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Inhibition of platelet activation suppresses reactive enteric glia and mitigates intestinal barrier dysfunction during sepsis.
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- Additional Information
- Source:
Publisher: BioMed Central Country of Publication: England NLM ID: 9501023 Publication Model: Electronic Cited Medium: Internet ISSN: 1528-3658 (Electronic) Linking ISSN: 10761551 NLM ISO Abbreviation: Mol Med Subsets: MEDLINE
- Publication Information:
Publication: 2018- : [London, United Kingdom] : BioMed Central
Original Publication: Cambridge, Mass. : Blackwell Scientific Publications, c1994-
- Subject Terms:
- Abstract:
Background: Intestinal barrier dysfunction, which is associated with reactive enteric glia cells (EGCs), is not only a result of early sepsis but also a cause of multiple organ dysfunction syndrome. Inhibition of platelet activation has been proposed as a potential treatment for septic patients because of its efficacy in ameliorating the organ damage and barrier dysfunction. During platelet activation, CD40L is translocated from α granules to the platelet surface, serving as a biomarker of platelet activation a reliable predictor of sepsis prognosis. Given that more than 95% of the circulating CD40L originate from activated platelets, the present study aimed to investigate if inhibiting platelet activation mitigates intestinal barrier dysfunction is associated with suppressing reactive EGCs and its underlying mechanism.
Methods: Cecal ligation and puncture (CLP) was performed to establish the sepsis model. 24 h after CLP, the proportion of activated platelets, the level of sCD40L, the expression of tight-junction proteins, the intestinal barrier function and histological damage of septic mice were analyzed. In vitro, primary cultured EGCs were stimulated by CD40L and LPS for 24 h and EGCs-conditioned medium were collected for Caco-2 cells treatment. The expression of tight-junction proteins and transepithelial electrical resistance of Caco-2 cell were evaluated.
Results: In vivo, inhibiting platelet activation with cilostazol mitigated the intestinal barrier dysfunction, increased the expression of ZO-1 and occludin and improved the survival rate of septic mice. The efficacy was associated with reduced CD40L + platelets proportion, decreased sCD40L concentration, and suppressed the activation of EGCs. Comparable results were observed upon treatment with compound 6877002, a blocker of CD40L-CD40-TRAF6 signaling pathway. Also, S-nitrosoglutathione supplement reduced intestinal damage both in vivo and in vitro. In addition, CD40L increased release of TNF-α and IL-1β while suppressed the release of S-nitrosoglutathione from EGCs. These EGCs-conditioned medium reduced the expression of ZO-1 and occludin on Caco-2 cells and their transepithelial electrical resistance, which could be reversed by CD40-siRNA and TRAF6-siRNA transfection on EGCs.
Conclusions: The inhibition of platelet activation is related to the suppression of CD40L-CD40-TRAF6 signaling pathway and the reduction of EGCs activation, which promotes intestinal barrier function and survival in sepsis mice. These results might provide a potential therapeutic strategy and a promising target for sepsis.
(© 2022. The Author(s).)
- References:
J Clin Invest. 2018 Nov 1;128(11):4764-4766. (PMID: 30320605)
Circulation. 2004 Jun 1;109(21):2524-8. (PMID: 15136493)
BMC Anesthesiol. 2021 Jan 22;21(1):26. (PMID: 33482737)
Am J Kidney Dis. 2002 May;39(5):937-47. (PMID: 11979337)
Biochem Med (Zagreb). 2013;23(1):107-11. (PMID: 23457771)
J Trauma Acute Care Surg. 2016 Jun;80(6):977-84. (PMID: 26891162)
Nature. 1980 Aug 14;286(5774):736-7. (PMID: 6997753)
World J Gastroenterol. 2014 Aug 28;20(32):11273-80. (PMID: 25170211)
Pharmacotherapy. 2019 Mar;39(3):317-334. (PMID: 30723937)
Gastroenterology. 2007 Apr;132(4):1344-58. (PMID: 17408650)
Nat Rev Immunol. 2014 Mar;14(3):141-53. (PMID: 24566914)
J Crit Care. 2017 Oct;41:177-182. (PMID: 28570959)
Cancer Cell. 2022 Sep 12;40(9):986-998.e5. (PMID: 36055226)
Intensive Care Med. 2014 Apr;40(4):613-5. (PMID: 24556910)
Physiol Rev. 2016 Oct;96(4):1211-59. (PMID: 27489307)
J Physiol. 2017 Jan 15;595(2):557-570. (PMID: 27106597)
J Transl Med. 2012 Aug 17;10:166. (PMID: 22901274)
Curr Pharmacol Rep. 2018 Feb;4(1):64-90. (PMID: 29527458)
Brain Behav Immun. 2018 Mar;69:255-263. (PMID: 29195783)
Clin Appl Thromb Hemost. 2021 Jan-Dec;27:1076029620943300. (PMID: 33586482)
Annu Rev Physiol. 2019 Feb 10;81:235-259. (PMID: 30379617)
Stroke. 2021 Oct;52(10):e635-e645. (PMID: 34517768)
Chest. 2012 Feb;141(2 Suppl):e89S-e119S. (PMID: 22315278)
J Clin Invest. 2018 Nov 1;128(11):5056-5072. (PMID: 30320600)
PLoS One. 2013 Jul 01;8(7):e69042. (PMID: 23840906)
Thromb Res. 2018 Jun;166:28-36. (PMID: 29655000)
Physiology (Bethesda). 2018 Jul 1;33(4):269-280. (PMID: 29897300)
J Cell Mol Med. 2020 Jan;24(1):996-1009. (PMID: 31701659)
Brain Behav Immun. 2017 Jan;59:173-189. (PMID: 27658543)
Pharmacol Ther. 2021 Mar;219:107709. (PMID: 33091428)
Crit Care Med. 2013 Oct;41(10):e275-85. (PMID: 23939348)
Circulation. 2002 Aug 20;106(8):896-9. (PMID: 12186789)
Nat Rev Neurosci. 2005 Sep;6(9):671-82. (PMID: 16136171)
Sci Rep. 2020 Jul 13;10(1):11507. (PMID: 32661347)
Biomed Res Int. 2018 Mar 26;2018:7497314. (PMID: 29780830)
BMC Genomics. 2009 Nov 02;10:507. (PMID: 19883504)
Crit Care. 2011 Mar 15;15(2):R97. (PMID: 21406105)
Infect Immun. 2003 Jun;71(6):3521-8. (PMID: 12761137)
Ann Intensive Care. 2017 Dec 1;7(1):115. (PMID: 29192366)
PLoS One. 2016 Mar 10;11(3):e0151335. (PMID: 26964064)
Gastroenterology. 2014 Dec;147(6):1230-7. (PMID: 25305504)
Neurochem Res. 2021 Jun;46(6):1410-1422. (PMID: 33656693)
Cell Signal. 2007 Aug;19(8):1765-71. (PMID: 17482796)
Nat Med. 2000 Feb;6(2):114. (PMID: 10655072)
Crit Care Med. 1992 Apr;20(4):458-67. (PMID: 1559357)
Exp Mol Med. 2018 Aug 16;50(8):1-9. (PMID: 30115904)
EBioMedicine. 2019 Mar;41:497-508. (PMID: 30878597)
Physiol Rev. 2007 Apr;87(2):545-64. (PMID: 17429041)
Cell Mol Neurobiol. 2020 Jul;40(5):801-812. (PMID: 31863221)
J Chem Inf Model. 2015 Feb 23;55(2):294-307. (PMID: 25622654)
Thromb Res. 2015 Aug;136(2):456-64. (PMID: 26116490)
Lancet Respir Med. 2014 May;2(5):380-6. (PMID: 24740011)
J Immunol. 1999 Oct 1;163(7):4049-57. (PMID: 10491009)
Adv Exp Med Biol. 2007;597:131-51. (PMID: 17633023)
Int Immunopharmacol. 2010 Sep;10(9):1077-85. (PMID: 20601185)
Trends Neurosci. 2015 Jun;38(6):364-74. (PMID: 25975510)
Nat Protoc. 2009;4(1):31-6. (PMID: 19131954)
Curr Opin Clin Nutr Metab Care. 2002 Nov;5(6):685-94. (PMID: 12394645)
Gastroenterology. 2017 Oct;153(4):1068-1081.e7. (PMID: 28711628)
Nat Rev Gastroenterol Hepatol. 2012 Nov;9(11):625-32. (PMID: 22890111)
Mol Med. 2015 Mar 26;21:219-26. (PMID: 25822797)
Chin Med J (Engl). 2016 Jul 20;129(14):1674-81. (PMID: 27411454)
Shock. 2020 Sep;54(3):330-336. (PMID: 31626040)
- Contributed Indexing:
Keywords: CD40L-CD40; Enteric glia cells; Intestinal barrier dysfunction; S-Nitrosoglutathione; Sepsis
- Accession Number:
0 (Occludin)
147205-72-9 (CD40 Ligand)
57564-91-7 (S-Nitrosoglutathione)
0 (TNF Receptor-Associated Factor 6)
0 (RNA, Small Interfering)
0 (Culture Media, Conditioned)
0 (Tight Junction Proteins)
- Publication Date:
Date Created: 20221119 Date Completed: 20221122 Latest Revision: 20221130
- Publication Date:
20231215
- Accession Number:
PMC9673322
- Accession Number:
10.1186/s10020-022-00562-w
- Accession Number:
36401163
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