Badziukh S. V.

LITERATURE REVIEWS

Scentific article

Wound healing is a multistage process that depends on the coordinated work of complex bimolecular mechanisms. Violation of the regulation of healing, at one of the stages, leads to the transition of the wound from acute to chronic.An imbalance of activator-inhibitor proteolytic systems is considered one of the main reasons for prolonging healing. The ability of the plasminogen/plasmin (Pg/Pm) system to exert a number of pleiotropic effects during the processes underlying tissue repair characterizes it as the master regulator of wound healing. Studies have shown that plasminogen (Pg) accumulates at the site of tissue damage and is converted to plasmin (Pm) by tissue-type protease (tPA) or urokinase-type protease (uPA). After activation of Pm, it provides cleaning of the wound from fibrin, neutrophils, is involved in the activation of growth factors and matrix metalloproteinases (MMP), and remodeling and formation of new connective tissue. Plasmin induces mitosis of fibroblasts and directly affects keratinocytes, activating their migration. After administration of Pg to mutant mice deficient in this protein, the healing of acute wounds and chronic wounds in mice with (STZ)-induced diabetes is accelerated. Full-thickness application of a plasminogen-loaded fibrin scaffold in mice with (STZ)-induced diabetes significantly increased the rate of wound closure compared to the scaffold used as a reference material. The introduction of plasminogen enhances the healing of radiation wounds, this effect is realized due to the pleiotropic effect on gene expression. Treatment of chronic wounds is long, expensive, and often unsuccessful, despite the development of surgical and drug innovations. The incidence of trophic ulcers of various genesis is 0.1-1.5%, in 24% of patients, the wounds do not heal for more than a year. The revealed properties of the Pg/Pm system to activate and regulate reparative processes indicate a great therapeutic potential in the treatment of wounds. Pg can be used as a new therapeutic strategy for the treatment of chronic wounds of different pathogenesis.

chronic wounds,healing,plasminogen,plasmin

1. Westby MJ, Norman G, Watson REB, Cullum NA, Dumville JC. Protease activity as a prognostic factor for wound healing in complex wounds. Wound Repair Regen. 2020;28(5):631-644. DOI: 10.1111/wrr.12835.
2. Morton LM, Phillips TJ. Wound healing and treating wounds: Differential diagnosis an devaluation of chronic wounds. J. Am. Acad. Dermatol. 2016;74(4):589-605. DOI: 10.1016/j.jaad.2015.08.068.
3. McCarty SM, Percival SL. Proteases and delayed wound healing. Adv Wound Care. 2013;2(8):438-447.DOI: 10.1089/wound.2012.0370.
4. Demidova–Rice TN, Hamblin MR, Herman IM. Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 1: normal and chronic wounds: 169 biology, causes and approaches to care. Adv. Skin Wound Care. 2012;25(7):304-314. DOI: 10.1097/01.ASW.0000 416006.55218.d0.
5. Meaume S, Perez J, Rethore V, Sebbane G, Dompmartin A, Bressieux JM, et al. Management of chronic wounds with an innovative absorbent wound dressing. J. Wound Care. 2012;21(7):315-322. DOI: 10.12968/jowc.2012. 21.7.315.
6. Greer JP. Wintrobe’s Clinical Hematology. 12-th Edition. Vol. 1. Lippincott Williams & Wilkins; 2008. 574 p.
7. Zhang L, Seiffert D, Fowler BJ, Jenkins GR, Thinnes TC, Loskutoff DJ, et al. Plasminogen has a broad extrahepatic distribution. Thromb Haemost. 2002 Mar;87(3):493-501.
8. Twining SS, Wilson PM, Ngamkitidechakul C. Extrahepatic synthesis of plasminogen in the human cornea is up-regulated by interleukins1alpha and -1beta. Biochem J. 1999 May 1;339(3):705-12.
9. Saksela O, Rifkin B. Cell-Associated Plasminogen Activation: Regulation and Physiological Functions. Ann. Rev. Cell. Biol. 1988;4:93-126. DOI: 10.1146/annurev.cb.04.110188.000521.
10. Fallah M, Viklund E, Bäckman A, Brodén J, Lundskog B, Johansson M, et al. Plasminogen is a master regulator and a potential drug candidate for the healing of radiation wounds. Cell Death Dis. 2020;11(3):201. DOI: 10.1038/s41419-020-2397-0.
11. Shen Y, Guo Y, Mikus P, Sulniute R, Wilczynska M, Ny T, et al. Plasminogen is a key proinflammatory regulator that accelerates the healing of acute and diabetic wounds. Blood. 2012;119(24):5879-5887. DOI: 10.1182/blood-2012-01-407825.
12. Schäfer BM, Maier K, Eickhoff U, Todd RF, Kramer MD. Plasminogen activation in healing human wounds. Am J Pathol. 1994;144(6):1269- 1280.
13. Sulniute R, Shen Y, Guo YZ, Fallah M, Ahlskog N, Ny L, et al. Plasminogen is a critical regulator of cutaneous wound healing. Thromb Haemost. 2016;115(5):1001-1009. DOI: 10.1160/TH15-08-0653.
14. Petrenko OM, Tyhomyrov AA. Rivni anhiohennykh rehuliatoriv i MMP-2, -9 aktyvnosti v ulser: opys vypadku. Ukrainskyi biokhimichnyi zhurnal. 2019;91(2):100-107[in Ukrainian].
15. Hirsch T, Spielmann M, Zuhaili B, Koehler T, Fossum M, Steinau HU, et al. Enhanced susceptibility to infections in a diabetic wound healing model. BMC Surg. 2008;8:5. DOI: 10.1186/1471-2482-8-5.
16. Anton J, Horrevoets G. Plasminogen activator inhibitor 1 (PAI-1): in vitro activities and clinical relevance. J. Haemotology. 2004;125(1):12- 23. DOI: 10.1111/j.1365-2141.2004.04844.x.
17. Rebalka IA, Raleigh MJ, D’Souza DM, Coleman SK, Rebalka AN, Hawke TJ. Inhibition of PAI-1 Via PAI-039 Improves Dermal Wound Closure in Diabetes. Diabetes. 2015;64(7):2593-2602. DOI: 10.2337/db14-1174.
18. Kolosovych IV, Hanol IV. Hemocoagulation factors of hemorrhagiccomplications in acute pancreatitis. Fiziolohichnyy zhurnal. 2022;68(1):56- 61. DOI: 10.15407/fz68.01.056.
19. Kanno Y, Hirade K, Ishisaki A, Nakajima K, Suga H, Into T, et al. Lack of alpha2-antiplasmin improves cutaneous wound healing via over-released vascular endothelial growth factor-induced angiogenesis in wound lesions. J Thromb Haemost. 2006;4(7):1602-1610. DOI: 10.1111/j.1538-7836.2006. 01978.x.
20. Romer J, Bugge TH, Pyke C, Lund LR, Flick MJ, Degen JL, et al. Impaired wound healing in mice with a disrupted plasminogen gene. Nat Med. 1996;2(3):287-292. DOI: 10.1038/nm0396-287.
21. Roth D, Piekarek M, Paulsson M, Christ H, Bloch W, Krieg T, et al. Plasmin modulates vascular endothelial growth factor-A-mediated angiogenesis during wound repair. Am J Pathol. 2006;168(2):670-684. DOI: 10.2353/ajpath.2006.050372.
22. Szabo I, Simon M Jr, Hunyadi J. Plasmin promotes keratinocyte migration and phagocytic-killing accompanied by suppression of cell proliferation which may facilitate re-epithelialization of wound beds. Clin Dev Immunol. 2004;11(3-4):233-240. DOI: 10.1080/17402520400001710.
23. Eriksson PO, Li J, Ny T, Hellström S. Spontaneous development of otitis media in plasminogen-deficient mice. Int. J. Med. Microbiol. 2006;296(7):501-509. DOI: 10.1016/j.ijmm.2006.04.002.
24. Jacobson LK, Johnson MB, Dedhia RD, Niknam-Bienia S, Wong AK. Impaired wound healing after radiation therapy: a systematic review of pathogenesis and treatment. JPRAS Open. 2017;13:92-105.
25. Mandal SK, Rao LV, Tran TT, Pendurthi UR. A novel mechanism of plasmin-induced mitogenesis in fibroblasts. J Thromb Haemost. 2005;3(1):163-169. DOI: 10.1111/j.1538-7836.2004.01054.x.
26. Ajjan RA, Gamlen T, Standeven KF, Mughal S, Hess K, Smith KA, et al. Diabetes is associated with posttranslational modifications in plasminogen resulting in reduced plasmin generation and enzyme-specific activity. Blood. 2013;122(1):134-142. DOI: 10.1182/ blood-2013-04-494641.
27. Gabison E, Chang JH, Hernández-Quintela E, Javier J, Lu PC, Ye H, et al. Anti-angiogenic role of angiostatin during corneal wound healing. Experimental Eye Research. 2004;78(3):579-589. DOI: 10.1016/j.exer.2003. 09.005.
28. Fallah M, Viklund E, Bäckman A, Brodén J, Lundskog B, Johansson M, et al. Plasminogen is a master regulator and a potential drug candidate for the healing of radiation wounds. Cell Death Dis. 2020;11(3):201. DOI: 10.1038/s41419-020-2397-0.
29. Kanno Y. The role of fibrinolytic regulators in vascular dysfunction of systemic sclerosis. Int J Mol Sci. 2019;20(3):619. DOI: 10.3390/ijms 20030619.
30. Al Kayal T, Buscemi M, Cavallo A, Foffa I, Soldani G, Losi P. Plasminogen-Loaded Fibrin Scaffold as Drug Delivery System for Wound Healing Applications. Pharmaceutics. 2022;14(2):251. DOI: 10.3390/pharmaceutics 14020251.

«Bulletin of problems biology and medicine» Issue 4 (167), 2022 year, 16-22 pages, index UDK 617.586:616.379-008.64-089.48/.816

10.29254/2077-4214-2022-4-167-16-22