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J Reconstr Microsurg 2021; 37(03): 242-248
DOI: 10.1055/s-0040-1717102
Original Article

Effects of Ischemic Preconditioning and C1 Esterase Inhibitor Administration following Ischemia-Reperfusion Injury in a Rat Skin Flap Model

Inmaculada Masa
1   Department of Plastic and Reconstructive Surgery, University Hospital Clínico San Carlos, Madrid, Spain
,
César Casado-Sánchez
2   Department of Plastic and Reconstructive Surgery, University Hospital La Paz, Madrid, Spain
,
Vicente Crespo-Lora
3   Department of Pathology, University of Granada, Granada, Spain
,
Alberto Ballestín 
4   Department of Microsurgery, Jesús Usón Minimally Invasive Surgery Centre, Cáceres, Spain
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Abstract

Background Ischemia-reperfusion (I/R) injury is a serious condition that can affect the success rate of microsurgical reconstructions of ischemic amputated limbs and complex tissue defects requiring free tissue transfers. The purpose of this study was to evaluate the effects of ischemic preconditioning (IPC) and C1 esterase inhibitor (C1-Inh) intravenous administration following I/R injury in a rat skin flap model.

Methods Superficial caudal epigastric skin flaps (3 cm × 7 cm) were performed on 50 Wistar rats that were randomly divided into five groups. Ischemia was not induced in the control group. All other flaps underwent 8 hours of ischemia prior to revascularization: I/R control group (8-hour ischemia), IPC group (preconditioning protocol + 8-hour ischemia), C1-Inh group (8-hour ischemia + C1-Inh), and IPC + C1-Inh group (preconditioning protocol + 8-hour ischemia + C1-Inh). Survival areas were macroscopically assessed after 1 week of surgery, and histopathological and biochemical evaluations were also measured.

Results There were no significant differences in flap survival between the treatment groups that were suffering 8 hours of ischemia and the control group. A significant increase in neovascularization and lower edema formation were observed in the IPC group compared with that in the I/R group. Biochemical parameters did not show any significant differences.

Conclusion Intravenous administration of C1-Inh did not significantly modulate I/R-related damage in this experimental model, but further research is needed. On the other hand, IPC reduces tissue damage and improves neovascularization, confirming its potential protective effects in skin flaps following I/R injury.

Keywords

C1 esterase inhibitor - Ischemic preconditioning - Ischemia reperfusion injury


Publication History

Received: 01 May 2020

Accepted: 18 August 2020

Article published online:
24 September 2020

© 2020. Thieme. All rights reserved.

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  • References

  • 1 Wang WZ, Baynosa RC, Zamboni WA. Update on ischemia-reperfusion injury for the plastic surgeon: 2011. Plast Reconstr Surg 2011; 128 (06) 685e-692e
    CrossrefPubMedGoogle Scholar
  • 2 Ballestín A, Casado JG, Abellán E. et al. Adipose-derived stem cells ameliorate ischemia-reperfusion injury in a rat skin free flap model. J Reconstr Microsurg 2018; 34 (08) 601-609
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 van den Heuvel MG, Buurman WA, Bast A, van der Hulst RR. Review: Ischaemia-reperfusion injury in flap surgery. J Plast Reconstr Aesthet Surg 2009; 62 (06) 721-726
    CrossrefPubMedGoogle Scholar
  • 4 Hausenloy DJ, Yellon DM. Ischaemic conditioning and reperfusion injury. Nat Rev Cardiol 2016; 13 (04) 193-209
    CrossrefPubMedGoogle Scholar
  • 5 Kinnunen I, Laurikainen E, Schrey A, Laippala P, Aitasalo K. Effect of acute ischemic preconditioning on blood-flow response in the epigastric pedicled rat flap. J Reconstr Microsurg 2002; 18 (01) 61-68
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Wang WZ. Investigation of reperfusion injury and ischemic preconditioning in microsurgery. Microsurgery 2009; 29 (01) 72-79
    CrossrefPubMedGoogle Scholar
  • 7 Buerke M, Murohara T, Lefer AM. Cardioprotective effects of a C1 esterase inhibitor in myocardial ischemia and reperfusion. Circulation 1995; 91 (02) 393-402
    CrossrefPubMedGoogle Scholar
  • 8 C1 esterase inhibitor (human). P T 2010; 35 (7 section 2): 2-3
    PubMedGoogle Scholar
  • 9 Davis III AE, Mejia P, Lu F. Biological activities of C1 inhibitor. Mol Immunol 2008; 45 (16) 4057-4063
    CrossrefPubMedGoogle Scholar
  • 10 Fries CA, Villamaria CY, Spencer JR, Rasmussen TE, Davis MR. C1 esterase inhibitor ameliorates ischemia reperfusion injury in a swine musculocutaneous flap model. Microsurgery 2017; 37 (02) 142-147
    CrossrefPubMedGoogle Scholar
  • 11 Ballestín A, Casado JG, Abellán E. et al. A pre-clinical rat model for the study of ischemia-reperfusion injury in reconstructive microsurgery. J Vis Exp 2019; 8 (153) DOI: 10.3791/60292.
    CrossrefPubMedGoogle Scholar
  • 12 Hissin PJ, Hilf R. A fluorometric method for determination of oxidized and reduced glutathione in tissues. Anal Biochem 1976; 74 (01) 214-226
    CrossrefPubMedGoogle Scholar
  • 13 Siemionow M, Arslan E. Ischemia/reperfusion injury: a review in relation to free tissue transfers. Microsurgery 2004; 24 (06) 468-475
    CrossrefPubMedGoogle Scholar
  • 14 Ballestín A, Casado JG, Abellán E. et al. Ischemia-reperfusion injury in a rat microvascular skin free flap model: a histological, genetic, and blood flow study. PLoS One 2018; 13 (12) e0209624
    CrossrefPubMedGoogle Scholar
  • 15 Shaughness G, Blackburn C, Ballestín A, Akelina Y, Ascherman JA. Predicting thrombosis formation in 1-mm-diameter arterial anastomoses with transit-time ultrasound technology. Plast Reconstr Surg 2017; 139 (06) 1400-1405
    CrossrefPubMedGoogle Scholar
  • 16 Najjar M, Lopez Jr. MM, Ballestin A. et al. Reestablishment of lymphatic drainage after vascularized lymph node transfer in a rat model. Plast Reconstr Surg 2018; 142 (04) 503e-508e
    CrossrefPubMedGoogle Scholar
  • 17 Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74 (05) 1124-1136
    CrossrefPubMedGoogle Scholar
  • 18 Zahir KS, Syed SA, Zink JR, Restifo RJ, Thomson JG. Ischemic preconditioning improves the survival of skin and myocutaneous flaps in a rat model. Plast Reconstr Surg 1998; 102 (01) 140-150 , discussion 151–152
    CrossrefPubMedGoogle Scholar
  • 19 Coskunfirat OK, Ozkan O, Dikici MB. The effect of ischemic preconditioning on secondary ischemia in skin flaps. Ann Plast Surg 2006; 57 (04) 431-434
    CrossrefPubMedGoogle Scholar
  • 20 Zahir TM, Zahir KS, Syed SA, Restifo RJ, Thomson JG. Ischemic preconditioning of musculocutaneous flaps: effects of ischemia cycle length and number of cycles. Ann Plast Surg 1998; 40 (04) 430-435
    CrossrefPubMedGoogle Scholar
  • 21 Saita Y, Yokoyama K, Nakamura K, Itoman M. Protective effect of ischaemic preconditioning against ischaemia-induced reperfusion injury of skeletal muscle: how many preconditioning cycles are appropriate?. Br J Plast Surg 2002; 55 (03) 241-245
    CrossrefPubMedGoogle Scholar
  • 22 Knudsen AR, Kannerup AS, Dich R. et al. Expression of genes involved in rat liver angiogenesis after ischaemia and reperfusion: effects of ischaemic pre- and post-conditioning. HPB (Oxford) 2010; 12 (08) 554-560
    CrossrefPubMedGoogle Scholar
  • 23 Hamilton K, Wolfswinkel EM, Weathers WM. et al. The delay phenomenon: a compilation of knowledge across specialties. Craniomaxillofac Trauma Reconstr 2014; 7 (02) 112-118
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Carroll WR, Esclamado RM. Ischemia/reperfusion injury in microvascular surgery. Head Neck 2000; 22 (07) 700-713
    CrossrefPubMedGoogle Scholar
  • 25 Smith GW, McArthur CJ, Simpson IJ. Circulating immune complexes in myocardial infarction. J Clin Lab Immunol 1983; 12 (04) 197-199
    PubMedGoogle Scholar
  • 26 Walport MJ. Complement. First of two parts. N Engl J Med 2001; 344 (14) 1058-1066
    CrossrefPubMedGoogle Scholar
  • 27 Riedemann NC, Ward PA. Complement in ischemia reperfusion injury. Am J Pathol 2003; 162 (02) 363-367
    CrossrefPubMedGoogle Scholar
  • 28 Ducruet AF, Mocco J, Mack WJ. et al. Pre-clinical evaluation of an sLe x-glycosylated complement inhibitory protein in a non-human primate model of reperfused stroke. J Med Primatol 2007; 36 (06) 375-380
    CrossrefPubMedGoogle Scholar
  • 29 Buerke M, Schwertz H, Seitz W, Meyer J, Darius H. Novel small molecule inhibitor of C1s exerts cardioprotective effects in ischemia-reperfusion injury in rabbits. J Immunol 2001; 167 (09) 5375-5380
    CrossrefPubMedGoogle Scholar
  • 30 Ferraresso M, Macor P, Valente M. et al. Posttransplant ischemia-reperfusion injury in transplanted heart is prevented by a minibody to the fifth component of complement. Transplantation 2008; 86 (10) 1445-1451
    CrossrefPubMedGoogle Scholar
  • 31 Lewis AG, Köhl G, Ma Q, Devarajan P, Köhl J. Pharmacological targeting of C5a receptors during organ preservation improves kidney graft survival. Clin Exp Immunol 2008; 153 (01) 117-126
    CrossrefPubMedGoogle Scholar
  • 32 Jiang H, Wagner E, Zhang H, Frank MM. Complement 1 inhibitor is a regulator of the alternative complement pathway. J Exp Med 2001; 194 (11) 1609-1616
    CrossrefPubMedGoogle Scholar
  • 33 Nielsen EW, Waage C, Fure H. et al. Effect of supraphysiologic levels of C1-inhibitor on the classical, lectin and alternative pathways of complement. Mol Immunol 2007; 44 (08) 1819-1826
    CrossrefPubMedGoogle Scholar
  • 34 Kunschak M, Engl W, Maritsch F. et al. A randomized, controlled trial to study the efficacy and safety of C1 inhibitor concentrate in treating hereditary angioedema. Transfusion 1998; 38 (06) 540-549
    CrossrefPubMedGoogle Scholar
  • 35 Khalil AA, Aziz FA, Hall JC. Reperfusion injury. Plast Reconstr Surg 2006; 117 (03) 1024-1033
    CrossrefPubMedGoogle Scholar
  • 36 Zhou T, Chuang CC, Zuo L. Molecular characterization of reactive oxygen species in myocardial ischemia-reperfusion injury. BioMed Res Int 2015; 2015: 864946
    CrossrefPubMedGoogle Scholar
  • 37 Gurlek A, Celik M, Parlakpinar H, Aydogan H, Bay-Karabulut A. The protective effect of melatonin on ischemia-reperfusion injury in the groin (inferior epigastric) flap model in rats. J Pineal Res 2006; 40 (04) 312-317
    CrossrefPubMedGoogle Scholar