Prevention of Gut Barrier Dysfunction During Acute Massive Blood Loss (Experimental Study)

Purpose of the study: to investigate the influence of hypovolemia correction by infusion of malate-containing preparations and subsequent glutamine-enriched nutritional support on the maintenance of gut barrier and overhydration in animals with acute massive blood loss/  

Materials and methods. Blood samples were harvested from the tail and portal veins of rats (n=100) at different time points after the acute blood loss (>30% V/V) . Bacterial blood cultures for growth, lipopolysaccharide and presepsin concentrations, colon structures and animal weight were analyzed in blood and plasma specimens 1 hour, one day and 3 days after the hypovolemia correction. To correct the hypovolemia, in the 1st series of experiments, the Ringer’s solution and standard nutrient mixture were used; in the 2nd series malatecontaining solution and standard nutrient mixture were administered; in the 3rd series a malate-containing solution and glutamine-enriched nutrient mixture were employed.

Results. In the portal vein blood of intact animals, endotoxin measurement was equal to 17.8Ѓ}3.9 pg/ml, that of presepsin — 405.6Ѓ}80.1 pg/ml. At all stages, tail and portal blood bacterial cultures were negative demonstrating an absence of bacterial growth and gut barrier intactness for live microorganisms. One hour after hypovolemia correction and blood reinfusion, multifold increase in endotoxin concentration in the blood from both portal and tail veins was accompanied by significant increase of presepsin concentration. 24 hours after the blood loss, in the animals of the 2nd and 3rd series, the levels of endotoxin, presepsin, and edema of the colon mucous membrane and submucosal space has become lower than those in the 1st series. Three days later, the advantages of glutamine-containing nutrition in the 3rd series of the experiment were determined that revealed decreasing the endotoxin and presepsin concentrations in the portal and tail vein blood and diminishing the levels of interstitial edema of colon and animal weight growth.

Conclusion. Administration of malate-containing infusion preparations and glutamine-enriched nutrition after an acute massive blood loss contributes to decreasing presepsin production in GIT organs, abrogating endotoxin translocation into the portal vein and systemic circulation, lessening severity of edema of the mucous membrane and submucosal space of the colon, and reducing the previously increased animal body mass.

1. Petrova M.V., Butrov A.V., Grechko A.V., Stepanova N.V., Nakade M., Storchai M.N., Mohan R., Mahmutova G.R. Infusion Effect on Postoperative Intestinal Failure. Obshchaya reanimatologiya=General Reanimatology. 2018; 14 (1): 50-57. [In Russ., In Engl.] DOI: 10.15360/1813-9779-2016-2-56-65

2. Bobrinskaya I.G., Moroz V.V., Yakovenko V.N., Kudryakov O.N., Spiridonova E.A., Soldatova V.Y. Selective Polygraphy and Resonant Stimulation of Digestive Tract in Early Postoperative Period in Peritonitis. Obshchaya reanimatologiya= General Reanimatology. 2016; 12 (2): 90-99. [In Russ., In Engl.] DOI: 10.15360/1813-9779-2016-2-90-99

3. Lang R., Patel D., Morris J.J., Rutschman R.L., Murray P.J. Shaping gene expression in activated and resting primary macrophages by IL-10. J. Immunol. 2002; 169: 2253-2263. DOI: 10.4049/jimmunol.169.5.2253

4. Martinez F.O., Gordon S., Locati М., Mantovani A. Transcriptional Profiling of the Human Monocyte-to-Macrophage Differentiation and Polarization: New Molecules and Patterns of Gene Expression. J. Immunol. 2006; 177: 7303-7311 DOI: 10.4049/jimmunol.177.10.7303

5. Heine H., Rietschel E.T., Ulmer A. The biology of endotoxin. J. Mol Biotechnol. 2001; Nov; 19 (3): 279-296. DOI: 10.1385/MB:19:3:279. PMID: 11721624

6. Balzan S., de Almeida Quadros C., de Cleva R., Zilberstein B., Cecconello I., Bacterial translocation: overview of mechanisms and clinical impact. J Gastroenterol. Hepatol. 2007; Apr; 22 (4): 464-471. DOI: 10.1111/j.1440-1746.2007.04933. PMID: 17376034

7. Chernevskaya E.A., Beloborodova N.V. Gut Microbiome in Critical Illness (Review). Obshchaya reanimatologiya= General Reanimatology. 2018; 14 (5): 96-119. [In Russ.] DOI: 10.15360/1813-9779-2018-5-96-119

8. Fulop A., Turoczi Z., Garbaidsz D., Harsdnyi L., Szijdrio A. Experimental models of hemorrhagic shock: a review. Eur. Surg. Res. 2013; 50 (2): 57-70 DOI: 10.1159/000348808

9. Lomas-Niera J.L., Perl M, Chung CS, Ayala A. Shock and hemorrhage: an overview of animal models. Shock. 2005; 24 (1): 33-39 PMID: 16374370

10. Lundsgaard-Hansen P. Component therapy of surgical hemorrhage: red cell concentrates, colloids and crystalloids. Bibl Haematol. 1980; (46): 147-69 PMID: 7378036

11. Medby C. Is There a Place for Crystalloids and Colloids in Remote Damage Control Resuscitation? Shock. 2014; 41: 47–50. DOI: 10.1097/shk.0000000000000117

12. Magnotti L.J., Upperman J.S., Xu D.Z., Lu Q., Deitch E.A. Gut-derived mesenteric lymph but not portal blood increases endothelial cell permeability and promotes lung injury after hemorrhagic shock. Ann. Surg. 1998; Oct; 228 (4): 518-527. PMID: 9790341

13. Wang Z.T., Yao Y.M., Xiao G.X., Sheng Z.Y. Improvement of bifidobacterial supplement on the barrier function of intestinal mucosa and microbe flora induced by thermal injury in rats. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2003; Mar; 15 (3): 154-158. PMID: 12831619

14. Garcia-Hernandez V., Quiros M., Nusrat A. Intestinal epithelial claudins: expression and regulation in homeostasis and inflammation. Ann. NY Acad. Sci. 2017; Jun; 1397 (1): 66-79. DOI: :10.1111/nyas.13360. PMID: 28493289

15. Baxevanos N., Giamarellos-Bourboulis E.J., Pistiki A., Korre M., Droggiti D.I., Tsaganos T. Bacterial translocation induces proinflammatory responses and is associated with early death in experimental severe injury. J. Surg. Res. 2013; Dec; 185 (2): 844-850 DOI: 10.1016/j.jss.2013.07.026. PMID: 23953792

16. Zhang Y, Zhang J, Xu T, Wu W, Huang F.F., Yu W.Q., Zhang S.Y., Liang T.B. Allicin ameliorates intraintestinal bacterial translocation after trauma/hemorrhagic shock in rats: The role of mesenteric lymph node dendritic cell. Surgery. 2017 Feb; 161 (2): 546-555. DOI: 10.1016/j.surg.2016.08.029.

17. Yakovlev A.Y., Kichin V.V., Nikolsky V.O., Kalentyev G.V., Ryabikov D.V., Ryabikova M.A., Protasov D.M., Galanina T.A., Smerkalov A.Y., Evdokimova O.S. Efficacy of Employment of Isotonic Sterofundin after Experimental Hemorrhagic Shock. Obshchaya reanimatiligiya=General Reanimatology. 2013; 9 (3): 24. [In Russ.]

18. Kojima M., Gimenes-Junior J.A., Chan T.W., Eliceiri B.P., Baird A., Costantini T.W., Coimbra R. Exosomes in postshock mesenteric lymph are key mediators of acute lung injury triggering the macrophage activation via Toll-like receptor 4. FASEB J. 2018; Jan; 32 (1): 97-110. DOI: 10.1096/fj.201700488R. PMID: 28855278

19. Kojima M., Gimenes-Junior J.A., Langness S., Morishita K., LavoieGagne O., Eliceiri B., Costantini T.W., Coimbra R. Exosomes, not protein or lipids, in mesenteric lymph activate inflammation: Unlocking the mystery of post-shock multiple organ failure. J. Trauma Acute Care Surg. 2017; Jan; 82 (1): 42-50. DOI: 10.1097/TA.0000000000001296. PMID: 27779585

20. Renner L., Kahlert S., Tesch T., Bannert E., Frahm J., Barta-Boszormenyi A., Kluess J., Kersten S., Schonfeld P., Rothkotter H.J., Danicke S. Chronic DON exposure and acute LPS challenge: effects on porcine liver morphology and function. Mycotoxin Res. 2017; Aug; 33 (3): 207218. DOI: 10.1007/s12550-017-0279-9. PMID: 28474303

21. Depboylu B., Giris M., Olgac V., Dodru-Abbasodlu S., Uysal M. Response of liver to lipopolysaccharide treatment in male and female rats. Exp. Toxicol. Pathol. 2013; 65: 645-650. DOI: 10.1016/j.etp.2012.07.004. PMID: 22884257

22. Zhou G., Dada L.A., Wu M., Kelly A., Trejo H., Zhou K., Varga J., Sznajder J.I. Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1. Am. J. Physiol. Lung. Cell. Mol. Physiol. 2009; 297 (6): 1120-1130. DOI: 10.1152/ajplung.00007.2009.

23. Kaistha A., Levine J. Inflammatory bowel disease: the classic gastrointestinal autoimmune disease. Curr. Probl. Pediatr. Adolesc. Health Care. 2014; Dec; 44 (11): 328-334. DOI: 10.1016/j.cppeds.2014.10.003. PMID: 25499459

24. Moroz V.V., Ryzhkov I.A. Acute Blood Loss: Regional Blood Flow and Microcirculation (Review, Part I). Obshchaya renimatologiya =General Reanimatology. 2016; 12 (2): 66-89. [In Russ., In Engl.] DOI: 10.15360/1813-9779-2016-2-56-65

25. Moroz V.V., Ryzhkov I.A. Acute Blood Loss: Regional Blood Flow and Microcirculation (Review, Part II). Obshchaya reanimatologiya=General Reanimatology. 2016; 12 (5): 65-94. [In Russ., In Engl.] DOI: 10.15360/1813-9779-2016-5-65-94

26. Zhao J, Yan C1, Xu L, Yan K1, Feng B, Zhao M, Niu G, Wu M, Chen C, Zhu H. The effect of pPolyHb on hemodynamic stability and mesenteric microcirculation in a rat model of hemorrhagic shock. Artif Cells Nanomed Biotechnol. 2017 Jun; 45 (4): 677-685. DOI: 10.1080/21691401.2017.1282869

27. Torres Filho I. Hemorrhagic Shock and the Microvasculature. Compr Physiol. 2017 Dec 12; 8 (1): 61-101. DOI: 10.1002/cphy.c170006. PMID: 29357125

28. Balogh Z., Wolfard A., Szalay L., Orosz E., Simonka J.A., Boros M. Dalteparin sodium treatment during resuscitation inhibits hemorrhagic shock induced leukocyte rolling and adhesion in the mesenteric microcirculation. J. Trauma. 2002; 52 (6): 1062-1069. DOI: 10.1097/0000537320020600000007. PMID: 12045631

29. Arai Y., Mizugishi K., Nonomura K., Naitoh K., Takaori-Kondo A., Yamashita K. Phagocytosis by human monocytesis required for the secretion of presepsin. J. Infect. Chemother. 2015; Aug; 21 (8): 564-569 DOI: 10.1016/j.jiac.2015.04.011.

30. Chenevier-Gobeaux C., Bardet V., Poupet H., Poyart C., Borderie D., Claessens Y. Presepsin (sCD14-ST) secretion and kinetics by peripheral blood mononuclear cells and monocytic THP-1 cell line. Clin. Chim. Acta. 2016; 74 (1): 93-97 DOI: 10.1684/abc.2015.1112

31. Bamba Y., Moro H., Aoki N., Koizumi T., Ohshima Y., Watanabe S. Increased presepsin levels are associated with the severity of fungal bloodstream infections. PLoS ONE 2018; Oct. 31, 13 (10): e0206089. DOI: 10.1371/journal.pone.0206089

32. Stavrou G., Arvanitidis K., Filidou E., Fotiadis K., Grosomanidis V., Ioannidis A., Tsaousi G., Michalopoulos A., Kolios G., Kotzampassi K. Combined Enteral and Parenteral Glutamine Supplementation in Endotoxaemic Swine: Effects on Portal and Systemic Circulation Levels. Med. Princ. Pract. 2018; Sep 5. DOI: 10.1159/000493481. PMID: 30184534

33. Fan J., Wu J., Wu L.D., Li G.P., Xiong M., Chen X., Meng Q.Y. Effect ofparenteral glutamine supplementation combined with enteral nutrition on Hsp90 expression and lymphoid organ apoptosis in severely burned rats. Burns. 2016; Nov; 42 (7): 1494-1506. DOI: 10.1016/j.burns.2016.02.009. Epub 2016 Sep 6. PMID: 27613477

34. Meng J., Wang Q., Liu K., Yang S., Fan X., Liu B., He C., Wu X. Systemic and Splanchnic Lipopolysaccharide and Endothelin-1 Plasma Levels in Liver Cirrhosis before and after Transjugular Intrahepatic Portosystemic Shunt. Gastroenterol. Res. Pract. 2016; 2016: 8341030. DOI: 10.1155/2016/8341030. Epub 2016 Jan 31. PMID: 26941788

35. Wu C.Y., Yeh Y.C., Chien C.T., Chao A., Sun W.Z., Cheng Y.J. Laser speckle contrast imaging forassessing microcirculatory changes in multiple splanchnic organs and the gracilismuscle during hemorrhagic shock and fluid resuscitation. Microvasc. Res. 2015; 101: 55–61. DOI: 10.1016/j.mvr.2015.06.003. PMID: 26093177

36. Gao F., Fu X, Qian M, Zhang Y, Li G, Hu J. Changes of small intestinal villi microcirculation in sidestream dark-field imaging with different target blood pressure in rabbits during endotoxin shock. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2017 Apr; 29 (4): 311-315. doi: 10.3760/cma.j.issn.2095-4352.2017.04.005.

37. Schulz K., Sommer O., Jargon D., Utzolino S., Clement H.W., Strate T., von Dobschuetz E. Cytokine and radical inhibition in septic intestinal barrier failure. J. Surg. Res. 2015; Feb; 193 (2): 831-840. DOI: 10.1016/j.jss.2014.08.056. PMID: 25277359

38. Liu P.S., Ho P.C. Determining Macrophage Polarization upon Metabolic Perturbation. Methods Mol. Biol. 2019; 1862: 173-186. DOI: 10.1007/978-1-4939-8769-6_13. PMID: 30315468

39. McNeil C.J., Hoskin S.O., Bremner D.M., Holtrop G., Lobley G.E. Whole-body and splanchnic amino acid metabolism in sheep during an acute endotoxin challenge. Br. J.Nutr. 2016 Jul; 116 (2): 211-22. DOI: 10.1017/S0007114516001860. PMID: 27189533

40. Kao R.L.C., Xu X., Xenocostas A., Parry N., Mele T., Martin C.M., Rui T. Cpeptide attenuates acute lung inflammation in a murine model of hemorrhagic shock and resuscitation by reducing gut injury. Trauma Acute Care Surg. 2017; Aug; 83 (2): 256-262. DOI: 10.1097/TA.0000000000001539. PMID: 28452895

41. Yi J., Slaughter A., Kotter C.V., Moore E.E., Hauser C.J., Itagaki K., Wohlauer M., Frank D.N., Silliman C., Banerjee A., Peltz E. A «clean case» of systemic injury: 13 mesenteric lymph after hemorrhagic shock elicits a sterile inflammatory response. Shock. 2015; Oct; 44 (4): 336340. DOI: 10.1097/SHK.0000000000000431

42. Kontouli Z., Staikou C., Iacovidou N., Mamais I., Kouskouni E., Papalois A., Papapanagiotou P., Gulati A., Chalkias A., Xanthos T. Resuscitation with centhaquin and 6% hydroxyethyl starch 130/0.4 improves survival in a swine model of hemorrhagic shock: a randomized experimental study. Eur. J. Trauma Emerg. Surg. 2018; Jul 13. DOI: 10.1007/s00068-018-0980-1 PMID: 30006694

43. Busuito C.M., Ledgerwood A.M., Lucas C.E. Colloid with high fresh frozen plasma/red blood cell resuscitation does not reduce postoperative fluid needs. J. Trauma Acute Care Surg. 2014 Apr.; 76 (4): 10081012. DOI: 10.1097/TA.0000000000000183 PMID: 24662864