Wound healing is a well-orchestrated, complex process leading to the repair of injured tissues. Two major proteolytic systems, the matrix metalloproteases and the plasminogen activator system, are involved in this process. The lack of plasminogen (plg) has previously been reported to cause a delay in wound closure in mice, and to be complemented by matrix metalloproteases. However, our previous finding that tympanic membrane perforations in plg-deficient mice do not heal indicated that plg has more important function in wound healing than previously regarded. In later studies, we have found that plg accumulates in the wound early during the healing process and potentiates the inflammatory response and the healing. In the present study, we have used incision and burn wound models in wild-type and plg-deficient mice to further investigate the role of plg in the later phases of the healing process, including its role after re-epithelization. In addition to the earlier observed delay of wound re-epithelization in plg-deficient mice, we have found that the tissue remodeling processes that take place after re-epithelization is also impaired in these mice. By morphological and immunohistochemical analyses, we found that plg-deficient mice had delayed granulation tissue formation, and were unable to clear the provisional matrix. Extensive fibrin deposition and persistent neutrophil infiltration even at day 60 post-wounding indicate that the inflammation was present subcutaneously in plg-deficient mice even at later time points. Importantly, intravenous or subcutaneous supplementation of plg-deficient mice by human plg led to a restored healing rate, and a healing pattern that was comparable to that in wild type mice.
Therefore, in addition to its important function in early stages of cutaneous wound healing, plg is also crucial for later phases, by clearing fibrin deposits and resolving inflammation after full re-epithelization of the wound. Our results suggest that plg may be a potential therapeutic agent for improving the healing of different types of skin wounds.