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Journal of Gastrointestinal Surgery

Published in:

01-05-2009 | Original Article

Somatostatin Limits Intestinal Ischemia-Reperfusion Injury in Macaques via Suppression of TLR4-NF-κB Cytokine Pathway

Authors: Hao Wu, Ling Liu, Qinghua Tan, Chunhui Wang, Meimei Guo, Yongmei Xie, Chengwei Tang

Published in: Journal of Gastrointestinal Surgery | Issue 5/2009

Abstract

Objective

Intestinal ischemia-reperfusion (IIR)-induced gut injury remains a challenge for critically ill patients despite the oxidative stress theory that has been elaborated. This study aimed to test whether Toll-like receptor 4 (TLR4) is involved in gut injury during IIR and whether somatostatin (SST) affects TLR4-nuclear factor-κB (NF-κB) cytokine pathway in the intestinal mucosa of macaques.

Design

Fifteen macaques were randomized into control, IIR, and SST + IIR groups. Pieces of isolated ileal epithelium from each animal were incubated with lipopolysaccharide (LPS), interferon-γ, or SST. Expression of TLR4 and NF-κBp65 was evaluated by immunohistochemical staining, Western blot analysis and reverse transcription polymerase chain reaction. Cytokine levels were measured by ELISA. Radioimmunoassay was used to determine of SST levels.

Measurements and Main Results

Significant overexpression (IIR vs control) of ileal TLR4 (0.17 ± 0.03 vs 0.05 ± 0.02), NF-κBp65 (0.55 ± 0.11 vs 0.15 ± 0.05), and TNF-α (213.2 ± 29.2 vs 56.0 ± 10.04) after IIR was greatly decreased (p < 0.05) by prophylactic use of SST (TLR4: 0.06 ± 0.02; NF-κBp65: 0.26 ± 0.09; TNF-α: 97.1 ± 32.3) in vivo. TLR4 expression in the ileal epithelium treated with LPS and SST (1,330 ± 93) was significantly lower than that in the ileal epithelium treated with LPS alone (2,088 ± 126) in vitro. SST levels in plasma (3.67 ± 0.41 ng/ml) and ileal mucosa (1,402.3 ± 160 ng/mg protein) of the IIR group were significantly lower than those (6.09 ± 1.29 ng/ml, 2,234. 8 ± 301.8 ng/mg protein) in the control group (p < 0.05).

Conclusions

Endogenous SST is a crucial inhibitor of massive inflammatory injury in the intestinal mucosa via direct suppression of the TLR4-NF-κB cytokine pathway induced by LPS in ileal epithelium. IIR attacks caused shortages of endogenous SST in the plasma and intestinal mucosa of macaques in this study. Therefore, preventive supplements of SST may limit intestinal injury of macaques by IIR.

Stechmiller JK, Treloar D, Allen N. Gut dysfunction in critically ill patients: a review of the literature. Am J Crit Care 1997;6:204–209.PubMed

McNeill JR, Stark RD, Greenway CV. Intestinal vasoconstriction after haemorrhage: role of vasopressin and angiotensin. Am J Physiol 1970;219:1342–1347.PubMed

Magnotti LJ, Deitch EA. Burns, bacterial translocation, gut barrier function, and failure. J Burn Care Rehabil 2005;26:383–391.PubMedCrossRef

Deitch EA, Xu D, Kaise VL. Role of the gut in the development of injury- and shock induced SIRS and MODS: the gut-lymph hypothesis, a review. Front Biosci 2006;11:520–528.PubMedCrossRef

Thoma-Uszynski S, Stenger S, Takeuchi O. Induction of direct antimicrobial activity through mammalian Toll-like receptor. Science 2001;291:1544–1547.PubMedCrossRef

Medzhitov R, Preston-Hulburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997;388:394–397.PubMedCrossRef

Faure E, Thomas L, Xu H. Bacterial lipopolysaccharide and IFN gamma induce Toll like receptor 2 and Toll like receptor 4 expression in human endothelial cells: role of NF-kappa B activation. J Immunol 2001;166:2018–2024.PubMed

Pearl-Yafe M, Fabian I, Halperin D, et al. Interferon-gamma and bacterial lipopolysaccharide act synergistically on human neutrophils enhancing interleukin-8, interleukin-1beta, tumor necrosis factor-alpha, and interleukin-12 p70 secretion and phagocytosis via upregulation of toll-like receptor 4. Shock 2007;27:226–231.PubMedCrossRef

Abreu MT, Arnold ET, Thomas LS, et al. TLR4 and MD-2 expression is regulated by immune-mediated signal in human intestinal epithelial cells. J Biol Chem 2002;277:20431–20437.PubMedCrossRef

10.

Chowers Y, Cahalon L, Lahav M, et al. Somatostatin through its specific receptor inhibits spontaneous and TNF-alpha and bacteria-induced IL-8 and IL-1 beta secretion from intestinal epithelial cells. J Immunol 2000;165:2955–2961.PubMed

11.

Than M, Nemeth J, Szilvassy Z, et al. Systemic anti-inflammatory effect of somatostatin released from capsaicin-sensitive vagal and sciatic sensory fibers of the rat and guinea-pig. Eur J Pharmacol 2000;399:251–258.PubMedCrossRef

12.

Tang C, Lan C, Liu R. Alleviation of multiple organ dysfunction syndrome by somatostatin via suppression of intestinal mucosal mast cells. Shock 2005;23:470–475.PubMedCrossRef

13.

Hacioglu A, Algin C, Pasaoglu O, et al. Protective effect of leptin against ischemia-reperfusion injury in the rat small intestine. BMC Gastroenterol 2005;5:37.PubMedCrossRef

14.

Poon RT, Yeung C, Lo CM, et al. Prophylactic effect of somatostatin on post-ERCP pancreatitis: a randomized controlled trial. Gastrointest Endosc 1999;49:593–598.PubMedCrossRef

15.

Rogler G, Daig R, Aschenbrenner E, et al. Establishment of long-term primary cultures of human small and large intestinal epithelial cells. Lab Invest 1998;78:889–890.PubMed

16.

Perreault N, Beaulieu JF. Primary cultures of fully differentiated and pure human intestinal epithelial cells. Exp Cell Res 1998;245:34–42.PubMedCrossRef

17.

Kaiser GC, Yan F, Polk DB. Mesalamine blocks tumor necrosis factor growth inhibition and nuclear factor kB activation in mouse coloncytes. Gastroenterology 1999;116:602–609.PubMedCrossRef

18.

Ozturk H, Duran H, Uzunlar AK. Mibefradil, a T-type Ca2+ channel blocker, protects against mesenteric ischemia-reperfusion-induced oxidative injury and histologic alterations in intestinal mucosa in rats. Dig Dis Sci 2006;51:1454–1460.PubMedCrossRef

19.

Green BT, Tendler DA. Ischemic colitis: a clinical review. South Med J 2005;98:217–222.PubMedCrossRef

20.

Shimazu R, Akashi S, Ogata H, et al. MD-2,a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor-4. J Exp Med 1999;189:1777–1782.PubMedCrossRef

21.

Yang H, Young DW, Gusovsky F, et al. Cellular events mediated by lipopolysaccharide stimulated toll-like receptor 4. MD2 is required for activation of mitogen-activated protein kinases and Elk-1. J Biol Chem 2000;275:20861–20866.PubMedCrossRef

22.

Nagai Y, Akashi S, Nagafuku, M, et al. Essential role of MD2 in LPS responsiveness and TLR4 distribution. Nat Immunol 2002;3:667–672.PubMed

23.

Konno K, Wakabayashi Y, Akashi-, Takamura S, et al. A molecule that is associated with Toll-like receptor 4 and regulates its cell surface expression. Biochem Biophys Res Commun 2006;339:1076–1082.PubMedCrossRef

24.

Feng CG, Scanga, CA, Collazo-Custodio CM, et al. Mice lacking myeloid differentiation factor 88 display profound defects in host resistance and immune responses to Mycobacterium avium infection not exhibited by Toll-like receptor 2 (TLR2)- and TLR4-deficient animals. J Immunol 2003;171:4758–4764.PubMed

25.

Hoebe K, Du X, Georgel P, et al. Identification of LPS as a key transducer of MyD88-independent TIR ignaling. Natur 2003;424:743–748.CrossRef

26.

Abraham E. NF-κB activation. Crit Care Med 2000;28(Suppl):100–104.CrossRef

27.

Nichols TC. NF-kappaB and reperfusion injury. Drug News Perspect 2004;17:99–104.PubMedCrossRef

Title: Somatostatin Limits Intestinal Ischemia-Reperfusion Injury in Macaques via Suppression of TLR4-NF-κB Cytokine Pathway
Authors: Hao Wu
Ling Liu
Qinghua Tan
Chunhui Wang
Meimei Guo
Yongmei Xie
Chengwei Tang
Publication date: 01-05-2009
Publisher: Springer-Verlag
Published in: Journal of Gastrointestinal Surgery / Issue 5/2009
Print ISSN: 1091-255X
Electronic ISSN: 1873-4626
DOI: https://doi.org/10.1007/s11605-009-0816-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Somatostatin Limits Intestinal Ischemia-Reperfusion Injury in Macaques via Suppression of TLR4-NF-κB Cytokine Pathway

Abstract

Objective

Design

Measurements and Main Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objective

Design

Measurements and Main Results

Conclusions

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