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DOI: 10.1160/TH15-08-0653
Plasminogen is a critical regulator of cutaneous wound healing
Financial Support: This research was supported by the National Cancer Foundation, Diabetesfonden, and The Medical Faculty of Umeå University.Publikationsverlauf
Received:
17. August 2015
Accepted after major revision:
05. Januar 2016
Publikationsdatum:
06. Dezember 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201605/lookinside/thumbnails/10.1160-th15-08-0653-1.jpg)
Summary
Wound healing is a complicated biological process that consist of partially overlapping inflammatory, proliferation and tissue remodelling phases. A successful wound healing depends on a proper activation and subsequent termination of the inflammatory phase. The failure to terminate the inflammation halts the completion of wound healing and is a known reason for formation of chronic wounds. Previous studies have shown that wound closure is delayed in plasminogendeficient mice, and a role for plasminogen in dissection of extracellular matrix was suggested. However, our finding that plasminogen is transported to the wound by inflammatory cells early during the healing process, where it potentiates inflammation, indicates that plasminogen may also have other roles in the wound healing process. Here we report that plasminogen-deficient mice have extensive fibrin and neutrophil depositions in the wounded area long after re-epithelialisation, indicating inefficient debridement and chronic inflammation. Delayed formation of granulation tissue suggests that fibroblast function is impaired in the absence of plasminogen. Therefore, in addition to its role in the activation of inflammation, plasminogen is also crucial for subsequent steps, including resolution of inflammation and activation of the proliferation phase. Importantly, supplementation of plasminogen-deficient mice with human plasminogen leads to a restored healing process that is comparable to that in wild-type mice. Besides of being an activator of the inflammatory phase during wound healing, plasminogen is also required for the subsequent termination of inflammation. Based on these results, we propose that plasminogen may be an important future therapeutic agent for wound treatment.
Supplementary Material to this article is available online at www.thrombosis-online.com.
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References
- 1 Bratton DL, Henson PM. Neutrophil clearance: when the party is over, clean-up begins. Trends Immunol 2011; 32: 350-357.
- 2 Mocsai A. Diverse novel functions of neutrophils in immunity, inflammation, and beyond. J Experimental Med 2013; 210: 1283-1299.
- 3 Koh TJ, DiPietro LA. Inflammation and wound healing: the role of the macrophage. Expert Rev Mol Med 2011; 13: e23.
- 4 Weber CE, Li NY, Wai PY. et al. Epithelial-mesenchymal transition, TGF-beta, and osteopontin in wound healing and tissue remodeling after injury. J Burn Care Res 2012; 33: 311-318.
- 5 Eming SA, Krieg T, Davidson JM. Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol 2007; 127: 514-525.
- 6 Lund LR, Romer J, Bugge TH. et al. Functional overlap between two classes of matrix-degrading proteases in wound healing. EMBO J 1999; 18: 4645-4656.
- 7 Romer J, Bugge TH, Pyke C. et al. Plasminogen and wound healing. Nature Med 1996; 2: 725.
- 8 Ra HJ, Parks WC. Control of matrix metalloproteinase catalytic activity. Matrix Biol 2007; 26: 587-596.
- 9 Blasi F. Proteolysis, cell adhesion, chemotaxis, and invasiveness are regulated by the u-PA-u-PAR-PAI-1 system. Thromb Haemost 1999; 82: 298-304.
- 10 Mignatti P, Rifkin DB. Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 1993; 73: 161-195.
- 11 Romer J, Bugge TH, Pyke C. et al. Impaired wound healing in mice with a disrupted plasminogen gene. Nature Med 1996; 2: 287-292.
- 12 Rovee DT MH. The epidermis in wound healing. Dermatology: clinical and basics science series, CRC Press; 2004
- 13 Busuttil SJ, Ploplis VA, Castellino FJ. et al. A central role for plasminogen in the inflammatory response to biomaterials. J Thromb Haemost 2004; 2: 1798-1805.
- 14 Schaiff WT, Eisenberg PR. Direct induction of complement activation by pharmacologic activation of plasminogen. Coronary Artery Dis 1997; 8: 9-18.
- 15 Syrovets T, Lunov O, Simmet T. Plasmin as a proinflammatory cell activator. J Leukocyte Biol 2012; 92: 509-519.
- 16 Eriksson PO, Li J, Ny T. et al. Spontaneous development of otitis media in plasminogen- deficient mice. Intern J Med Microbiol 2006; 296: 501-509.
- 17 Shen Y, Guo Y, Mikus P. et al. Plasminogen is a key proinflammatory regulator that accelerates the healing of acute and diabetic wounds. Blood 2012; 119: 5879-5887.
- 18 Ploplis VA, Carmeliet P, Vazirzadeh S. et al. Effects of disruption of the plasminogen gene on thrombosis, growth, and health in mice. Circulation 1995; 92: 2585-2593.
- 19 Ny A, Leonardsson G, Hagglund AC. et al. Ovulation in plasminogen-deficient mice. Endocrinology 1999; 140: 5030-5035.
- 20 Li J, Eriksson PO, Hansson A. et al. Plasmin/plasminogen is essential for the healing of tympanic membrane perforations. Thromb Haemost 2006; 96: 512-519.
- 21 Church D, Elsayed S, Reid O. et al. Burn wound infections. Clin Microbiol Rev 2006; 19: 403-434.
- 22 Lund LR, Green KA, Stoop AA. et al. Plasminogen activation independent of uPA and tPA maintains wound healing in gene-deficient mice. EMBO J 2006; 25: 2686-2697.
- 23 Jogi A, Rono B, Lund IK. et al. Neutralisation of uPA with a monoclonal antibody reduces plasmin formation and delays skin wound healing in tPA-deficient mice. PloS one 2010; 5: e12746.
- 24 Green KA, Almholt K, Ploug M. et al. Profibrinolytic effects of metalloproteinases during skin wound healing in the absence of plasminogen. J Invest Dermatol 2008; 128: 2092-2101.
- 25 Guo Y, Li J, Hagstrom E. et al. Protective effects of plasmin(ogen) in a mouse model of Staphylococcus aureus-induced arthritis. Arthritis Rheumatism 2008; 58: 764-772.
- 26 Drew AF, Tucker HL, Kombrinck KW. et al. Plasminogen is a critical determinant of vascular remodeling in mice. Circulation Res 2000; 87: 133-139.
- 27 Sulniute R, Lindh T, Wilczynska M. et al. Plasmin is essential in preventing periodontitis in mice. Am J Pathol 2011; 179: 819-828.
- 28 Bezerra JA, Bugge TH, Melin-Aldana H. et al. Plasminogen deficiency leads to impaired remodeling after a toxic injury to the liver. Proc Natl Acad Sci USA 1999; 96: 15143-15148.
- 29 Pohl JF, Melin-Aldana H, Sabla G. et al. Plasminogen deficiency leads to impaired lobular reorganisation and matrix accumulation after chronic liver injury. Am J Pathol 2001; 159: 2179-2186.
- 30 Ng VL, Sabla GE, Melin-Aldana H. et al. Plasminogen deficiency results in poor clearance of non-fibrin matrix and persistent activation of hepatic stellate cells after an acute injury. J Hepatol 2001; 35: 781-789.
- 31 Kawao N, Nagai N, Tamura Y. et al. Urokinase-type plasminogen activator and plasminogen mediate activation of macrophage phagocytosis during liver repair in vivo. Thromb Haemost 2012; 107: 749-759.
- 32 Rosenwald M, Koppe U, Keppeler H. et al. Serum-derived plasminogen is activated by apoptotic cells and promotes their phagocytic clearance. J Immunol 2012; 189: 5722-5728.
- 33 Das R, Ganapathy S, Mahabeleshwar GH. et al. Macrophage gene expression and foam cell formation are regulated by plasminogen. Circulation 2013; 127: 1209-1218 e1-16.
- 34 Guo Y, Li J, Hagstrom E. et al. Beneficial and detrimental effects of plasmin( ogen) during infection and sepsis in mice. PloS one 2011; 6: e24774.
- 35 Hepburn L, Prajsnar TK, Klapholz C. et al. Innate immunity. A Spaetzle-like role for nerve growth factor beta in vertebrate immunity to Staphylococcus aureus. Science 2014; 346: 641-646.
- 36 Kawamoto K, Matsuda H. Nerve growth factor and wound healing. Prog Brain Res 2004; 146: 369-384.
- 37 Sulniute R, Lindh T, Wilczynska M. et al. Plasmin is essential in preventing periodontitis in mice. Am J Pathol 2012; 179: 819-828.
- 38 Miles LA, Parmer RJ. Plasminogen receptors: the first quarter century. Semin Thromb Hemost 2013; 39: 329-337.
- 39 Deryugina EI, Quigley JP. Cell surface remodelling by plasmin: a new function for an old enzyme. J Biomed Biotechnol 2012; 2012: 564259.