Effect of remote ischemic post-conditioning on systemic inflammatory response and survival rate in lipopolysaccharide-induced systemic inflammation model

Yun-Hee Kim, Dae-Wui Yoon, Je-Hyeong Kim, Jeoung-Hyuk Lee, Choon-Hak Lim, Yun-Hee Kim, Dae-Wui Yoon, Je-Hyeong Kim, Jeoung-Hyuk Lee, Choon-Hak Lim

Abstract

Background: Remote ischemic preconditioning (RIPC) and postconditioning (RpostC) have protective effects on ischemia and reperfusion injury. The effects have been reported to activate heme oxygenase-1 (HO-1) and attenuate nuclear factor kappa B (NF-κB) and subsequently reduce systemic inflammation. Ischemic preconditioning prevented inflammatory responses by modulating HO-1 expression in endotoxic shock model. Therefore, we investigated whether RpostC could have protective effects on lipopolysaccharide (LPS)-induced systemic inflammation.

Methods: The LPS-induced sepsis mice received LPS (20 mg/kg) intraperitoneally. Remote ischemic conditioning was induced with three 10-min ischemia/10-min reperfusion cycles of the right hind limbs using tourniquet before LPS injection (RIPC) or after LPS injection (RpostC). The effects of RIPC and RpostC were examined for the survival rate, serum cytokines, NF-κB, HO-1 and liver pathology in the LPS injected mice.

Results: Survival rate within 120 hours significantly increased in the LPS injected and remote ischemic conditioned mice than in LPS only injected mice (60-65% vs 5%, respectively, p < 0.01). Tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) increased markedly in the LPS only injected mice, however, remote ischemic conditioning suppressed the changes (p < 0.05). Interleukin-10 (IL-10) level was significantly higher in the LPS injected and RpostC treated mice than in the LPS only injected mice (p = 0.014). NF-κB activation was significantly attenuated (p < 0.05) and HO-1 levels were substantially higher in the LPS injected and remote ischemic conditioned mice than in the LPS only injected mice. Neutrophil infiltration was significantly attenuated in the LPS injected and remote ischemic conditioned mice than in the only LPS injected mice (p < 0.05).

Conclusions: RpostC attenuated inflammatory responses and improved survival outcomes of mice with LPS-induced systemic inflammation. The mechanism may be caused by modifying NF-κB mediated expression of cytokines.

Keywords: Remote ischemic postconditioning; Remote ischemic preconditioning; Systemic inflammation.

Figures

Figure 1
Figure 1
Experimental protocol. Mice were randomly divided into six experimental groups (n = 6, each group) according to each target measurements: (1) Saline group, received an injection of saline (intraperitoneally: i.p.); (2) LPS group, received an injection of LPS (20 mg/kg, i.p.); (3) RIPC/Saline group, subjected to remote conditioning, followed immediately by an i.p. injections of saline; (4) Saline/RpostC group, received an injection of saline i.p., followed immediately by remote conditioning; (5) RIPC/LPS group, was subjected to remote conditioning, followed immediately by an injection of LPS (20 mg/kg, i.p.); (6) LPS/RpostC group, received an injection of LPS (20 mg/kg, i.p.), followed immediately by remote conditioning. Remote conditioning was induced with three 10-min ischemia/10-min reperfusion cycles of the right hind limbs using tourniquet.
Figure 2
Figure 2
Survival rate. The survival rate of RIPC/LPS (n = 20) and LPS/RpostC (n = 20) groups were significantly greater than that of LPS group (n = 40) (p < 0.001, p < 0.01, respectively). There was no significant difference between the RIPC/LPS and LPS/RpostC groups. LPS group, received an injection of LPS (20 mg/kg, i.p.); RIPC/LPS group, was subjected to remote conditioning, followed immediately by an injection of LPS (20 mg/kg, i.p.); LPS/RpostC group, received an injection of LPS (20 mg/kg, i.p.), followed immediately by remote conditioning. RIPC: remote ischemic preconditioning, RpostC: remote ischemic postconditioning.
Figure 3
Figure 3
Effects of RIPC and RpostC on levels of TNF-α, IL-6, IL-1β and IL-10. The concentration of TNF-α (A) and IL-6 (B) levels were measured at 1 hour and 4 hours after LPS (or saline) injection. IL-1β (C) and IL-10 (D) levels were at 1 hour after LPS injection (or saline) in each group. Mice were treated with saline (Saline group), RIPC plus saline (RIPC/Saline group), saline plus RpostC (Saline/RpostC group), LPS (20 mg/kg, i.p.; LPS group), RIPC plus LPS (RIPC/LPS group), and LPS plus RpostC (LPS/RpostC group). i.p.: intraperitoneal. RIPC: remote ischemic preconditioning, RpostC: remote ischemic postconditioning. Data are expressed as mean ± SEM (n = 6 in each group). † P < 0.05 versus Saline, RIPC/Saline, Saline/ RpostC at 1 h after LPS injection or saline injection. *P < 0.05 versus LPS group at 1 h after LPS injection or saline injection. ‡ P < 0.05 versus Saline, RIPC/Saline, Saline/ RpostC at 4 h after LPS injection or saline injection. # P < 0.05 versus LPS group at 4 h after LPS injection or saline injection. ND, not detectable.
Figure 4
Figure 4
NF-κB DNA binding activity. The NF-κB activity was measured at 1 hour after LPS (or saline) injection in liver tissue homogenate. Mice were treated with saline (Saline group), RIPC plus saline (RIPC/Saline group), saline plus RpostC (Saline/RpostC group), LPS (20 mg/kg, i.p.; LPS group), RIPC plus LPS (RIPC/LPS group), and LPS plus RpostC (LPS/RpostC group). i.p.: intraperitoneal. RIPC: remote ischemic preconditioning, RpostC: remote ischemic postconditioning. Data are expressed as mean ± SEM (n = 6 in each group). *P < 0.05 versus LPS group. † P < 0.05 versus Saline, RIPC/Saline, Saline/RpostC.
Figure 5
Figure 5
HO-1 activity. Quantification of the HO-1 levels was higher in the RIPC/LPS and LPS/RpostC compared with Saline group at 1 h after LPS or saline injection (p < 0.05). Mice were treated with saline (Saline group), RIPC plus saline (RIPC/Saline group), saline plus RpostC (Saline/RpostC group), LPS (20 mg/kg, i.p.; LPS group), RIPC plus LPS (RIPC/LPS group), and LPS plus RpostC (LPS/RpostC group). i.p.: intraperitoneal. RIPC: remote ischemic preconditioning, RpostC: remote ischemic postconditioning. Data are expressed as mean ± SEM (n = 6 in each group). *P < 0.05 versus LPS group. † P < 0.05 versus Saline.
Figure 6
Figure 6
Liver histopathological changes. (A) Saline group (B) RIPC/Saline (C) Saline/RpostC group (D) LPS group (E) RIPC/LPS group (F) LPS/RpostC group. Neutrophil accumulation within liver sinusoid substantially reduced in the RIPC/LPS group (E) and LPS/RpostC group (F) compared with that in the LPS group (D) at 12 h after LPS injection. The brown colored neutrophils are stained with anti-mouse Ly-6G (black arrows). Magnification × 400. (G) Quantification of intrahepatic sinusoidal neutrophils by counting PMNs in 16 random high-power fields. Magnification × 400. Mice were treated with saline (Saline group), RIPC plus saline (RIPC/Saline group), saline plus RpostC (Saline/RpostC group), LPS (20 mg/kg, i.p.; LPS group), RIPC plus LPS (RIPC/LPS group), and LPS plus RpostC (LPS/RpostC group). i.p.: intraperitoneal. RIPC: remote ischemic preconditioning, RpostC: remote ischemic postconditioning. Data are expressed as mean ± SEM (n = 6 in each group). *P < 0.05 versus LPS group. Data are † P < 0.05 versus Saline, RIPC/Saline, Saline/RpostC.

References

    1. Wenzel RP. Treating sepsis. N Engl J Med. 2002;347:966–967. doi: 10.1056/NEJMp020096.
    1. Dhainaut JF, Marin N, Mignon A, Vinsonneau C. Hepatic response to sepsis: interaction between coagulation and inflammatory processes. Crit Care Med. 2001;29:S42–S47.
    1. Matuschak GM, Rinaldo JE. Organ interactions in the adult respiratory distress syndrome during sepsis. Role of the liver in host defense. Chest. 1988;94:400–406. doi: 10.1378/chest.94.2.400.
    1. Browder W, Ha T, Chuanfu L, Kalbfleisch JH Jr, Ferguson DA, Williams DL. Early activation of pulmonary nuclear factor kappaB and nuclear factor kappaB and nuclear factor interleukin-6 in polymicrobial sepsis. J Trauma. 1999;46:590–596. doi: 10.1097/00005373-199904000-00006.
    1. Yoshidome H, Kato A, Edwards MJ, Lentsch AB. Interleukin-10 suppresses hepatic ischemia/reperfusion injury in mice: implications of a central role for nuclear factor kappaB. Hepatology. 1999;30:203–208. doi: 10.1002/hep.510300120.
    1. Gibbs PE, Maines MD. Biliverdin inhibits activation of NF-kappaB. reversal of inhibition by human biliverdin reductase. Int J Cancer. 2007;121:2567–2574. doi: 10.1002/ijc.22978.
    1. Bellezza I, Tucci A, Galli F, Grottelli S, Mierla AL, Pilolli F, Minelli A. Inhibition of NF-κB nuclear translocation via HO-1 activation underlies α-tocopheryl succinate toxicity. J Nutr Biochem. 2012;23:1583–1591. doi: 10.1016/j.jnutbio.2011.10.012.
    1. Mallick IH, Winslet MC, Seifalian AM. Ischemic preconditioning of small bowel mitigates the late phase of reperfusion injury: heme oxygenase mediates cytoprotection. Am J Surg. 2010;199:223–231. doi: 10.1016/j.amjsurg.2009.01.011.
    1. Zeynalov E, Shah ZA, Li RC, Dore S. Heme oxygenase 1 is associated with ischemic preconditioning-induced protection against brain ischemia. Neurobiol Dis. 2009;35:264–269. doi: 10.1016/j.nbd.2009.05.010.
    1. Xu B, Gao X, Xu J, Lei S, Xia ZY, Xu Y, Xia Z. Ischemic postconditioning attenuates lung reperfusion injury and reduces systemic proinflammatory cytokine release via heme oxygenase 1. J Surg Res. 2011;166:e157–e164. doi: 10.1016/j.jss.2010.11.902.
    1. Xia ZY, Gao J, Ancharaz AK, Liu KX, Xia Z, Luo T. Ischaemic post-conditioning protects lung from ischaemia-reperfusion injury by up-regulation of haeme oxygenase-1. Injury. 2010;41:510–516. doi: 10.1016/j.injury.2009.03.002.
    1. Lai IR, Chang KJ, Chen CF. The mechanism of hepatic heme oxygenase-1 expression by limb remote ischemic preconditioning. Transplantation. 2007;83:364. doi: 10.1097/01.tp.0000244732.30613.9c.
    1. Kanoria S, Seifalian AM, Williams R, Davidson BR. Hind limb remote preconditioning of the liver: a role for nitric oxide and HO-1. Transplantation. 2007;83:363–364. doi: 10.1097/01.tp.0000244731.93810.4f.
    1. Lai IR, Chang KJ, Chen CF, Tsai HW. Transient limb ischemia induces remote preconditioning in liver among rats: the protective role of heme oxygenase-1. Transplantation. 2006;81:1311–1317. doi: 10.1097/01.tp.0000203555.14546.63.
    1. Tapuria N, Kumar Y, Habib MM, Abu Amara M, Seifalian AM, Davidson BR. Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury–a review. J Surg Res. 2008;150:304–330. doi: 10.1016/j.jss.2007.12.747.
    1. Loukogeorgakis SP, Williams R, Panagiotidou AT, Kolvekar SK, Donald A, Cole TJ, Yellon DM, Deanfield JE, MacAllister RJ. Transient limb ischemia induces remote preconditioning and remote postconditioning in humans by a K(ATP)-channel dependent mechanism. Circulation. 2007;116:1386–1395. doi: 10.1161/CIRCULATIONAHA.106.653782.
    1. Harkin DW, Barros D’Sa AA, McCallion K, Hoper M, Campbell FC. Ischemic preconditioning before lower limb ischemia-reperfusion protects against acute lung injury. J Vasc Surg. 2002;35:1264–1273. doi: 10.1067/mva.2002.121981.
    1. Tamion F, Richard V, Renet S, Thuillez C. Intestinal preconditioning prevents inflammatory response by modulating heme oxygenase-1 expression in endotoxic shock model. Am J Physiol Gastrointest Liver Physiol. 2007;293(6):G1308–G1314. doi: 10.1152/ajpgi.00154.2007.
    1. Wen T, Wu ZM, Liu Y, Tan YF, Ren F, Wu H. Upregulation of heme oxygenase-1 with hemin prevents D-galactosamine and lipopolysaccharide-induced acute hepatic injury in rats. Toxicology. 2007;237:184–193. doi: 10.1016/j.tox.2007.05.014.
    1. Ando H, Takamura T, Ota T, Nagai Y, Kobayashi K. Cerivastatin improves survival of mice with lipopolysaccharide-induced sepsis. J Pharmacol Exp Ther. 2000;294:1043–1046.
    1. Yang J, Qu JM, Summah H, Zhang J, Zhu YG, Jiang HN. Protective effects of imipramine in murine endotoxin-induced acute lung injury. Eur J Pharmacol. 2010;638:128–133. doi: 10.1016/j.ejphar.2010.04.005.
    1. Zhong J, Deaciuc IV, Burikhanov R, de Villiers WJ. Lipopolysaccharide-induced liver apoptosis is increased in interleukin-10 knockout mice. Biochim Biophys Acta. 2006;1762:468–477. doi: 10.1016/j.bbadis.2005.12.012.
    1. Movat HZ, Cybulsky MI, Colditz IG, Chan MK, Dinarello CA. Acute inflammation in gram-negative infection: endotoxin, interleukin 1, tumor necrosis factor, and neutrophils. Fed Proc. 1987;46:97–104.
    1. Ohzato H, Yoshizaki K, Nishimoto N, Ogata A, Tagoh H, Monden M, Gotoh M, Kishimoto T, Mori T. Interleukin-6 as a new indicator of inflammatory status: detection of serum levels of interleukin-6 and C-reactive protein after surgery. Surgery. 1992;111:201–209.
    1. Debets JM, Kampmeijer R, van der Linden MP, Buurman WA, van der Linden CJ. Plasma tumor necrosis factor and mortality in critically ill septic patients. Crit Care Med. 1989;17:489–494. doi: 10.1097/00003246-198906000-00001.
    1. Veres B, Gallyas F Jr, Varbiro G, Berente Z, Osz E, Szekeres G, Szabo C, Sumegi B. Decrease of the inflammatory response and induction of the Akt/protein kinase B pathway by poly-(ADP-ribose) polymerase 1 inhibitor in endotoxin-induced septic shock. Biochem Pharmacol. 2003;65:1373–1382. doi: 10.1016/S0006-2952(03)00077-7.
    1. Remick DG, Newcomb DE, Bolgos GL, Call DR. Comparison of the mortality and inflammatory response of two models of sepsis : lipopolysaccharide vs. cecal ligation and puncture. Shock. 2000;13:110–116. doi: 10.1097/00024382-200013020-00004.
    1. Lutz J, Thurmel K, Heemann U. Anti-inflammatory treatment strategies for ischemia/reperfusion injury in transplantation. J Inflamm. 2010;7:1476–9255.
    1. Abraham E. Nuclear factor-kappaB and its role in sepsis-associated organ failure. J Infect Dis. 2003;15:S364–S369.
    1. Roller J, Laschke MW, Scheuer C, Menger MD. Heme oxygenase (HO)-1 protects from lipopolysaccharide (LPS)-mediated liver injury by inhibition of hepatic leukocyte accumulation and improvement of microvascular perfusion. Langenbecks Arch Surg. 2010;395:387–394. doi: 10.1007/s00423-010-0603-8.
    1. Duckers HJ, Boehm M, True AL, Yet SF, San H, Park JL, Clinton Webb R, Lee ME, Nabel GJ, Nabel EG. Heme oxygenase-1 protects against vascular constriction and proliferation. Nat Med. 2001;7:693–698. doi: 10.1038/89068.
    1. Otterbein LE, Soares MP, Yamashita K, Bach FH. Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol. 2003;24:449–455. doi: 10.1016/S1471-4906(03)00181-9.
    1. Menger MD, Rucker M, Vollmar B. Capillary dysfunction in striated muscle ischemia/reperfusion: on the mechanisms of Capillary “No-Reflow”. Shock. 1997;8:2–7. doi: 10.1097/00024382-199707000-00002.
    1. Wang ZH, Liang YB, Tang H, Chen ZB, Li ZY, Wu JG, Yang Q, Zeng LJ, Hu XC, Ma ZF. Expression and effects of microRNA-155 in the livers of septic mice. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2012;24:154–157.
    1. Plasenzotti R, Stoiber B, Posch M, Windberger U. Red blood cell deformability and aggregation behaviour in different animal. Clin Hemorheol Microcirc. 2004;31:105–111.
    1. Morrell MR, Micek ST, Kollef MH. The management of severe sepsis and septic shock. Infect Dis Clin North Am. 2009;23:485–501. doi: 10.1016/j.idc.2009.04.002.
    1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303–1310. doi: 10.1097/00003246-200107000-00002.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner