Advertisement

Unfractionated Heparin Protects Microcirculation in Endotoxemic Rats by Antagonizing Histones

Published:October 15, 2022DOI:https://doi.org/10.1016/j.jss.2022.09.019

      Abstract

      Introduction

      Levels of extracellular histones are highly increased in sepsis and may facilitate microcirculatory dysfunction. Unfractionated heparin (UFH) binds histones and neutralizes their cytotoxicity. We investigated the effect of UFH on microcirculatory dysfunction by interacting with extracellular histones in endotoxemic rats.

      Methods

      Twenty-four Wistar rats were randomly divided into three groups: control, lipopolysaccharide (LPS) group, and LPS + UFH group. In the LPS and LPS + UFH groups, 10 mg/kg LPS was injected to induce endotoxemia, and 100 IU/kg/h UFH was administered intravenously in the LPS + UFH group. The rats underwent midline laparotomy, and then intestinal microcirculation was evaluated using an incident dark field microscope. Circulating histones and microstructures of the rat intestinal microvascular endothelium were also detected. Additionally, the antagonistic effect of UFH on histone-induced cytotoxicity was investigated in human intestinal microvascular endothelial cells.

      Results

      UFH protected the microcirculation of the intestinal serosa and mucosa in endotoxemic rats, as evidenced by increased total vessel density, perfused vessel density, and proportion of perfused vessels of both the serosa and mucosa, and increased microcirculatory flow index of the mucosa in the LPS + UFH group. UFH treatment decreased the levels of circulating histones and alleviated intestinal microvascular endothelial injuries in endotoxemic rats. Furthermore, UFH inhibited histone cytotoxicity in vitro.

      Conclusions

      UFH attenuated microcirculatory dysfunction in endotoxemic rats by antagonizing extracellular histones, thereby providing a potential therapeutic strategy for sepsis.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Surgical Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Singer M.
        • Deutschman C.S.
        • Seymour C.W.
        • et al.
        The third international consensus definitions for sepsis and septic shock (Sepsis-3).
        JAMA. 2016; 315: 801-810
        • Colbert J.F.
        • Schmidt E.P.
        Endothelial and microcirculatory function and dysfunction in sepsis.
        Clin chest Med. 2016; 37: 263-275
        • Ince C.
        The microcirculation is the motor of sepsis.
        Crit Care. 2005; 9: S13-S19
        • Aird W.C.
        The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome.
        Blood. 2003; 101: 3765-3777
        • Xu J.
        • Zhang X.
        • Pelayo R.
        • et al.
        Extracellular histones are major mediators of death in sepsis.
        Nat Med. 2009; 15: 1318-1321
        • Chen R.
        • Kang R.
        • Fan X.G.
        • Tang D.
        Release and activity of histone in diseases.
        Cell Death Dis. 2014; 5e1370
        • Zhu C.
        • Liang Y.
        • Li X.
        • Chen N.
        • Ma X.
        Unfractionated heparin attenuates histone-mediated cytotoxicity in vitro and prevents intestinal microcirculatory dysfunction in histone-infused rats.
        The J Trauma acute Care Surg. 2019; 87: 614-622
        • Zhao D.
        • Ding R.
        • Mao Y.
        • Wang L.
        • Zhang Z.
        • Ma X.
        Heparin rescues sepsis-associated acute lung injury and lethality through the suppression of inflammatory responses.
        Inflammation. 2012; 35: 1825-1832
        • Ding R.
        • Zhao D.
        • Guo R.
        • Zhang Z.
        • Ma X.
        Treatment with unfractionated heparin attenuates coagulation and inflammation in endotoxemic mice.
        Thromb Res. 2011; 128: e160-e165
        • Wildhagen K.C.
        • Garcia de Frutos P.
        • Reutelingsperger C.P.
        • et al.
        Nonanticoagulant heparin prevents histone-mediated cytotoxicity in vitro and improves survival in sepsis.
        Blood. 2014; 123: 1098-1101
        • Yeh Y.C.
        • Wang M.J.
        • Lin C.P.
        • et al.
        Enoxaparin sodium prevents intestinal microcirculatory dysfunction in endotoxemic rats.
        Crit Care. 2012; 16: R59
        • Aykut G.
        • Veenstra G.
        • Scorcella C.
        • Ince C.
        • Boerma C.
        Cytocam-IDF (incident dark field illumination) imaging for bedside monitoring of the microcirculation.
        Intensive Care Med Exp. 2015; 3: 40
        • Hutchings S.
        • Watts S.
        • Kirkman E.
        The Cytocam video microscope. A new method for visualising the microcirculation using Incident Dark Field technology.
        Clin Hemorheol Microcirc. 2016; 62: 261-271
        • Boerma E.C.
        • Mathura K.R.
        • van der Voort P.H.
        • Spronk P.E.
        • Ince C.
        Quantifying bedside-derived imaging of microcirculatory abnormalities in septic patients: a prospective validation study.
        Crit Care. 2005; 9: R601-R606
        • Abrams S.T.
        • Zhang N.
        • Manson J.
        • et al.
        Circulating histones are mediators of trauma-associated lung injury.
        Am J Respir Crit Care Med. 2013; 187: 160-169
        • Delaby C.
        • Pilard N.
        • Goncalves A.S.
        • Beaumont C.
        • Canonne-Hergaux F.
        Presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and down-regulated by hepcidin.
        Blood. 2005; 106: 3979-3984
        • Pan B.
        • Alam H.B.
        • Chong W.
        • et al.
        CitH3: a reliable blood biomarker for diagnosis and treatment of endotoxic shock.
        Scientific Rep. 2017; 7: 8972
        • Viera A.J.
        • Garrett J.M.
        Understanding interobserver agreement: the kappa statistic.
        Fam Med. 2005; 37: 360-363
        • De Backer D.
        • Ricottilli F.
        • Ospina-Tascon G.A.
        Septic shock: a microcirculation disease.
        Curr Opin Anaesthesiol. 2021; 34: 85-91
        • Hiltebrand L.B.
        • Krejci V.
        • tenHoevel M.E.
        • Banic A.
        • Sigurdsson G.H.
        Redistribution of microcirculatory blood flow within the intestinal wall during sepsis and general anesthesia.
        Anesthesiology. 2003; 98: 658-669
        • Zhang H.
        • Sun Y.
        • An X.
        • Ma X.
        Unfractionated heparin improves the intestinal microcirculation in a canine septic shock model.
        Mediators Inflamm. 2021; 20219985397
        • Allam R.
        • Scherbaum C.R.
        • Darisipudi M.N.
        • et al.
        Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4.
        J Am Soc Nephrol : JASN. 2012; 23: 1375-1388
        • Xu J.
        • Zhang X.
        • Monestier M.
        • Esmon N.L.
        • Esmon C.T.
        Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury.
        J Immunol. 2011; 187: 2626-2631
        • Jaimes F.
        • De La Rosa G.
        • Morales C.
        • et al.
        Unfractioned heparin for treatment of sepsis: a randomized clinical trial (The HETRASE Study).
        Crit Care Med. 2009; 37: 1185-1196
        • Zarychanski R.
        • Abou-Setta A.M.
        • Kanji S.
        • et al.
        The efficacy and safety of heparin in patients with sepsis: a systematic review and metaanalysis.
        Crit Care Med. 2015; 43: 511-518
        • Li X.
        • Li X.
        • Zheng Z.
        • Liu Y.
        • Ma X.
        Unfractionated heparin suppresses lipopolysaccharide-induced monocyte chemoattractant protein-1 expression in human microvascular endothelial cells by blocking Kruppel-like factor 5 and nuclear factor-kappaB pathway.
        Immunobiology. 2014; 219: 778-785
        • Brotherton T.W.
        • Jagannadham M.V.
        • Ginder G.D.
        Heparin binds to intact mononucleosomes and induces a novel unfolded structure.
        Biochemistry. 1989; 28: 3518-3525
        • Young E.
        The anti-inflammatory effects of heparin and related compounds.
        Thromb Res. 2008; 122: 743-752
        • Iba T.
        • Hashiguchi N.
        • Nagaoka I.
        • Tabe Y.
        • Kadota K.
        • Sato K.
        Heparins attenuated histone-mediated cytotoxicity in vitro and improved the survival in a rat model of histone-induced organ dysfunction.
        Intensive Care Med Exp. 2015; 3: 36
        • Giefing-Kroll C.
        • Berger P.
        • Lepperdinger G.
        • Grubeck-Loebenstein B.
        How sex and age affect immune responses, susceptibility to infections, and response to vaccination.
        Aging Cell. 2015; 14: 309-321