Elsevier

Resuscitation

Volume 83, Issue 6, June 2012, Pages 774-781
Resuscitation

Experimental paper
Mechanisms of the beneficial effect of NHE1 inhibitor in traumatic hemorrhage: Inhibition of inflammatory pathways

https://doi.org/10.1016/j.resuscitation.2011.11.025Get rights and content

Abstract

This study evaluated the effects of sodium-hydrogen exchanger (NHE1) inhibition on enhancing fluid resuscitation outcomes in traumatic hemorrhagic shock, and examined the mechanisms related to NHE1 inhibitor-induced protection and recovery from hemorrhagic shock. Traumatic hemorrhage was modeled in anesthetized pigs by producing tibia fractures followed by hemorrhage of 25 ml/kg for 20 min, and then a 4 mm hepatic arterial tear with surgical repair after 20 min. Animals then underwent low volume fluid resuscitation with either hextend (n = 6) or 3 mg/kg BIIB513 (NHE1 inhibitor) + hextend (n = 6). The experiment was terminated 6 h after the beginning of resuscitation. In association with traumatic hemorrhagic shock, there was a decrease in cardiac index, stimulation of the inflammatory response, myocardial, liver and kidney injury. The administration of the NHE1 inhibitor at the time of resuscitation attenuated shock-resuscitation-induced myocardial hypercontracture and resulted in a significant increase in stroke volume index, compared to vehicle-treated controls. NHE1 inhibition also reduced the inflammatory response, and lessened myocardial, liver and kidney injury. In addition, NHE1 inhibition reduced NF-κB activation and iNOS expression, and attenuated of ERK1/2 phosphorylation. Results from the present study indicate that NHE1 inhibition prevents multiple organ injury by attenuating shock-resuscitation-induced myocardial hypercontracture and by inhibiting NF-κB activation and neutrophil infiltration, reducing iNOS expression and ERK1/2 phosphorylation, thereby, reducing systemic inflammation and thus multi-organ injury.

Introduction

Hemorrhagic shock is the leading cause of death and complications in combat casualties and civilian trauma. Shock and resuscitation trigger a global ischemia/reperfusion phenomenon, in which the vast amounts of ischemic metabolites and tissue factors produced from hypoxic cells will reach the central blood upon resuscitation, and activate inflammatory cascades that contribute to the development of circulatory failure and multi-organ dysfunction.1, 2 Thus, strategies directed at preventing circulatory failure and multi-organ dysfunction would provide an opportunity to limit shock-resuscitation induced morbidity and mortality.

The Na+/H+ exchanger (NHE) family is a group of pH-regulatory proteins present in cell plasma membrane. The housekeeping isoform NHE1 is present in all mammalian cells and is the predominant isoform in cardiomyocytes and in neutrophils.3, 4 The NHE1 is believed to play a central role in the pathogenesis of ischemia–reperfusion injury and inhibition of NHE1 has a strong protective effect against tissue damage in heart, brain, lung, liver, kidney, gut, skeletal muscle, and as well as vascular system secondary to ischemia–reperfusion.5, 6, 7, 8, 9 Furthermore, there is substantial evidence indicating that NHE1 regulates inflammatory processes, and inhibition of NHE1 attenuates neutrophil activation, chemokine production, and leukocyte–endothelial cell interactions, thus protects from tissue inflammatory injury.10, 11, 12 We have previously shown that the response to fluid resuscitation after traumatic hemorrhage is improved by the addition of the NHE1 inhibitor BIIB513. That BIIB513 treatment improves cardiovascular-pulmonary function, blood oxygen transportation, and reduces pro-inflammatory response.13, 14 To further investigate the mechanisms related to NHE1 inhibitor-induced protection and recovery from traumatic hemorrhagic shock, the present study tested the hypothesis that NHE1 inhibition attenuates tissue inflammatory injury, prevents multiple organ failure by inhibiting nuclear factor (NF)-κB activation with subsequent down-regulation of downstream pro-inflammatory cytokines, and neutrophil infiltration.

Section snippets

Animal preparation

Twelve male Yorkshire pigs (25.7 ± 3.5 kg) were randomly assigned to two study groups. Group 1: consisted of six pigs that were treated with vehicle (hextend) and served as the control group. Group 2: in which six pigs received 3 mg/kg BIIB513 (NHE1 inhibitor) immediately before resuscitation with hextend.

All animal studies were approved by the Institutional Animal Care and Use Committee and complied with the Animal Welfare Act. Animals were anesthetized with ketamine, 10 mg/kg, i.m., and maintained

Hemodynamic and myocardial performance

Traumatic hemorrhagic shock resulted in a severe impairment of the indices of cardiovascular performance (Table 1, Table 2, Fig. 1). There was no significant difference between the two experimental groups immediately after hemorrhage. Initial low volume fluid resuscitation resulted in a partial recovery of systemic blood pressure and cardiac output. The addition of NHE1 inhibition with BIIB513, significantly improved systemic blood pressure and cardiac output to fluid resuscitation, attenuated

Discussion

This study was undertaken to evaluate the effects of NHE1 inhibition on enhancing fluid resuscitation outcomes in traumatic hemorrhagic shock, and to investigate the mechanisms related to NHE1 inhibitor-induced protection and recovery. We found that NHE1 inhibition prevents circulatory failure by improving cardiac performance through attenuating myocardial ischemia hypercontracture; and that NHE1 inhibition prevents multiple organ injury by inhibiting nuclear factor (NF)-κB activation and

Conflict of interest statement

No conflicts of interest to declare.

Acknowledgements

This work was supported by a USAMRMC grant W81XWH-06-1-0719 (Wu D.); and in part by the World Class University Program (R31-20029) funded by the Ministry of Education, Science and Technology, Republic of Korea.

References (34)

  • Y.V. Mukhin et al.

    ERK is regulated by sodium-proton exchanger in rat aortic vascular smooth muscle cells

    J Biol Chem

    (2004)
  • A.E. Baue et al.

    Systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF): are we winning the battle?

    Shock

    (1998)
  • Y. Le Tulzo et al.

    Hemorrhage increases cytokine expression in lung mononuclear cells in mice: involvement of catecholamines in nuclear factor-kappaB regulation and cytokine expression

    J Clin Invest

    (1997)
  • T. Fukushima et al.

    Na+/H+ exchange activity during phagocytosis in human neutrophils: role of Fcgamma receptors and tyrosine kinases

    J Cell Biol

    (1996)
  • M. Karmazyn et al.

    Role of Na+/H+ exchange in cardiac physiology and pathophysiology: mediation of myocardial reperfusion injury by the pH paradox

    Cardiovasc Res

    (1993)
  • S.E. McAllister et al.

    Na+/H+ exchange inhibitor cariporide attenuates skeletal muscle infarction when administered before ischemia or reperfusion

    J Appl Physiol

    (2009)
  • R.J. Gumina et al.

    Na(+)/H(+) exchange inhibition-induced cardioprotection in dogs: effects on neutrophils versus cardiomyocytes

    Am J Physiol Heart Circ Physiol

    (2000)
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    A Spanish translated version of the abstract of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2011.11.025.

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