Plant polyphenols attenuate hepatic injury after hemorrhage/resuscitation by inhibition of apoptosis, oxidative stress, and inflammation via NF-kappaB in rats
Oxidative stress and inflammation contribute to hepatic injury after hemorrhage/resuscitation (H/R). Natural plant polyphenols, i.e., green tea extract (GTE) possess high anti-oxidant and anti-inflammatory activities in various models of acute inflammation. However, possible protective effects and feasible mechanisms by which plant polyphenols modulate pro-inflammatory, apoptotic, and oxidant signaling after H/R in the liver remain unknown. Therefore, we investigated the effects of GTE and its impact on the activation of NF-kappaB in the pathogenesis of hepatic injury induced by H/R.
Twenty-four female LEWIS rats (180–250 g) were fed a standard chow (ctrl) or a diet containing 0.1% polyphenolic extracts (GTE) from Camellia sinensis starting 5 days before H/R. Rats were hemorrhaged to a mean arterial pressure of 30 ± 2 mmHg for 60 min and resuscitated (H/R and GTE H/R groups). Control groups (sham, ctrl, and GTE) underwent surgical procedures without H/R. Two hours after resuscitation, tissues were harvested.
Plasma alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) increased 3.5-fold and fourfold, respectively, in vehicle-treated rats as compared to GTE-fed rats. Histopathological analysis revealed significantly decreased hepatic necrosis and apoptosis in GTE-fed rats after H/R. Real-time PCR showed that GTE diminished gene expression of pro-apoptotic caspase-8 and Bax, while anti-apoptotic Bcl-2 was increased after H/R. Hepatic oxidative (4-hydroxynonenal) and nitrosative (3-nitrotyrosine) stress as well as systemic IL-6 level and hepatic IL-6 mRNA were markedly reduced in GTE-fed rats compared with controls after H/R. Plant polyphenols also decreased the activation of both JNK and NFκB.
Taken together, GTE application blunts hepatic damage, apoptotic, oxidative, and pro-inflammatory changes after H/R. These results underline the important roles of JNK and NF-kappaB in inflammatory processes after H/R and the beneficial impact of plant polyphenols in preventing their activation.
KeywordsPlant polyphenols Green tea extract NF-kappaB Hemorrhagic shock Liver Apoptosis In vivo
- 4.Bogner V, Keil L, Kanz KG, Kirchhoff C, Leidel BA, Mutschler W, Biberthaler P (2009) Very early posttraumatic serum alterations are significantly associated to initial massive RBC substitution, injury severity, multiple organ failure and adverse clinical outcome in multiple injured patients. Eur J Med Res 14(7):284–291CrossRefGoogle Scholar
- 7.Partrick DA, Moore FA, Moore EE, Barnett CC Jr, Silliman CC (1996) Neutrophil priming and activation in the pathogenesis of postinjury multiple organ failure. New Horiz 4(2):194–210Google Scholar
- 9.Redl H, Gasser H, Schlag G, Marzi I (1993) Involvement of oxygen radicals in shock related cell injury. Br Med Bull 49(3):556–565Google Scholar
- 11.Akgur FM, Brown MF, Zibari GB, McDonald JC, Epstein CJ, Ross CR, Granger DN (2000) Role of superoxide in hemorrhagic shock-induced P-selectin expression. Am J Physiol Heart Circ Physiol 279(2):H791–H797Google Scholar
- 13.Meng ZH, Dyer K, Billiar TR, Tweardy DJ (2001) Essential role for IL-6 in postresuscitation inflammation in hemorrhagic shock. Am J Physiol Cell Physiol 280(2):C343–C351Google Scholar
- 15.Lee CW, Lin CC, Lin WN, Liang KC, Luo SF, Wu CB, Wang SW, Yang CM (2007) TNF-alpha induces MMP-9 expression via activation of Src/EGFR, PDGFR/PI3K/Akt cascade and promotion of NF-kappaB/p300 binding in human tracheal smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 292(3):L799–L812CrossRefGoogle Scholar
- 21.Hara Y (1994) Antioxidative action of tea polyphenols: Part 1. Am Biotechnol Lab 12(8):48Google Scholar
- 22.Zhao BL, Li XJ, He RG, Cheng SJ, Xin WJ (1989) Scavenging effect of extracts of green tea and natural antioxidants on active oxygen radicals. Cell Biophys 14(2):175–185Google Scholar
- 23.Kuriyama S (2008) The relation between green tea consumption and cardiovascular disease as evidenced by epidemiological studies. J Nutr 138(8):1548S–1553SGoogle Scholar
- 25.Zhong Z, Froh M, Connor HD, Li X, Conzelmann LO, Mason RP, Lemasters JJ, Thurman RG (2002) Prevention of hepatic ischemia-reperfusion injury by green tea extract. Am J Physiol Gastrointest Liver Physiol 283(4):G957–G964Google Scholar
- 27.Fiorini RN, Donovan JL, Rodwell D, Evans Z, Cheng G, May HD, Milliken CE, Markowitz JS, Campbell C, Haines JK, Schmidt MG, Chavin KD (2005) Short-term administration of (-)-epigallocatechin gallate reduces hepatic steatosis and protects against warm hepatic ischemia/reperfusion injury in steatotic mice. Liver Transpl 11(3):298–308CrossRefGoogle Scholar
- 28.Relja B, Lehnert M, Seyboth K, Bormann F, Hohn C, Czerny C, Henrich D, Marzi I (2010) Simvastatin reduces mortality and hepatic injury after hemorrhage/resuscitation in rats. Shock 34(1):46–54Google Scholar
- 30.Lehnert M, Relja B, Sun-Young L, V, Schwestka B, Henrich D, Czerny C, Froh M, Borsello T, Marzi I (2008) A peptide inhibitor of C-jun N-terminal kinase modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation. Shock 30(2):159–165Google Scholar
- 32.Granger DN, Benoit JN, Suzuki M, Grisham MB (1989) Leukocyte adherence to venular endothelium during ischemia-reperfusion. Am J Physiol 257(5 Pt 1):G683–G688Google Scholar
- 33.Jaeschke H, Bautista AP, Spolarics Z, Spitzer JJ (1992) Superoxide generation by neutrophils and Kupffer cells during in vivo reperfusion after hepatic ischemia in rats. J Leukoc Biol 52(4):377–382Google Scholar
- 34.Farber JL (1994) Mechanisms of cell injury by activated oxygen species. Environ Health Perspect 102(10):17–24Google Scholar
- 39.Westwick JK, Weitzel C, Leffert HL, Brenner DA (1995) Activation of Jun kinase is an early event in hepatic regeneration. J Clin Invest 95(2):803–810Google Scholar
- 40.Lehnert M, Uehara T, Bradford BU, Lind H, Zhong Z, Brenner DA, Marzi I, Lemasters JJ (2006) Lipopolysaccharide-binding protein modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation. Am J Physiol Gastrointest Liver Physiol 291(3):G456–G463CrossRefGoogle Scholar
- 43.Schreck R, Rieber P, Baeuerle PA (1991) Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J 10(8):2247–2258Google Scholar
- 45.Han YJ, Kwon YG, Chung HT, Lee SK, Simmons RL, Billiar TR, Kim YM (2001) Antioxidant enzymes suppress nitric oxide production through the inhibition of NF-kappa B activation: role of H(2)O(2) and nitric oxide in inducible nitric oxide synthase expression in macrophages. Nitric Oxide 5(5):504–513CrossRefGoogle Scholar
- 52.Yang R, Martin-Hawver L, Woodall C, Thomas A, Qureshi N, Morrison D, Van WC, III (2007) Administration of glutamine after hemorrhagic shock restores cellular energy, reduces cell apoptosis and damage, and increases survival. JPEN J Parenter Enteral Nutr 31(2):94–100Google Scholar
- 53.Maitra SR, Bhaduri S, El-Maghrabi MR, Shapiro MJ (2005) Inhibition of matrix metalloproteinase on hepatic transforming growth factor beta1 and caspase-3 activation in hemorrhage. Acad Emerg Med 12(9):797–803Google Scholar
- 57.Webster GA, Perkins ND (1999) Transcriptional cross talk between NF-kappaB and p53. Mol Cell Biol 19(5):3485–3495Google Scholar