SARM1mediates TLR9-induced vascular hyperpermeability following hemorrhagic shock

Research Article
American Journal of BioMedicine Volume 3, Issue 10, pages 644-657
Published: October 25, 2015

Morrison R. Doellea, Benjamin M. Predmore, Adrienne A. Kiss, Henri A. Leuvenink, Robert Clements mail of corresponding author


Hemorrhagic shock (HS) result in multiple organ dysfunction syndrome (MODS) and inflammatory response. It is one of the world's leading causes of death within the first 40 years of life and thus a significant health problem. The exact mechanism is not clear. TLRs are stimulated both by pathogen-associated molecular patterns as well as by damage-associated molecular patterns, including trauma and hemorrhagic shock. In the present study, we investigated whether the SARM1 responsible for mediats-TLR9-induces inflammatory process and vascular hyperpermeability following hemorrhagic shock. Here we produced an in vivo model of severe hemorrhagic shock in adult wild type mice (40 ± 2 mmHg for 90 min, fluid resuscitation for 30 min) was employed. Mesenteric postcapillary venules were examined for changes in hyperpermeability by intravital microscopy. Blood samples were collected for measurement of tumor necrosis factor (TNF) using ELISA. Biopsies were obtained from organs for light microscopic examination. Our data suggest that SARM1 promising a new mechanisim of TLR9 involved in regulation of hemorrhagic shock and therapeutic target for the treatment of hemorrhagic shock.

Keywords: Hemorrhagic shock; Inflammatory response; SARM1; TLR9

Copyright © 2015 by The American Society for BioMedicine and BM-Publisher, Inc.



1. Durham RM, Moran JJ, Mazuski JE, et al. Multiple organ failure in trauma patients. J. Trauma 2003; 55(4):608–16. [PubMed]

2. Sawant DA, Tharakan B, Hunter FA, Childs EW. The role of intrinsic apoptotic signaling in hemorrhagic shock-induced microvascular endothelial cell barrier dysfunction. J Cardiovasc Transl Res 2014; 7:711–718. [PubMed]

3. Mannucci PM, Levi M. Prevention and treatment of major blood loss. N Engl J Med 2007; 356:2301–11. [PubMed]

4. Lenz A, Franklin GA, Cheadle WG. Systemic inflammation after trauma. Injury 2007; 38(12):1336–45. [PubMed]

5. Tharakan B, Corprew R, Hunter FA, et al. 17β-estradiol mediates protection against microvascular endothelial cell hyperpermeability. Am J Surg 2009; 197:147–154. [PubMed]

6. Wetzel G, Relja B, Klarner A, et al. Myeloid knockout of HIF-1 α does not markedly affect hemorrhage/resuscitation-induced inflammation and hepatic injury. Mediators Inflamm 2014; 2014:930419. [PubMed]

7. Junger WG, Rhind SG, Rizoli SB, et al. Resuscitation of traumatic hemorrhagic shock patients with hypertonic saline-without dextran-inhibits neutrophil and endothelial cell activation. Shock 2012; 38(4):341–50. [PubMed]

8. Taie S, Yokono S, Ueki M, Ogli K. Effects of ulinastatin (urinary trypsin inhibitor) on ATP, intracellular pH, and intracellular sodium transients during ischemia and reperfusion in the rat kidney in vivo. J Anesth 2001; 15:33–38. [PubMed]

9. Tracey KJ, Cerami A. Tumor necrosis factor: A pleiotropic cytokine and therapeutic target. Annu Rev Med 1994; 45:491–503. [PubMed]

10. Alam HB, Stanton K, Koustova E, Burris D, Rich N, Rhee P. Effect of different resuscitation strategies on neutrophil activation in a swine model of hemorrhagic shock. Resuscitation 2004; 60(1):91–9. [PubMed]

11. Qin ZS, Tian P, Wu X, Yu HM, Guo N. Effects of ulinastatin administered at different time points on the pathological morphologies of the lung tissues of rats with hyperthermia. Exp Ther Med 2014; 7:1625–1630. [PubMed]

12. O’Carroll AM, Lolait SJ, Harris LE, Pope GR. The apelin receptor APJ: Journey from an orphan to a multifaceted regulator of homeostasis. J Endocrinol 2013; 219:R13–35. [PubMed]

13. Rizoli SB, Kapus A, Parodo J, Rotstein OD. Hypertonicity prevents lipopolysaccharide-stimulated CD11b/CD18 expression in human neutrophils in vitro: role for p38 inhibition. J. Trauma 1999; 46(5):794–8. [PubMed]

14. Wang L, Luo H, Chen X, Jiang Y, Huang Q. Functional characterization of S100A8 and S100A9 in altering monolayer permeability of human umbilical endothelial cells. PLoS One 2014; 9:e90472. [PubMed]

15. Soliman M. Inhibition of Na(+)-H(+) exchange before resuscitation following hemorrhagic shock is cardioprotective in rats. J Saudi Heart Assoc 2009; 21:159–63. [PubMed]

16. Powers KA, Woo J, Khadaroo RG, Papia G, Kapus A, Rotstein OD. Hypertonic resuscitation of hemorrhagic shock upregulates the anti-inflammatory response by alveolar macrophages. Surgery 2003; 134(2):312–8. [PubMed]

17. Zhang XJ, Mei WL, Tan GH, et al. Strophalloside Induces apoptosis of SGC-7901 cells through the mitochondrion-dependent caspase-3 pathway. Molecules 2015; 20:5714–5728. [PubMed]

18. Soliman MM. Na(+)-H(+) exchange blockade, using amiloride, decreases the inflammatory response following hemorrhagic shock and resuscitation in rats. Eur J Pharmacol 2011; 650:324–7. [PubMed]

19. Vrints CJ. Pathophysiology of the no-reflow phenomenon. Acute Card Care 2009; 11(2):69–76. [PubMed]

20. Li T, Liu Y, Li G, et al. Polydatin attenuates ipopolysaccharide-induced acute lung injury in rats. Int J Clin Exp Pathol 2014; 7:8401–8410. [PubMed]

21. Sinha K, Das J, Pal PB, Sil PC. Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol 2013; 87:1157–1180. [PubMed]

22. Kellum JA, Song M, Li J. Science review: extracellular acidosis and the immune response: clinical and physiologic implications. Critical care 2004; 8(5):331–6. [PubMed]

23. Moon PF, Kramer GC. Hypertonic saline-dextran resuscitation from hemorrhagic shock induces transient mixed acidosis. Crit Care Med 1995; 23(2):323–31. [PubMed]

24. Inoue Y, Chen Y, Pauzenberger R, Hirsh MI, Junger WG. Hypertonic saline up-regulates A3 adenosine receptor expression of activated neutrophils and increases acute lung injury after sepsis. Crit Care Med 2008; 36(9):2569–75. [PubMed]

25. Slimani H, Zhai Y, Yousif NG, et al. Enhanced monocyte chemoattractant protein-1 production in aging mice exaggerates cardiac depression during endotoxemia. Crit Care 2014;18(5):527. [PubMed]

26. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2001; 2:675–680. [PubMed]

27. Kumar A, Haery C, Parrillo JE. Myocardial dysfunction in septic shock. Crit Care Clin 2000; 16:251–287. [PubMed]

28. Su X, Sykes JB, Ao L, Raeburn CD, Fullerton DA, Meng X. Extracellular heat shock cognate protein 70 induces cardiac functional tolerance to endotoxin: differential effect on TNF-alpha and ICAM-1 levels in heart tissue. Cytokine 2010; 51:60–66. [PubMed]

29. Szokodi I, Tavi P, Földes G, et al. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ Res 2002; 91:434–40. [PubMed]

30. Durum R, Memon JF, Mackall TN, et al. Critical role of farnesyltransferase inhibitor in protective myocardial function after endotoxemia in rat model. American Journal of BioMedicine 2014; 2(7):827-839. [Abstract/Full-Text]

Limited access article

limited access This article with limited access need to be buy, before continue with your purchase please read carefully the AJBM terms and conditions of purchase.

Purchase this article at rate $55.00 and received Full-Text/PDF
You will have online immediate access to article following the completion of this purchase and you may download and print a copy of each article for your personal use. Use the coding below to purchase your article as PDF by credit card, debit card, payball will be asked to supply your billing card information.


For any technique error please contact us and will be response to sending purchase article by email.

Thank you for visiting American Journal of BioMedicine.  * = Required fields

[gravityform id=”6″ name=”Feedback”]

Print Friendly, PDF & Email