Postconditioning improvement effects of ulinastatin on brain injury following cardiopulmonary resuscitation

Sui,Bo; Li,Yongwang; Ma,Li

doi:10.3892/etm.2014.1876

Postconditioning improvement effects of ulinastatin on brain injury following cardiopulmonary resuscitation

Authors:
- Bo Sui
- Yongwang Li
- Li Ma
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Affiliations: Department of Anesthesiology, The Second Artillery General Hospital, Beijing 100088, P.R. China, Department of Anesthesiology, The Second Artillery General Hospital, Beijing 100088, P.R. China, Department of Gynecology and Obstetrics, The Second Artillery General Hospital, Beijing 100088, P.R. China
Published online on: August 4, 2014 https://doi.org/10.3892/etm.2014.1876
Pages: 1301-1307

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Abstract

The aim of the present study was to determine the effects of ulinastatin (UTI) on brain injury in rats subjected to cardiopulmonary resuscitation (CPR) following asphyxial cardiac arrest (CA) and identify the underlying mechanisms. In total, 100 healthy male Wistar rats were randomly divided into control and treatment groups (n=50). After 4 min of asphyxial CA, all the rats were immediately subjected to CPR. The treatment group animals were administered 15 mg/kg UTI at the onset of resuscitation. The mortality rate in the two groups was recorded at 24 h post‑resuscitation. In addition, neurological function was evaluated at 24, 48 and 72 h post‑resuscitation using a neurological deficit scale (NDS). Furthermore, the effects of UTI on the Toll‑like receptor 4 (TLR4) signaling pathway in brain tissues were determined by assessing TLR4 mRNA expression, nuclear factor (NF)‑κB activity and tumor necrosis factor (TNF)‑α and interleukin (IL)‑6 levels at 1, 3, 6, 12, 24, 48 and 72 h post‑resuscitation. After 24 h, the mortality rate significantly decreased in the treatment group when compared with the control animals (10 vs. 30%; P<0.05). Additionally, an overt improvement was observed in the NDS score following UTI treatment when compared with the control (P<0.01). Finally, statistically significant decreases in the levels of TLR4 mRNA expression, NF‑κB activity and TNF‑α and IL‑6 were observed in the treatment group at each time point (P<0.01). Therefore, UTI treatment at the onset of CPR significantly inhibits the TLR4 signaling pathway, thereby alleviating the inflammatory responses following resuscitation and improving neurological function.

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1	Cobb LA, Fahrenbruch CE, Olsufka M and Copass MK: Changing incidence of out-of-hospital ventricular fibrillation, 1980–2000. JAMA. 288:3008–3013. 2002.PubMed/NCBI
2	de Vreede-Swagemakers JJ, Gorgels AP, Dubois-Arbouw WI, et al: Out-of-hospital cardiac arrest in the 1990’s: a population-based study in the Maastricht area on incidence, characteristics and survival. J Am Coll Cardiol. 30:1500–1505. 1997.
3	Peters R and Boyde M: Improving survival after in-hospital cardiac arrest: the Australian experience. Am J Crit Care. 16:240–247. 2007.PubMed/NCBI
4	Adrie C, Adib-Conquy M, Laurent I, et al: Successful cardiopulmonary resuscitation after cardiac arrest as a ‘sepsis-like’ syndrome. Circulation. 106:562–568. 2002.
5	Neumar RW, Nolan JP, Adrie C, et al: Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council. Circulation. 118:2452–2483. 2008.
6	Lu YC, Yeh WC and Ohashi PS: LPS/TLR4 signal transduction pathway. Cytokine. 42:145–151. 2008. View Article : Google Scholar
7	Li YW, Jin HL, Wang BG, et al: Toll-like receptor 4 signal pathway may be involved in cerebral ischemic tolerance induced by hypoxic preconditioning: experiment with rats. Zhonghua Yi Xue Za Zhi. 87:2458–2462. 2007.(In Chinese).
8	Caso JR, Pradillo JM, Hurtado O, et al: Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation. 115:1599–1608. 2007. View Article : Google Scholar : PubMed/NCBI
9	Xu L, Ren B, Li M, et al: Ulinastatin suppresses systemic inflammatory response following lung ischemia-reperfusion injury in rats. Transplant Proc. 40:1310–1311. 2008. View Article : Google Scholar : PubMed/NCBI
10	Bae HB, Jeong CW, Li M, et al: Effects of urinary trypsin inhibitor on lipopolysaccharide-induced acute lung injury in rabbits. Inflammation. 35:176–182. 2012. View Article : Google Scholar : PubMed/NCBI
11	Ueki M, Taie S, Chujo K, et al: Urinary trypsin inhibitor reduces inflammatory response in kidney induced by lipopolysaccharide. J Biosci Bioeng. 104:315–320. 2007. View Article : Google Scholar : PubMed/NCBI
12	Xiao F, Pardue S, Arnold T, et al: Effect of ifenprodil, a polyamine site NMDA receptor antagonist, on brain edema formation following asphyxial cardiac arrest in rats. Resuscitation. 61:209–219. 2004. View Article : Google Scholar : PubMed/NCBI
13	Geocadin RG, Malhotra AD, Tong S, et al: Effect of acute hypoxic preconditioning on qEEG and functional recovery after cardiac arrest in rats. Brain Res. 1064:146–154. 2005. View Article : Google Scholar : PubMed/NCBI
14	Geocadin RG, Ghodadra R, Kimura T, et al: A novel quantitative EEG injury measure of global cerebral ischemia. Clin Neurophysiol. 111:1779–1787. 2000. View Article : Google Scholar : PubMed/NCBI
15	McCaul CL, McNamara PJ, Engelberts D, et al: Epinephrine increases mortality after brief asphyxial cardiac arrest in an in vivo rat model. Anesth Analg. 102:542–548. 2006. View Article : Google Scholar : PubMed/NCBI
16	Fink EL, Alexander H, Marco CD, et al: Experimental model of pediatric asphyxial cardiopulmonary arrest in rats. Pediatr Crit Care Med. 5:139–144. 2004. View Article : Google Scholar : PubMed/NCBI
17	Ren B, Wu H, Zhu J, et al: Ulinastatin attenuates lung ischemia-reperfusion injury in rats by inhibiting tumor necrosis factor alpha. Transplant Proc. 38:2777–2779. 2006. View Article : Google Scholar : PubMed/NCBI
18	Nakanishi K, Takeda S, Sakamoto A and Kitamura A: Effects of ulinastatin treatment on the cardiopulmonary bypass-induced hemodynamic instability and pulmonary dysfunction. Crit Care Med. 34:1351–1357. 2006. View Article : Google Scholar : PubMed/NCBI
19	Koga Y, Fujita M, Tsuruta R, et al: Urinary trypsin inhibitor suppresses excessive superoxide anion radical generation in blood, oxidative stress, early inflammation, and endothelial injury in forebrain ischemia/reperfusion rats. Neurol Res. 32:925–932. 2010. View Article : Google Scholar
20	Ito K, Mizutani A, Kira S, et al: Effect of Ulinastatin, a human urinary trypsin inhibitor, on the oleic acid-induced acute lung injury in rats via the inhibition of activated leukocytes. Injury. 36:387–394. 2005. View Article : Google Scholar : PubMed/NCBI
21	Inoue K and Takano H: Urinary trypsin inhibitor as a therapeutic option for endotoxin-related inflammatory disorders. Expert Opin Investig Drugs. 19:513–520. 2010. View Article : Google Scholar : PubMed/NCBI
22	Tanaka R, Fujita M, Tsuruta R, et al: Urinary trypsin inhibitor suppresses excessive generation of superoxide anion radical, systemic inflammation, oxidative stress, and endothelial injury in endotoxemic rats. Inflamm Res. 59:597–606. 2010. View Article : Google Scholar
23	Wang X, Xue Q, Yan F, et al: Ulinastatin as a neuroprotective and anti-inflammatory agent in infant piglets model undergoing surgery on hypothermic low-flow cardiopulmonary bypass. Paediatr Anaesth. 23:209–216. 2013. View Article : Google Scholar : PubMed/NCBI
24	Xu CE, Zhang MY, Zou CW and Gou L: Evaluation of the pharmacological function of ulinastatin in experimental animals. Molecules. 17:9070–9080. 2012. View Article : Google Scholar : PubMed/NCBI
25	Karikó K, Weissman D and Welsh FA: Inhibition of Toll-like receptor and cytokine signaling - a unifying theme in ischemic tolerance. J Cereb Blood Flow Metab. 24:1288–1304. 2004.PubMed/NCBI
26	Aderem A and Ulevitch RJ: Toll-like receptors in the induction of the innate immune response. Nature. 406:782–787. 2000. View Article : Google Scholar : PubMed/NCBI
27	Raeburn CD, Sheppard F, Barsness KA, et al: Cytokines for surgeons. Am J Surg. 183:268–273. 2002. View Article : Google Scholar : PubMed/NCBI
28	Song M and Kellum JA: Interleukin-6. Crit Care Med. 33(12 Suppl): S463–S465. 2005. View Article : Google Scholar : PubMed/NCBI