Importantly, plasminogen supplementation activates wound healing also in diabetic mice, and enhances wound healing in wild type mice and rats. Our pilot studies in humans have shown that that plasminogen injections around chronic wounds activate and completes the healing of wounds including diabetic wounds. Our studies suggest that plasminogen will become a future drug for healing of diabetic wounds as well as other wounds.
Studies on the mechanisms involved in development of radiation-induced wounds
Studies on the mechanisms involved in development of chronic diabetic wounds
Studies on mechanisms by which plasminogen regulates/activates wound healing
Studies on using plasminogen as wound healing agents