C1 Esterase Inhibitor Reduces Lower Extremity Ischemia/Reperfusion Injury and Associated Lung Damage

Claudia Duehrkop,Steven H. Sacks,Robert Rieben,Martin Spycher,Rolf Spirig,Richard A. G. Smith,Yara Banz,Sylvia Miescher,Marc W. Nolte,Muriel Moser

doi:10.1371/journal.pone.0072059

Claudia Duehrkop, Steven H. Sacks + Show 8 more

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https://doi.org/10.1371/journal.pone.0072059

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Abstract

BackgroundIschemia/reperfusion injury of lower extremities and associated lung damage may result from thrombotic occlusion, embolism, trauma, or surgical intervention with prolonged ischemia and subsequent restoration of blood flow. This clinical entity is characterized by high morbidity and mortality. Deprivation of blood supply leads to molecular and structural changes in the affected tissue. Upon reperfusion inflammatory cascades are activated causing tissue injury. We therefore tested preoperative treatment for prevention of reperfusion injury by using C1 esterase inhibitor (C1 INH).Methods and FindingsWistar rats systemically pretreated with C1 INH (n = 6), APT070 (a membrane-targeted myristoylated peptidyl construct derived from human complement receptor 1, n = 4), vehicle (n = 7), or NaCl (n = 8) were subjected to 3h hind limb ischemia and 24h reperfusion. The femoral artery was clamped and a tourniquet placed under maintenance of a venous return. C1 INH treated rats showed significantly less edema in muscle (P<0.001) and lung and improved muscle viability (P<0.001) compared to controls and APT070. C1 INH prevented up-regulation of bradykinin receptor b1 (P<0.05) and VE-cadherin (P<0.01), reduced apoptosis (P<0.001) and fibrin deposition (P<0.01) and decreased plasma levels of pro-inflammatory cytokines, whereas deposition of complement components was not significantly reduced in the reperfused muscle.ConclusionsC1 INH reduced edema formation locally in reperfused muscle as well as in lung, and improved muscle viability. C1 INH did not primarily act via inhibition of the complement system, but via the kinin and coagulation cascade. APT070 did not show beneficial effects in this model, despite potent inhibition of complement activation. Taken together, C1 INH might be a promising therapy to reduce peripheral ischemia/reperfusion injury and distant lung damage in complex and prolonged surgical interventions requiring tourniquet application.

Highlights

Lower extremity ischemia/reperfusion injury (IRI), which may result from thrombotic occlusion, embolism, trauma or surgical intervention through tourniquet application and subsequent restoration of blood flow, is of essential clinical importance
Hemorrhage, edema formation and myocyte destruction were apparent in NaCl, vehicle- and APT070 treated rats, whereas C1 esterase inhibitor (C1 INH) treated rats showed only minimal tissue damage (Figure 1E–H)
The present study aimed to investigate the effects of C1 INH treatment on peripheral IRI and related remote lung damage

Summary

Introduction

Lower extremity ischemia/reperfusion injury (IRI), which may result from thrombotic occlusion, embolism, trauma or surgical intervention through tourniquet application and subsequent restoration of blood flow, is of essential clinical importance. The hypoxic state of ischemia leads to expression of non-muscle myosin heavy chain type II or annexin IV on the cell surface, which function as neo-epitopes for natural antibodies [1],[2] This immune complex formation already occurs prior to tourniquet release and paves the way for activation of the complement system. Ischemia/reperfusion injury of lower extremities and associated lung damage may result from thrombotic occlusion, embolism, trauma, or surgical intervention with prolonged ischemia and subsequent restoration of blood flow. This clinical entity is characterized by high morbidity and mortality. We tested preoperative treatment for prevention of reperfusion injury by using C1 esterase inhibitor (C1 INH)

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