DOI: https://doi.org/10.22263/2312-4156.2018.6.18
Nebylitsin Y.S.1, Lazuko S.S.2, Kut’ko E.A.2
Ischemia-reperfusion syndrome of lower limbs
1Vitebsk State Medical University Clinic, Vitebsk, Republic of Belarus
2Vitebsk State Order of Peoples’ Friendship Medical University, Vitebsk, Republic of Belarus
Vestnik VGMU. 2018;17(6):18-31.
Abstract.
A block of pathologic processes, developing in the lower limbs in case of acute disturbance of the arterial blood flow with its subsequent recovery refers to the term «ischemia-reperfusion syndrome». This syndrome can be divided into two phases, different in pathogenesis, but at the same time interconnected with each other – ischemia and reperfusion.
In ischemia phase tissue damage begins due to the developing oxygen deficit and the disturbance of high-energy cell substrates synthesis. Because of hypoxia the cascade of pathologic reactions is triggered, which lead to function disturbance of vitally important cell structures. The researches show, that irreversible changes in lower limb muscles start after 3 hours of absolute ischemia and almost completely finish by 6 hours.
Reperfusion phase starts immediately after the recovery of lower limb blood flow in case of irreversible tissue damages. In this phase the aggravation of limb damage occurs, its severity being greater when the ischemia phase lasts for a longer period of time. The main damaging factors in this phase are reactive oxygen and nitrogen forms (ROF and RNF) and leukocytes. ROF and RNF lead to «oxidative-nitrosative stress» development which results in the triggering of cell death pathways – apoptosis and necroptosis.
The process of endothelial glycocalyx degradation and the developing endothelial dysfunction are important aspects of the ischemia-reperfusion syndrome pathogenesis. In different parts of the microvascular beds the disorder of the certain endothelial function dominates: the vascular tone regulation disorder in the arterioles, disorder of the barrier function and leukocyte adhesion control in postcapillary venules. The degree of endothelial dysfunction can be evaluated in the laboratory with the help of «endothelial dysfunction markers», the identification ofwhich is very important for describing the severity of the developing endothelial dysfunction and possible searching for therapeutic targets for the prevention of its development.
Key words: ischemia, reperfusion, inflammation, microcirculation.
References
1. Gilliland C, Shah J, Martin JG, Miller MJ Jr. Acute limb ischemia. Tech Vasc Interv Radiol. 2017 Dec;20(4):274-80. doi: http://dx.doi.org/10.1053/j.tvir.2017.10.008
2. Zasimovich VN, Ioskevich NN. Reperfusion-reoxygenation syndrome as a problem of reconstructive surgery of arteries in chronic lower limb ischemia of atherosclerotic origin. Novosti Khirurgii. 2017;25(6):632-42. doi: http://dx.doi.org/10.18484/2305-0047.2017.6.632 (In Russ.)
3. Marshalov DV, Petrenko AP, Glushach IA. Reperfusion syndrome: concept, definition, classification. Patologiia Krovoobrashcheniia Kardiokhirurgiia. 2008;(3):67-72. (In Russ.)
4. Blaisdell FW. The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review. Cardiovascular Surgery. 2002 Dec;10(6):620-30. doi: http://dx.doi.org/10.1016/S0967-2109(02)00070-4
5. Hausenloy DJ, Kaski JC, Gersh BJ, Yellon DM. Myocardial reperfusion injury as a New Frontier for Clinical Therapy. In: Hausenloy DJ, Kaski JC, Gersh BJ, Yellon DM, editors. Management of Myocardial Reperfusion Injury. London: Springer; 2012. Р. 3-10. doi: http://dx.doi.org/10.1007/978-1-84996-019-9_1
6. Patlola RR, Walker C. Acute Ischemic Syndromes of the Peripheral Arteries. In: Lanzer P. PanVascular Medicine. 2nd ed. Berlin Heidelberg: Springer; 2015. P. 3073-98.
7. Lindsay TF, Liauw S, Romaschin AD, Walker PM. The effect of ischemia/reperfusion on adenine nucleotide metabolism and xanthine oxidase production in skeletal muscle. J Vasc Surg. 1990 Jul;12:8-15. doi: http://dx.doi.org/10.1016/0741-5214(90)90360-M
8. Swartz WM, Cha CJ, Clowes GH Jr, Randall HT. The effect of prolonged ischemia on high energy phosphate metabolism in skeletal muscle. Surg Gynecol Obstet. 1978 Dec;147(6):872-6.
9. Haljamäe H, Enger E. Human skeletal muscle energy metabolism during and after complete tourniquet ischemia. Ann Surg. 1975 Jul;182(1):9-14.
10. Labbe R, Lindsay T, Walker PM. The extent and distribution of skeletal muscle necrosis after graded periods of complete ischemia. J Vasc Surg. 1987 Aug;6(2):152-7. doi: http://dx.doi.org/10.1067/mva.1987.avs0060152
11. Petrasek PF, Homer-Vanniasinkam S, Walker PM. Determinants of ischemic injury to skeletal muscle. J Vasc Surg. 1994 Apr;19(4):623-31. doi: http://dx.doi.org/10.1016/S0741-5214(94)70035-4
12. Szydlowska K, Tymianski M. Calcium ischemia and excitotoxicity. Cell Calcium. 2010 Feb;47(2):122-9. doi: http://dx.doi.org/10.1016/j.ceca.2010.01.003
13. Contreras L, Drago I, Zampese E, Pozzan T. Mitochondria: the calcium connection. Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):607-18. doi: http://dx.doi.org/10.1016/j.bbabio.2010.05.005
14. Lesnefsky EJ, Chen Q, Tandler B, Hoppel CL. Mitochondrial Dysfunction and Myocardial Ischemia-Reperfusion: Implications for Novel Therapies. Annual Review of Pharmacology and Toxicology. 2017 Jan;57:535-65. doi: http://dx.doi.org/10.1146/annurev-pharmtox-010715-103335
15. Andrews NW, Almeida PE, Corrotte M. Damage Control: Cellular Mechanisms of Plasma Membrane Repair. Trends in Cell Biology. 2014 Dec;24(12):734-42. doi: http://dx.doi.org/10.1016/j.tcb.2014.07.008
16. Granger DN, Homer-Vanniasinkam S. Physiology of reperfusion injury. In: White RA, Hollier LH. Vascular Surgery: Basic Science and Clinical Correlations, 2nd Edition. Oxford: Blackwell Publishing; 2005. P. 245-50.
17. Wright VP, Klawitter PF, Iscru DF, Merola AJ, Clanton TL. Superoxide scavengers augment contractile but not energetic responses to hypoxia in rat diaphragm. J Appl Physiol. 2005 May;98(5):1753-60. doi: http://dx.doi.org/10.1152/japplphysiol.01022.2004
18. Bernardi P, Di Lisa F. The mitochondrial permeability transition pore: Molecular nature and role as a target in cardioprotection. J Mol Cell Cardiol. 2015 Jan;78:100-6. doi: http://dx.doi.org/10.1016/j.yjmcc.2014.09.023
19. Lee H-L, Chen C-L, Yeh ST, Zweier JL, Chen Y-R. Biphasic modulation of the mitochondrial electron transport chain in myocardial ischemia and reperfusion. Am J Physiol Heart Circ Physiol. 2012 Apr;302(7):H1410-22. doi: http://dx.doi.org/10.1152/ajpheart.00731.2011
20. Bilenko MV. Ischemic and reperfusion injuries of organs: (molecular mechanisms, ways of prevention and treatment). Moscow, RF: Meditsina; 1989. 368 р. (In Russ.)
21. Gielis JF, Beckers PAJ, Briedé JJ, Cos P, Van Schil PE. Oxidative and nitrosative stress during pulmonary ischemia-reperfusion injury: from the lab to the OR. Ann Transl Med. 2017 Ьфк;5(6):131. doi: http://dx.doi.org/10.21037/atm.2017.03.32
22. Ha T, Liu L, Kelley J, Kao R, Williams D, Li C. Toll-like receptors: new players in myocardial ischemia/reperfusion injury. Antioxid Redox Signal. 2011 Oct;15(7):1875-93. doi: http://dx.doi.org/10.1089/ars.2010.3723
23. Granger DN, Kvietys PR. Reperfusion injury and reactive oxygen species: the evolution of a concept. Redox Biology. 2015 Dec;6:524-51. doi: http://dx.doi.org/10.1016/j.redox.2015.08.020
24. Halestrap AP. A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection. Biochem Soc Trans. 2010 Aug;38(4):841-60. doi: http://dx.doi.org/10.1042/BST0380841
25. Loor G, Kondapalli J, Iwase H, Chandel NS, Waypa GB, Guzy RD, et al. Mitochondrial oxidant stress triggers cell death in simulated ischemia-reperfusion. Biochim Biophys Acta. 2011 Jul;1813(7):1382-94. doi: http://dx.doi.org/10.1016/j.bbamcr.2010.12.008
26. Wu MY, Yiang GT, Liao WT, Tsai AP, Cheng YL, et al. Current Mechanistic Concepts in Ischemia and Reperfusion Injury. Cell Physiol Biochem. 2018;46(4):1650-67. doi: http://dx.doi.org/10.1159/000489241
27. Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009 Jun;137(6):1112-23. doi: http://dx.doi.org/10.1016/j.cell.2009.05.037
28. Hüttemann M, Helling S, Sanderson TH, Sinkler C, Samavati L, Mahapatra G, et al. Regulation of mitochondrial respiration and apoptosis through cell signaling: cytochrome c oxidase and cytochrome c in ischemia/reperfusion injury and inflammation. Biochim Biophys Acta. 2012 Apr;1817(4):598-609. doi: http://dx.doi.org/10.1016/j.bbabio.2011.07.00
29. Kumar P, Shen Q, Pivetti CD, Lee ES, Wu MH, Yuan SY. Molecular mechanisms of endothelial hyperpermeability: implications in inflammation. Expert Rev Mol Med. 2009 Jun;11:e19. doi: http://dx.doi.org/10.1017/S1462399409001112
30. Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell Biology of Ischemia/Reperfusion Injury. Int Rev Cell Mol Biol. 2012;298:229-317. doi: http://dx.doi.org/10.1016/B978-0-12-394309-5.00006-7
31. Fujii E, Yoshioka T, Ishida H, Irie K, Muraki T. Evaluation of iNOS-dependent and independent mechanisms of the microvascular permeability change induced by lipopolysaccharide. Br J Pharmacol. 2000 May;130(1):90-4. doi: http://dx.doi.org/10.1038/sj.bjp.0703277
32. Moody BF, Calvert JW. Emergent role of gasotransmitters in ischemia-reperfusion injury. Med Gas Res. 2011 Apr;1(1):3. doi: http://dx.doi.org/10.1186/2045-9912-1-3
33. Harrison DG. Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest. 1997 Nov;100(9):2153-7. doi: http://dx.doi.org/10.1172/JCI119751
34. Luo S, Lei H, Qin H, Xia Y. Molecular mechanisms of endothelial NO synthase uncoupling. Curr Pharm Des. 2014;20(22):3548-53. doi: http://dx.doi.org/10.2174/13816128113196660746
35. Parish JM, Somers VK. Obstructive sleep apnea and cardiovascular disease. Mayo Clin Proc. 2004 Aug;79(8):1036-46. doi: http://dx.doi.org/10.4065/79.8.1036
36. Manukhina EB, Jasti D, Vanin AF, Downey HF. Intermittent hypoxia conditioning prevents endothelial dysfunction and improves nitric oxide storage in spontaneously hypertensive rats. Exp Biol Med (Maywood). 2011 Jul;236(7):867-73. doi: http://dx.doi.org/10.1258/ebm.2011.011023
37. Zhu T, Yao Q, Wang W, Yao H, Chao J. iNOS Induces Vascular Endothelial Cell Migration and Apoptosis Via Autophagy in Ischemia/Reperfusion Injury. Cell Physiol Biochem. 2016;38(4):1575-88. doi: http://dx.doi.org/10.1159/000443098
38. Huribal M, McMillen MA. Role of Endothelin in Ischemia-Reperfusion Injury. Ann N Y Acad Sci. 1994 Jun;723:484-5. doi: http://dx.doi.org/10.1111/j.1749-6632.1994.tb36784.x
39. Phillipson M, Kubes P. The neutrophil in vascular inflammation. Nat Med. 2011 Nov;17(11):1381-90. doi: http://dx.doi.org/10.1038/nm.2514
40. Granger DN. Ischemia-reperfusion: mechanisms of microvascular dysfunction and the influence of risk factors for cardiovascular disease. Microcirculation. 1999 Sep;6(3):167-78.
41. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994 Jan;76(2):301-14. doi: http://dx.doi.org/10.1016/0092-8674(94)90337-9
42. Sun B, Fan H, Honda T, Fujimaki R, Lafond-Walker A, Masui Y, et al. Activation of NF-kB and Expression of ICAM-1 in Ischemic-reperfused Canine Myocardium. J Mol Cell Cardiol. 2001 Jan;33(1):109-19. doi: http://dx.doi.org/10.1006/jmcc.2000.1280
43. Carden DL, Granger DN. Pathophysiology of ischaemia-reperfusion injury. J Pathol. 2000 Feb;190(3):255-66. doi: http://dx.doi.org/10.1002/(SICI)1096-9896(200002)190:3<255::AID-PATH526>3.0.CO;2-6
44. Maiocchi S, Alwis I, Wu MCL, Yuan Y, Jackson SP. Thromboinflammatory Functions of Platelets in Ischemia-Reperfusion Injury and Its Dysregulation in Diabetes. Semin Thromb Hemost. 2018 Mar;44(2):102-13. doi: http://dx.doi.org/10.1055/s-0037-1613694
45. Mohan Rao LV, Esmon CT, Pendurthi UR. Endothelial cell protein C receptor: a multiliganded and multifunctional receptor. Blood. 2014;124(10):1553-1562. doi: http://dx.doi.org/10.1182/blood-2014-05-578328
46. Sieve I, Münster-Kühnel AK, Hilfiker-Kleiner D. Regulation and function of endothelial glycocalyx layer in vascular diseases. Vascul Pharmacol. 2018 Jan;100:26-33. doi: http://dx.doi.org/10.1016/j.vph.2017.09.002
47. Tsui JC, Baker DM, Biecker E, Shaw S, Dashwood MR. Altered Endothelin-1 Levels in Acute Lower Limb Ischemia and Reperfusion. Angiology. 2004 Sep-Oct;55(5):533-9. doi: http://dx.doi.org/10.1177/000331970405500509
48. Zhang C, Wa J, Xu X, Potter BJ, Gao X. Direct relationship between levels of TNFα expression and endothelial dysfunction in reperfusion injury. Basic Res Cardiol. 2010 Jul;105(4):453-64. doi: http://dx.doi.org/10.1007/s00395-010-0083-6
49. Lindsberg PJ, Mattila OS, Strbian D. Mast Cell as an Early Responder in Ischemic Brain Injury. In: Chen J, Zhang J, Hu X, editors. Non-Neuronal Mechanisms of Brain Damage and Repair After Stroke. Switzerland: Springer; 2016. P. 255-72. doi: http://dx.doi.org/10.1007/978-3-319-32337-4_13
50. Gandhi C, Motto DG, Jensen M, Lentz SR, Chauhan AK. ADAMTS13 deficiency exacerbates VWF-dependent acute myocardial ischemia/reperfusion injury in mice. Blood. 2012 Dec;120(26):5224-30. doi: http://dx.doi.org/10.1182/blood-2012-06-440255
Information about authors:
Nebylitsin Y.S. – Candidate of Medical Sciences, associate professor, head of the department of plastic surgery & cosmetology, Vitebsk State Order of Peoples’ Friendship Medical University Clinic;
Lazuko S.S. – Candidate of Biological Sciences, associate professor, head of the Chair of Normal Physiology, Vitebsk State Order of Peoples’ Friendship Medical University;
Kut’ko E.A. – the sixth-year medical student, Vitebsk State Order of Peoples’ Friendship Medical University.
Correspondence address: Republic of Belarus, 210039, Vitebsk, 20 Pobedy ave., Vitebsk State Medical University Clinic, the department of plastic surgery & cosmetology. E-mail: Этот адрес электронной почты защищён от спам-ботов. У вас должен быть включен JavaScript для просмотра. – Yuriy S. Nebylitsin.
