SpringerLink
Log in

Role of Toll-Like Receptor 4 in the Pathophysiology of Severe Acute Pancreatitis in Mice

  • Original Article
  • Published:
Surgery Today Aims and scope Submit manuscript

Abstract

Purpose

Multiple organ dysfunction and infection are major contributors to the high mortality associated with severe acute pancreatitis (SAP). Toll-like receptor 4 (TLR4) recognizes the lipopolysaccharide of gram-negative bacilli and is involved in inflammatory response and host defense. We examined the effects of TLR4-deficiency in SAP in mice.

Methods

Closed duodenal loop-induced pancreatitis was induced in C3H/HeN (wild-type) and C3H/HeJ (TLR4-deficient) mice. We compared the severity of pancreatitis, liver and kidney dysfunction, and bacterial translocation to the pancreas between the two types of mice 12 h after the induction of SAP.

Results

The severity of pancreatitis was similar in the two types of mice. The TLR4-deficient mice had significantly lower serum levels of aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine; significantly lower serum levels of interleukin-1 and tumor necrosis factor; reduced apoptosis of the liver and kidney; and a significantly higher rate of positive gram-negative bacterial cultures of the pancreas. TLR4 protein expression in the liver, kidney, and small intestine was increased 4 h after the induction of SAP, and decreased 12 h after the induction of SAP.

Conclusions

TLR4 is implicated in the mechanism of organ dysfunction and bacterial translocation in SAP, and TLR4 may trigger the inflammatory response and function defensively against infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. S Tenner G Sica M Hughes E Noordhoek S Feng M Zinner et al. (1997) ArticleTitleRelationship of necrosis to organ failure in severe acute pancreatitis Gastroenterology 113 899–903 Occurrence Handle9287982 Occurrence Handle10.1016/S0016-5085(97)70185-9 Occurrence Handle1:STN:280:ByiH3svgvFI%3D

    Article  PubMed  CAS  Google Scholar 

  2. A Buter CW Imrie CR Carter S Evans CJ McKay (2002) ArticleTitleDynamic nature of early organ dysfunction determines outcome in acute pancreatitis Br J Surg 89 298–302 Occurrence Handle11872053 Occurrence Handle10.1046/j.0007-1323.2001.02025.x Occurrence Handle1:STN:280:DC%2BD387jsleqsQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  3. HG Beger R Bittner S Block M Buchler (1986) ArticleTitleBacterial contamination of pancreatic necrosis: a prospective clinical study Gastroenterology 91 433–8 Occurrence Handle3522342 Occurrence Handle1:STN:280:BimB2cflt1Y%3D

    PubMed  CAS  Google Scholar 

  4. MW Buchler B Gloor CA Muller H Friess CA Seiler W Uhl (2000) ArticleTitleAcute necrotizing pancreatitis: treatment strategy according to the status of infection Ann Surg 232 619–26 Occurrence Handle11066131 Occurrence Handle10.1097/00000658-200011000-00001 Occurrence Handle1:STN:280:DC%2BD3crhtF2rtA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  5. NS Runkel FG Moody GS Smith LF Rodriguez MT LaRocco TA Miller (1991) ArticleTitleThe role of the gut in the development of sepsis in acute pancreatitis J Surg Res 51 18–23 Occurrence Handle2067354 Occurrence Handle10.1016/0022-4804(91)90064-S Occurrence Handle1:STN:280:By6B1Mrmtl0%3D

    Article  PubMed  CAS  Google Scholar 

  6. DS Medich TK Lee MF Melhem MI Rowe WH Schraut KK Lee (1993) ArticleTitlePathogenesis of pancreatic sepsis Am J Surg 165 46–50 Occurrence Handle8418702 Occurrence Handle10.1016/S0002-9610(05)80403-9 Occurrence Handle1:STN:280:ByyC3MfosVQ%3D

    Article  PubMed  CAS  Google Scholar 

  7. L Gianotti R Munda JW Alexander JI Tchervenkov GF Babcock (1993) ArticleTitleBacterial translocation: a potential source for infection in acute pancreatitis Pancreas 8 551–8 Occurrence Handle8302791 Occurrence Handle10.1097/00006676-199309000-00004 Occurrence Handle1:STN:280:ByuC3svmsVE%3D

    Article  PubMed  CAS  Google Scholar 

  8. R Medzhitov P Preston-Hurlburt CA Janeway SuffixJr (1997) ArticleTitleA human homologue of the Drosophila Toll protein signals activation of adaptive immunity Nature 388 394–7 Occurrence Handle9237759 Occurrence Handle10.1038/41131 Occurrence Handle1:CAS:528:DyaK2sXkvVChurc%3D

    Article  PubMed  CAS  Google Scholar 

  9. K Takeda T Kaisho S Akira (2003) ArticleTitleToll-like receptors Annu Rev Immunol 21 335–76 Occurrence Handle12524386 Occurrence Handle10.1146/annurev.immunol.21.120601.141126 Occurrence Handle1:CAS:528:DC%2BD3sXjtF2isrg%3D

    Article  PubMed  CAS  Google Scholar 

  10. A Yoshimura E Lien RR Ingalls E Tuomanen R Dziarski D Golenbock (1999) ArticleTitleCutting edge: recognition of gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2 J Immunol 163 1–5 Occurrence Handle10384090 Occurrence Handle1:CAS:528:DyaK1MXktF2rsLc%3D

    PubMed  CAS  Google Scholar 

  11. AO Aliprantis RB Yang MR Mark S Suggett B Devaux JD Radolf et al. (1999) ArticleTitleCell activation and apoptosis by bacterial lipoproteins through Toll-like receptor-2 Science 285 736–9 Occurrence Handle10426996 Occurrence Handle10.1126/science.285.5428.736 Occurrence Handle1:CAS:528:DyaK1MXltVehsLg%3D

    Article  PubMed  CAS  Google Scholar 

  12. A Poltorak X He I Smirnova MY Liu C Van Huffel X Du et al. (1998) ArticleTitleDefective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene Science 282 2085–8 Occurrence Handle9851930 Occurrence Handle10.1126/science.282.5396.2085 Occurrence Handle1:CAS:528:DyaK1cXotVyjsbk%3D

    Article  PubMed  CAS  Google Scholar 

  13. K Hoshino O Takeuchi T Kawai H Sanjo T Ogawa Y Takeda et al. (1999) ArticleTitleCutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product J Immunol 162 3749–52 Occurrence Handle10201887 Occurrence Handle1:CAS:528:DyaK1M**tFGqsL4%3D

    PubMed  CAS  Google Scholar 

  14. DL Williams T Ha C Li JH Kalbfleisch J Schweitzer W Vogt et al. (2003) ArticleTitleModulation of tissue Toll-like receptor 2 and 4 during the early phases of polymicrobial sepsis correlates with mortality Crit Care Med 31 1808–18 Occurrence Handle12794424 Occurrence Handle10.1097/01.CCM.0000069343.27691.F3

    Article  PubMed  Google Scholar 

  15. M Hausmann S Kiessling S Mestermann G Webb T Spottl T Andus et al. (2002) ArticleTitleToll-like receptors 2 and 4 are up-regulated during intestinal inflammation Gastroenterology 122 1987–2000 Occurrence Handle12055604 Occurrence Handle10.1053/gast.2002.33662 Occurrence Handle1:CAS:528:DC%2BD38Xlt12gsLY%3D

    Article  PubMed  CAS  Google Scholar 

  16. H Ikushima T Nishida K Takeda T Ito T Yasuda M Yano et al. (2004) ArticleTitleExpression of Toll-like receptors 2 and 4 is downregulated after operation Surgery 135 376–85 Occurrence Handle15041961 Occurrence Handle10.1016/j.surg.2003.08.016

    Article  PubMed  Google Scholar 

  17. H Miyaso Y Morimoto M Ozaki S Haga S Shinoura Y Choda et al. (2005) ArticleTitleObstructive jaundice increases sensitivity to lipopolysaccharide via TLR4 upregulation: possible involvement in gut-derived hepatocyte growth factor-protection of hepatocytes J Gastroenterol Hepatol 20 1859–66 Occurrence Handle16336445 Occurrence Handle10.1111/j.1440-1746.2005.03953.x Occurrence Handle1:CAS:528:DC%2BD28XkslSnsg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  18. Y Li ZG Zhou QJ **a J Zhang HG Li GQ Cao et al. (2005) ArticleTitleToll-like receptor 4 detected in exocrine pancreas and the change of expression in cerulein-induced pancreatitis Pancreas 30 375–81 Occurrence Handle15841051 Occurrence Handle10.1097/01.mpa.0000160959.21580.41 Occurrence Handle1:CAS:528:DC%2BD2MXks1Wmsro%3D

    Article  PubMed  CAS  Google Scholar 

  19. HS Wu L Zhang Y Chen XJ Guo L Wang JB Xu et al. (2005) ArticleTitleEffect of nitric oxide on Toll-like receptor 2 and 4 gene expression in rats with acute lung injury complicated by acute hemorrhage necrotizing pancreatitis Hepatobiliary Pancreat Dis Int 4 609–13 Occurrence Handle16286274 Occurrence Handle1:CAS:528:DC%2BD2MXhtlWrtrzK

    PubMed  CAS  Google Scholar 

  20. K Takase Y Takeyama J Nishikawa T Ueda Y Hori M Yamamoto et al. (1999) ArticleTitleApoptotic cell death of renal tubules in experimental severe acute pancreatitis Surgery 125 411–20 Occurrence Handle10216532 Occurrence Handle1:STN:280:DyaK1M3jt1Wkug%3D%3D

    PubMed  CAS  Google Scholar 

  21. Y Takeyama Y Hori K Takase T Ueda M Yamamoto Y Kuroda (2000) ArticleTitleApoptotic cell death of hepatocytes in rat experimental severe acute pancreatitis Surgery 127 55–64 Occurrence Handle10660759 Occurrence Handle10.1067/msy.2000.99875 Occurrence Handle1:STN:280:DC%2BD3c7is1GqtA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  22. BM Sultzer (1968) ArticleTitleGenetic control of leucocyte responses to endotoxin Nature 219 1253–4 Occurrence Handle4877918 Occurrence Handle10.1038/2191253a0 Occurrence Handle1:CAS:528:DyaF1cXkvFClt74%3D

    Article  PubMed  CAS  Google Scholar 

  23. AD O'Brien DL Rosenstreich I Scher GH Campbell RP MacDermott SB Formal (1980) ArticleTitleGenetic control of susceptibility to Salmonella typhimurium in mice: role of the LPS gene J Immunol 124 20–4 Occurrence Handle6985638

    PubMed  Google Scholar 

  24. AL Cross L Asher M Seguin L Yuan N Kelly C Hammack et al. (1995) ArticleTitleThe importance of a lipopolysaccharide-initiated, cytokine-mediated host defense mechanism in mice against extraintestinally invasive Escherichia coli J Clin Invest 96 676–86 Occurrence Handle7635960 Occurrence Handle1:CAS:528:DyaK2MXnsVagtLc%3D Occurrence Handle10.1172/JCI118110

    Article  PubMed  CAS  Google Scholar 

  25. T Takayashiki H Yoshidome F Kimura M Otsuka Y Shimizu A Kato et al. (2004) ArticleTitleIncreased expression of Toll-like receptor 4 enhances endotoxin-induced hepatic failure in partially hepatectomized mice J Hepatol 41 621–8 Occurrence Handle15464243 Occurrence Handle10.1016/j.jhep.2004.06.026 Occurrence Handle1:CAS:528:DC%2BD2cXotF2isLk%3D

    Article  PubMed  CAS  Google Scholar 

  26. PN Cunningham Y Wang R Guo G He RJ Quigg (2004) ArticleTitleRole of Toll-like receptor 4 in endotoxin-induced acute renal failure J Immunol 172 2629–35 Occurrence Handle14764737 Occurrence Handle1:CAS:528:DC%2BD2cXpslajtg%3D%3D

    PubMed  CAS  Google Scholar 

  27. G Baumgarten P Knuefermann H Wrigge C Putensen H Stapel K Fink et al. (2006) ArticleTitleRole of Toll-like receptor 4 for the pathogenesis of acute lung injury in Gram-negative sepsis Eur L Anaesthesiol 23 1041–8 Occurrence Handle10.1017/S0265021506001098 Occurrence Handle1:CAS:528:DC%2BD28XhtlCmtbvL

    Article  CAS  Google Scholar 

  28. JM Prince RM Levy R Yang KP Mollen MP Fink Y Vodovotz et al. (2006) ArticleTitleToll-like receptor-4 signaling mediates hepatic injury and systemic inflammation in hemorrhagic shock J Am Coll Surg 202 407–17 Occurrence Handle16500244 Occurrence Handle10.1016/j.jamcollsurg.2005.11.021

    Article  PubMed  Google Scholar 

  29. CM Pastor J Pugin B Kwak M Chanson F Mach A Hadengue et al. (2004) ArticleTitleRole of Toll-like receptor 4 on pancreatic and pulmonary injury in a mice model of acute pancreatitis associated with endotoxemia Crit Care Med 32 1759–63 Occurrence Handle15286555 Occurrence Handle10.1097/01.CCM.0000133020.47243.8E Occurrence Handle1:CAS:528:DC%2BD2cXmtFCgtbw%3D

    Article  PubMed  CAS  Google Scholar 

  30. DJ van Westerloo S Weijer MJ Bruno AF de Vos C Van't Veer T van der Poll (2005) ArticleTitleToll-like receptor 4 deficiency and acute pancreatitis act similarly in reducing host defense during murine Escherichia coli peritonitis Crit Care Med 33 1036–43 Occurrence Handle15891333 Occurrence Handle10.1097/01.CCM.0000162684.11375.85 Occurrence Handle1:CAS:528:DC%2BD2MXkt1ahsL4%3D

    Article  PubMed  CAS  Google Scholar 

  31. X Wang L Wu K Wu R Zhang Y Dong (2005) ArticleTitleRoles of endotoxin-related signaling molecules in the progression of acute necrotizing pancreatitis in mice Pancreas 31 251–7 Occurrence Handle16163057 Occurrence Handle10.1097/01.mpa.0000175179.62916.17 Occurrence Handle1:CAS:528:DC%2BD2MXhtFeksbzE

    Article  PubMed  CAS  Google Scholar 

  32. A Hietaranta H Mustonen P Puolakkainen R Haapiainen E Kemppainen (2004) ArticleTitleProinflammatory effects of pancreatic elastase are mediated through TLR4 and NF-kappaB Biochem Biophys Res Commun 323 192–6 Occurrence Handle15351720 Occurrence Handle10.1016/j.bbrc.2004.08.077 Occurrence Handle1:CAS:528:DC%2BD2cXntlOit70%3D

    Article  PubMed  CAS  Google Scholar 

  33. GB Johnson GJ Brunn JL Platt (2004) ArticleTitleCutting edge: an endogenous pathway to systemic inflammatory response syndrome (SIRS)-like reactions through Toll-like receptor 4 J Immunol 172 20–4 Occurrence Handle14688304 Occurrence Handle1:CAS:528:DC%2BD3sXpvFehtL0%3D

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterological Surgery, Kobe University Graduate School of Medical Sciences, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    Hidehiro Sawa, Takashi Ueda, Takeo Yasuda, Makoto Shinzeki, Takahiro Nakajima & Yoshikazu Kuroda

  2. Department of Surgery, Kinki University School of Medicine, Osaka-Sayama, Japan

    Yoshifumi Takeyama

Authors
  1. Hidehiro Sawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takashi Ueda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoshifumi Takeyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takeo Yasuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Makoto Shinzeki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takahiro Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshikazu Kuroda
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sawa, H., Ueda, T., Takeyama, Y. et al. Role of Toll-Like Receptor 4 in the Pathophysiology of Severe Acute Pancreatitis in Mice. Surg Today 37, 867–873 (2007). https://doi.org/10.1007/s00595-007-3520-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00595-007-3520-x

Key words

Search

Navigation