Understanding Red Blood Cell Rheology in Sepsis and its Role in Clinical Practice. From Biomolecular Aspects to Possible Therapeutic Interventions

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Erythrocyte rheology is of interest in understanding microcirculation and oxygen delivery and consumption alterations induced by sepsis and septic shock. Several mechanisms are proposed: (i) direct or indirect RBC membrane alterations, (ii) abnormal intraerythrocytic homeostasis, (iii) RBCs interaction with other cells and extracellular molecules, (iiii) increased reactive species production and altered redox homeostasis. In this review, we describe in part these mechanisms and what’s the impact of these hemorheological disturbances on the outcome and mortality rate. Also, we outline the possible therapeutic interventions and further perspectives regarding sepsis and septic shock management.

1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Jama 2016;315(8):801

2. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Medicine 2003;29(4):530-8

3. Baskurt OK, Meiselman HJ. Blood rheology and hemodynamics. Seminars in Thrombosis and Hemostasis 2003;29(5):435-50

4. Baskurt OK, Neu B, Meiselman, HJ. Red Blood Cell Aggregation. Boca Raton. J Lab Clin Med 1997;130(2):183-90

5. Nemeth N, Deak A, Szentkereszty Z, Peto K. Effects and influencing factors on hemorheological variables taken into consideration in surgical pathophysiology research. Clinical Hemorheology and Microcirculation 2018;69(1-2):133-40

6. Baskurt OK. In vivo correlates of altered blood rheology. Biorheology 2008;45(6):629-38

7. Totsimon K, Biro K, Szabo ZE, Toth K, Kenyeres P, Marton Z. The relationship between hemorheological parameters and mortality in critically ill patients with and without sepsis. Clinical Hemorheology and Microcirculation 2017;65(2):119-129

8. Piagnerelli M, Zouaoui Boudjeltia K, Vanhaeverbeek M, Vincent JL. Red blood cell rheology in sepsis. Intensive Care Med 2003;29:1052-1061

9. Bateman R, Sharpe M, Singer M, Ellis C. The Effect of Sepsis on the Erythrocyte. International Journal of Molecular Sciences 2017;18(9):1932

10. Lenz C, Rebel A, Waschke K, Koehler R, Frietsch T. Blood viscosity modulates tissue perfusion - sometimes and somewhere. Transfusion Alternatives in Transfusion Medicine 2007;9(4):265-72

11. Beck N. Anemia: General Considerations. Diagnostic Hematology. London: Springer 2009;199-218

12. Rhodes A, Evans LE, Alhazzani W Levy MM, Antonelli M, Ferrer R et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Medicine 2017;43(3):304-377

13. Toth K, Kesmarky G. Clinical significance of hemorheological alterations In: Baskurt OK, Hardeman MR, Rampling MW, Meiselman HJ, (eds) Handbook of Hemorheology and Hemodynamics, Amsterdam 2007:392-404

14. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Medicine 1985;13:18-829

15. Reinhart WH, Cagienard F, Schulzki T, Venzin RM. The passage of a hemodialysis filter affects hemorheology, red cell shape, and platelet aggregation. Clinical Hemorheology and Microcirculation 2014;57:49-62

16. Hasler C, Owen G, Brunner W, Reinhart W. Echinocytosis induced by haemodialysis. Nephrology Dialysis Transplantation 1998;13(12):3132-3137

17. Eichelbronner O, Sibbald WJ, Chin-Yee IH. Intermittent flow increases endotoxin-induced adhesion of human erythrocytes to vascular endothelial cells. Intensive Care Medicine 2003;29:709-714

18. Simmonds MJ, Meiselman HJ, Baskurt OK. Blood rheology and aging. Journal of Geriatric Cardiology 2013;10(3):291-301

19. Ellsworth ML. The red blood cell as an oxygen sensor: what is the evidence? Acta Physiologica Scandinavica 2000;168:551- 559

20. Jensen FB. The dual roles of red blood cells in tissue oxygen delivery: oxygen carriers and regulators of local blood flow. Journal of Experimental Biology 2009;212:3387- 3393

21. Huisjes R, Bogdanova A, Solinge WWV, Schiffelers RM, Kaestner L, Wijk RV. Squeezing for Life - Properties of Red Blood Cell Deformability. Frontiers in Physiology 2018;9:656

22. Bor-Kucukatay M, Wenby RB, Meiselman HJ, Baskurt OK. Effects of nitric oxide on red blood cell deformability. American Journal of Physiology-Heart and Circulatory Physiology 2003;284(5)

23. Nans A, Mohandas N, Stokes DL. Native Ultrastructure of the Red Cell Cytoskeleton by Cryo-Electron Tomography. Biophysical Journal 2011;101(10):2341-50

24. Gallagher PG. Hereditary elliptocytosis: spectrin and protein 4.1R. Seminars in Hematology 2004;41(2):142-64

25. Reggiori G, Occhipinti G, De Gasperi A, Vincent JL, Piagnerelli M. Early alterations of red blood cell rheology in critically ill patients. Critical Care Medicine 2009;37:3041-3046

26. Nemeth N, Berhes M, Kiss F, Hajdu E, Deak A, Molnar A, Szabo J, Fulesdi B. Early hemorheological changes in a porcine model of intravenously given E. coli induced fulminant sepsis. Clinical Hemorheology and Microcirculation 2015;61:479-496

27. Bateman RM, Jagger JE, Sharpe MD, Ellsworth ML, Mehta S, Ellis CG. Erythrocyte deformability is a nitric oxide-mediated factor in decreased capillary density during sepsis. American Journal of Physiology- Heart and Circulatory Physiolog 2001;280(6):H2848-56

28. Moutzouri AG, Skoutelis AT, Gogos CG, Missirlis YM, Athanassiou GM. Red blood cell deformability in patients with sepsis: A marker for prognosis and monitoring of severity. Clinical Hemorheology and Microcirculation 2007;36:291-299

29. Donadello K, Piagnerelli M, Reggiori G, Gottin L, Scolletta S, Occhipinti G, et al. Reduced red blood cell deformability over time is associated with a poor outcome in septic patients. Microvascular Research 2015;101:8-14

30. Machiedo GW. The Incidence of Decreased Red Blood Cell Deformability in Sepsis and the Association With Oxygen Free Radical Damage and Multiple-System Organ Failure. Archives of Surgery 1989;124(12):1386

31. Langenfeld JE, Livingston DH, Machiedo GW. Red cell deformability is an early indicator of infection. Surgery 1991;110:398- 403

32. Sadaka F, O’Brien J, Prakash S. Red Cell Distribution Width and Outcome in Patients With Septic Shock. Journal of Intensive Care Medicine 2012;28(5):307-13

33. Lorente L, Martín MM, Abreu-González P, Solé-Violán J, Ferreres J, Labarta L, et al. Red Blood Cell Distribution Width during the First Week Is Associated with Severity and Mortality in Septic Patients. PLoS ONE 2014;9(8):e105436

34. Kim CH, Park JT, Kim EJ, Han JH, Han JS, Choi JY, et al. An increase in red blood cell distribution width from baseline predicts mortality in patients with severe sepsis or septic shock. Critical Care 2013;17(6):R282

35. Jo YH, Kim K, Lee JH, Kang C, Kim T, Park H-M, et al. Red cell distribution width is a prognostic factor in severe sepsis and septic shock. The American Journal of Emergency Medicine 2013;31(3):545-8

36. Kumar S, Jandial A, Bhalla A, Sharma N, Varma N, Varma S. Elevated red cell distribution width as a prognostic marker in severe sepsis: A prospective observational study. Indian Journal of Critical Care Medicine 2017;21(9):552

37. Debari V, Mahmood N, Mathew J, Kang B, Khan M. Broadening of the red blood cell distribution width is associated with increased severity of illness in patients with sepsis. International Journal of Critical Illness and Injury Science 2014;4(4):278

38. Piagnerelli M, Boudjeltia KZ, Brohee D, Piro P, Carlier E, Vincent J-L, et al. Alterations of red blood cell shape and sialic acid membrane content in septic patients. Critical Care Medicine 2003;31(8):2156-62

39. Piagnerelli M, Vincent J-L, Boudjeltia KZ, Brohee D, Vanhaeverbeek M. Modifications of Red Blood Cell Shape and Glycoproteins Membrane Content in Septic Patients. Advances in Experimental Medicine and Biology Oxygen Transport To Tissue XXIII 2003;109-14

40. Qadri SM, Donkor DA, Nazy I, Branch DR, Sheffield WP. Bacterial neuraminidase-mediated erythrocyte desialylation provokes cell surface aminophospholipid exposure. European Journal of Haematology 2018;100(5):502-10

41. Rogers ME, Williams DT, Niththyananthan R, Rampling MW, Heslop KE, Johnston DG. Decrease in erythrocyte glycophorin sialic acid content is associated with increased erythrocyte aggregation in human diabetes. Clinical Science 1992;82(3):309-13

42. Venerando B, Fiorilli A, Croci G, Tringali C, Goi G, Mazzanti L et al. Acidic and neutral sialidase in the erythrocyte membrane of type 2 diabetic patients. Blood 2002;99:1064-1070

43. Moutzouri AG, Athanassiou GA, Dimitropoulou D, Skoutelis AT, Gogos CA. Severe sepsis and diabetes mellitus have additive effects on red blood cell deformability. Journal of Infection 2008;57(2):147-51

44. Milligan TW, Baker CJ, Straus DC, Mattingly SJ. Association of elevated levels of extracellular neuraminidase with clinical isolates of type III group B streptococci. Infection and Immunity 1978;21(3):738-746

45. Mattingly SJ, Milligan TW, Pierpont AA, Straus DC. Extracellular neuraminidase production by clinical isolates of group B streptococci from infected neonates. Journal of Clinical Microbiology 1980;12(4): 633-635

46. Liukkonen J, Haataja S, Tikkanen K, Kelm S, Finne J. Identification of N-acetylneuraminyl alpha 2->3 poly-N-acetyllactosamine glycans as the receptors of sialic acid-binding Streptococcus suis strains. The Journal of Biological Chemistry 1992;267(29):21105-11

47. Parkkinen J, Rogers GN, Korhonen T, Dahr W, Finne J. Identification of the O-linked sialyloligosaccharides of glycophorin A as the erythrocyte receptors for S-fimbriated Escherichia coli. Infection and Immunity 1986;54(1):37-42

48. Qadri SM, Donkor DA, Bhakta V, Eltringham- Smith LJ, Dwivedi DJ, Moore JC, et al. Phosphatidylserine externalization and procoagulant activation of erythrocytes induced byPseudomonas aeruginosavirulence factor pyocyanin. Journal of Cellular and Molecular Medicine 2016;20(4):710- 20

49. Piagnerelli M, Boudjeltia KZ, Rapotec A, Richard T, Brohée D, Babar S, et al. Neuraminidase alters red blood cells in sepsis. Critical Care Medicine 2009;37(4):1244-50

50. Gut H, King SJ, Walsh MA. Structural and functional studies ofStreptococcus pneumoniaeneuraminidase B: An intramoleculartrans- sialidase. FEBS Letters 2008;582(23-24):3348-52

51. Durocher JR, Payne RC, Conrad ME. Role of sialic acid in erythrocyte survival. Blood 1975;45:11-20

52. Waugh RE. Effects of 2,3-diphosphoglycerate on the mechanical properties of erythrocyte membrane. Blood 1986;68(1):231-8

53. Suzuki Y, Nakajima T, Shiga T, Maeda N. Influence of 2,3-diphosphoglycerate on the deformability of human erythrocytes. Biochimica et Biophysica Acta (BBA) - Biomembranes 1990;1029(1):85-90

54. Lizcano A, Secundino I, Döhrmann S, Corriden R, Rohena C, Diaz S, et al. Erythrocyte sialoglycoproteins engage Siglec-9 on neutrophils to suppress activation. Blood 2017;129(23):3100-10

55. Dinkla S, Eijk LTV, Fuchs B, Schiller J, Joosten I, Brock R, et al. Inflammation-associated changes in lipid composition and the organization of the erythrocyte membrane. BBA Clinical 2016;5:186-92

56. Qadri SM, Bissinger R, Solh Z, Oldenborg P-A. Eryptosis in health and disease: A paradigm shift towards understanding the (patho)physiological implications of pro26 grammed cell death of erythrocytes. Blood Reviews 2017;31(6):349-61

57. Velásquez FC, Maté S, Bakás L, Herlax V. ntroduction of eryptosis by low concentrations f E. coli alpha-hemolysin. Biochimica t Biophysica Acta (BBA) - Biomembranes 015;1848(11):2779-88

58. Föller M, Shumilina E, Lam R, Mohamed , Kasinathan R, Huber S, et al. Induction f Suicidal Erythrocyte Death by Listeriolysin rom Listeria monocytogenes. ellular Physiology and Biochemistry 007;20(6):1051-60

59. Foller M, Biswas R, Mahmud H, Akel A, Shumilina E, Wieder T, et al. Effect of peptidoglycans n erythrocyte survival. International ournal of Medical Microbiology 009;299:75-85

60. Wang K, Mahmud H, Foller M, Biswas R, Lang KS, Bohn E, et al. Lipopeptides in he triggering of erythrocyte cell membrane crambling. Cellular Physiology and Biochemistry 008;22:381-6

61. Abed M, Towhid ST, Mia S, Pakladok T, Alesutan , Borst O et al. Sphingomyelinase-induced dhesion of eryptotic erythrocytes to ndothelial cells. American Journal of Physiology- ell Physiology 2012;303:C991- 999

62. Abed M, Towhid ST, Pakladok T, Alesutan , Gotz F, Gulbins E, et al. Effect of bacterial eptidoglycan on erythrocyte death nd adhesion to endothelial cells. International ournal of Medical Microbiology 013;303:182-9

63. Bogdanova A, Makhro A, Wang J, Lipp P, Kaestner L. Calcium in red blood cells-A erilous balance. International Journal of olecular Sciences 2013;14:9848-9872

64. Todd JC, Mollitt DL. Effect of sepsis on rythrocyte intracellular calcium homeostasis. ritical Care Medicine 1995;23:459- 65

65. Desai TK, Carlson RW, Geheb MA. Prevalence and nical implications of hypocalcemia n acutely III patients in a medical intensive are setting. The American Journal ofMedicine 1988;84(2):209-14

66. Snyder LM, Fortier NL, Trainor J, JacobsJ, Leb L, Lubin B, et al. Effect of hydrogen eroxide exposure on normal human erythrocytedeformability, morphology, surfacecharacteristics, and spectrin-hemoglobincross-linking. Journal of Clinical Investigation 985;76(5):1971-7

67. Jain SK, Mohandas N, Clark MR, ShohetSB. The effect of malonyldialdehyde, a product of lipid peroxidation, on the deformability, dehydration and51Cr-survival f erythrocytes. British Journal of Haematology


68. Kempe DS, Akel A, Lang PA, Hermle T, Biswas R, Muresanu J, et al. Suicidal erythrocyte eath in sepsis. Journal of Molecular edicine 2007;85:273-81

69. Saldanha C, Silva-Herdade A. Erythrocyte itric Oxide. Novel Prospects in Oxidative nd Nitrosative Stress Pinar Atukeren, IntechOpen, DOI: 10.5772/intechopen.75931

70 Bordin L, Brunati AM, Donella-Deana A, Baggio B, Toninello A, Clari G. Band 3 is ananchor protein and a target for SHP-2 tyrosine hosphatase in human erythrocytes.Blood 2002;100:276-278

71. Bordin L, Fiore C, Bragadin M, Brunati M, Clari G. Regulation of membrane

band 3 Tyr-phosphorylation by proteolysisof p72Syk and possible involvement in senescenceprocess. Acta Biochimica et Biophysica inica 2009;41(10):846-51

72. Condon MR, Feketova E, MachiedoGW, Deitch EA, Spolarics Z. Augmented rythrocyte band-3 phosphorylation n septic mice. Biochimica et Biophysica cta (BBA) - Molecular Basis of Disease2007;1772(5):580-6

73. Lin X, Rogers S, Timm D, Angelo A, JayaP, Melanie E et al. Sepsis Induced Red Cell Dysfunction (SiRD): Physiology and Mechanisms. Blood 2017;130(1):3469

74. Spolarics Z, Condon MR, Siddiqi M, Machiedo GW, Deitch EA. Red blood cell dysfunction in septic glucose-6-phosphate dehydrogenase-deficient mice. American Journal of Physiology-Heart and Circulatory Physiology 2004;286(6)

75. Zipser Y, Piade A, Barbul A, Korenstein R, Kosower NS. Ca2 promotes erythrocyte band 3 tyrosine phosphorylation via dissociation of phosphotyrosine phosphatase from band 3. Biochemical Journal 2002;368(1):137-44

76. Mallozzi C, Di Stasi AM, Minetti M. Peroxynitrite modulates tyrosine-dependent signal transduction pathway of human erythrocyte band 3. FASEB J 1997;11:1281-90

77. Sega MF, Chu H, Christian J, Low PS. Interaction of deoxyhemoglobin with the cytoplasmic domain of murine erythrocyte band 3. Biochemistry 2012;51:3264-72

78. Galli F, Rossi R, Simplicio PD, Floridi A, Canestrari F. Protein Thiols and Glutathione Influence the Nitric Oxide-Dependent Regulation of the Red Blood Cell Metabolism. Nitric Oxide 2002;6(2):186-99

79. Clancy RM, Levartovsky D, Leszczynska- Piziak J, Yegudin J, Abramson SB. Nitric oxide reacts with intracellular glutathione and activates the hexose monophosphate shunt in human neutrophils: evidence for S-nitrosoglutathione as a bioactive intermediary. Proceedings of the National Academy of Sciences 1994;91(9):3680-4

80. Jagger JE, Bateman RM, Ellsworth ML, Ellis CG. Role of erythrocyte in regulating local O2delivery mediated by hemoglobin oxygenation. American Journal of Physiology- Heart and Circulatory Physiology 2001;280(6)

81. Bateman RM, Sharpe MD, Jagger JE, Ellis CG. Sepsis impairs microvascular autoregulation and delays capillary response within hypoxic capillaries. Critical Care 2015;19(1)

82. Lopes de Almeida JP, Freitas-Santos T, Saldanha C. Evidence that the degree of band 3 phosphorylation modulates human erythrocytes nitric oxide efflux-in vitro model of fibrinogenemia. Clinical Hemorheology

and 2011;49:407-416

83. Silva-Herdade AS, Freitas T, Almeida JP, Saldanha C. Fibrinogen signaling in erythrocyte nitric oxide mobilization in presence of PI3-K and adenylyl cyclase inhibitors. European Journal of Biomedical and Pharmaceutical Sciences 2016;3:28-34

84. Piagnerelli M., Cotton F, van Nuffelen M, Vincent JL, Gulbis B. Modifications in erythrocyte membrane protein content are not responsible for the alterations in rheology seen in sepsis. Shock 2012;37:17-21

85. Chillar RK, Slawskyand P, Desforges JF. Red Cell 2,3-Diphosphoglycerate and Adenosine Triphosphate in Patients with Shock. British Journal of Haematology. 1971;21(2):183-8.

86. Watkins GM, Rabelo A, Plzak LF, Shel- don GF. The Left Shifted Oxyhemoglobin Curve in Sepsis. Annals of Surgery 1974;180(2):213-20

87. Myburgh JA, Webb RK, Worthley LIG. The P50 is reduced in critically ill patients. Intensive Care Medicine 1991;17(6):355-8

88. Ibrahim EEDS, Mclellan SA, Walsh TS. Red blood cell 2,3-diphosphoglycerate concentration and in vivo P50 during early critical illness*. Critical Care Medicine 2005;33(10):2247-52

89. Schindler M, Koppel DE, Sheetz MP. Modulation of membrane protein lateral mobility by polyphosphates and polyamines. Proceedings of the National Academy of Sciences 1980;77(3):1457-61

90. Sheetz MP, Casaly J. Phosphate metabolite regulation of spectrin interactions. Scandinavian Journal of Clinical and Laboratory Investigation 1981;41(sup156):117-22

91. Muller, Becker, Kranzlin, Schachinger, Huber, Nylen, et al. Disordered calcium homeostasis of sepsis: association with calcitonin precursors. European Journal of Clinical Investigation 2000;30(9):823-31

92. Ruef P, Ehrhard M, Frommhold D, Koch L, Fritzsching B, Poeschl J. Lipid a decreases human erythrocytes deformability by increasing intracellular Ca2+: Effects of verapamil, staurosporine and the rho-kinase inhibitor Y-27632. Clinical Hemorheology and Microcirculation 2011;49:315-322

93. Deaciuc I, Spitzer J. Calcium content in liver and heart and its intracellular distribution in liver during endotoxicosis and sepsis in rats. Cell Calcium 1987;8(5):365-76

94. Celes MRN, Malvestio LM, Suadicani SO, Prado CM, Figueiredo MJ, et al. Disruption of Calcium Homeostasis in Cardiomyocytes Underlies Cardiac Structural and Functional Changes in Severe Sepsis. PLOS ONE 2013;8(7):e68809

95. Zaloga GP, Washburn D, Black KW, Prielipp R. Human sepsis increases lymphocyte intracellular calcium. Critical Care Medicine 1993;21(2):196-202

96. Smith BD, Celle PLL, Siefring GE, Lowe- Krentz L, Lorand L. Effects of the calcium- mediated enzymatic cross-linking of membrane proteins on cellular deformability. The Journal of Membrane Biology 1981;61(2):75-80

97. Lau YT, Hsieh CC, Liu MS, Hwang TL, Chen MF, Cheng HS. Erythrocyte Ca2+ pump is defective during sepsis. Circulatory Shock 1994;44:121-125

98. Todd JC, Mollitt DL. Leukocyte Modulation Inhibits Endotoxin-Induced Disruption Of Intracellular Calcium Homeostasis. The Journal of Trauma: Injury, Infection, and Critical Care 1994;37(6):1018-9

99. Helms CC, Gladwin MT, Kim-Shapiro DB. Erythrocytes and Vascular Function: Oxygen and Nitric Oxide. Frontiers in Physiology 2018;9

100. Hoffman JF. ATP compartmentation in human erythrocytes. Current Opinion in Hematology 1997;4(2):112-5

101. Bergfeld GR, Forrester T. Release of ATP from human erythrocytes in response to a brief period of hypoxia and hypercapnia. Cardiovascular Research 1992;26(1):40-7

102. Locovei S, Bao L, Dahl G. Pannexin 1 in erythrocytes: Function without a gap. Proceedings of the National Academy of Sciences 2006;103(20):7655-9

103. Ellsworth ML, Forrester T, Ellis CG, Dietrich HH. The erythrocyte as a regulator of vascular tone. American Journal of Physiology- Heart and Circulatory 1995;269(6)

104. Mathie R, Ralevic V, Alexander B, Burnstock G. Nitric oxide is the mediator of ATP-induced dilatation of the rabbit hepatic arterial vascular bed. British Journal of Pharmacology 1991;103(2):1602-6

105. Busse R, Ogilvie A, Pohl U. Vasomotor activity of diadenosine triphosphate and diadenosine tetraphosphate in isolated arteries. American Journal of Physiology-Heart and Circulatory Physiology 1988;254(5)

106. Sprague RS, Ellsworth ML, Stephenson AH, Lonigro AJ. ATP: the red blood cell link to NO and local control of the pulmonary circulation. American Journal of Physiology- Heart and Circulatory Physiology 1996;271(6)

107. Sprague RS, Stephenson AH, Dimmitt RA, Weintraub NL, Branch CA, Mcmurdo L, et al. Effect of L-NAME on pressure-flow relationships in isolated rabbit lungs: role of red blood cells. American Journal of Physiology- Heart and Circulatory Physiology 1995;269(6)

108. Serroukh Y, Djebara S, Lelubre C, Boudjeltia KZ, Biston P, Piagnerelli M. Alterations of the Erythrocyte Membrane during Sepsis. Critical Care Research and Practice 2012;2012:1-7

109. Forsyth AM, Wan J, Owrutsky PD, Abkarian M, Stone HA. Multiscale approach to link red blood cell dynamics, shear viscosity, and ATP release. Proceedings of the National Academy of Sciences 2011;108(27):10986-91

110. Rozier MD, Zata VJ, Ellsworth ML. Lactate interferes with ATP release from red blood cells. American Journal of Physiology-Heart and Circulatory Physiology 2007;292(6)

111. Greve A-S, Skals M, Fagerberg SK, Tonnus W, Ellermann-Eriksen S, Evans RJ, et al. P2X1, P2X4, and P2X7 Receptor Knock Out Mice Expose Differential Outcome of Sepsis Induced by α-Haemolysin Producing Escherichia coli. Frontiers in Cellular and Infection Microbiology 2017;7

112. Skals M, Jorgensen NR, Leipziger J, Praetorius HA.-Hemolysin from Escherichia coli uses endogenous amplification through P2X receptor activation to induce hemolysis. Proceedings of the National Academy of Sciences 2009;106(10):4030-5

113. Skals M, Leipziger J, Praetorius HA. Haemolysis induced by α-toxin from Staphylococcus aureus requires P2X receptor activation. Pflügers Archiv - European Journal of Physiology 2011;462(5):669-79

114. Nagahama M, Seike S, Shirai H, Takagishi T, Kobayashi K, Takehara M, et al. Role of P2X7 receptor in Clostridium perfringens beta-toxin-mediated cellular injury. Biochimica et Biophysica Acta (BBA) - General Subjects 2015;1850(11):2159-67

115. Prauchner CA. Oxidative stress in sepsis: Pathophysiological implications justifying antioxidant co-therapy. Burns 2017;43(3):471-85

116. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock. Chest 2017;151(6):1229-38

117. Goode HF, Cowley HC, Walker BE, Howdle PD, Webster NR. Decreased antioxidant status and increased lipid peroxidation in patients with septic shock and secondary organ dysfunction. Critical Care Medicine 1995;23(4):646-51

118. Metnitz PGH, Bartens C, Fischer M, Fridrich P, Steltzer H, Druml W. Antioxidant status in patients with acute respiratory distress syndrome. Intensive Care Medicine 1999;25(2):180-5

119. Pascual C, Karzai W, Meier-Hellmann A, Oberhoffer M, Horn A, Bredle D, et al. Total plasma antioxidant capacity is not always decreased in sepsis. Critical Care Medicine 1998;26(4):705-9

120. Richard C, Lemonnier F, Thibault M, Couturier M, Auzepy P. Vitamin E deficiency and lipoperoxidation during adult respiratory distress syndrome. Critical Care 1990;18(1):4-9

121. Luca L, Rogobete AF, Bedreag OH. Oxidative Stress and Antioxidant Therapy in Critically Ill Polytrauma Patients with Severe Head Injury. The Journal of Critical Care Medicine 2015;1(3):83-91

122. Dewas C, Dang PM-C, Gougerot-Pocidalo M-A, El-Benna J. TNF- Induces Phosphorylation of p47phox in Human Neutrophils: Partial Phosphorylation of p47phox Is a Common Event of Priming of Human Neutrophils by TNF- and Granulocyte-Macrophage Colony-Stimulating Factor. The Journal of Immunology 2003;171(8):4392-8

123. Faivre B, Menu P, Labrude P, Vigneron C. Hemoglobin Autooxidation/Oxidation Mechanisms and Methemoglobin Prevention or Reduction Processes in the Bloodstream Literature review and outline of autooxidation reaction. Artificial Cells, Blood Substitutes, and Biotechnology 1998;26(1):17-26

124. Baskurt OK, Temiz A, Meiselman HJ. Effect of Superoxide Anions on Red Blood Cell Rheologic Properties. Free Radical Biology and Medicine 1998;24(1):102-10

125. Srour MA, Bilto YY, Juma M, Irhimeh MR. Exposure of human erythrocytes to oxygen radicals causes loss of deformability, increased osmotic fragility, lipid peroxidation and protein degradatioin. Clinical Hemorheology and Microcirculation 2000;23:13- 21

126. Snyder LM, Fortier NL, Trainor J, Jacobs J, Leb L, Lubin B, et al. Effect of hydrogen peroxide exposure on normal human erythrocyte deformability, morphology, surface characteristics, and spectrin-hemoglobin cross-linking. Journal of Clinical Investigation 1985;76(5):1971-7

127. Weiss SJ. The role of superoxide in the destruction of erythrocyte targets by human neutrophils. Journal of Biological Chemistry 1980;255:9912-9917

128. Powell RJ, Machiedo GW, Rush BF Jr., Dikdan G. Effect of α-tocopherol on red cell deformability and survival in sepsis. Current Surg 1989;46:380-382

129. Uyesaka N, Hasegawa S, Ishioka N, Ishioka R, Shio H, Schechter AN. Effects of superoxide anions on red cell deformability and membrane proteins. Biorheology 1992;29:217-229

130. Jain SK, Ross JD, Levy GJ, Little RL, Duett J. The accumulation of malonyldialdehyde, an end product of membrane lipid peroxidation, can cause potassium leak in normal and sickle red blood cells. Biochemical Medicine and Metabolic Biology 1989;42(1):60-5

131. Oliveira YPAD, Pontes-De-Carvalho LC, Couto RD, Noronha-Dutra AA. Oxidative stress in sepsis. Possible production of free radicals through an erythrocyte-mediated positive feedback mechanism. The Brazilian Journal of Infectious Diseases 2017;21(1):19-26

132. McKenney J, Valeri CR, Mohandas N, Fortier N, Giorgio A, Snyder LM. Decreased in vivo survival of hydrogen peroxide-damaged

baboon red blood cells. Blood 1990;76:206-211

133. Butterfield D, Sun B, Bellary S, Arden WA, Anderson KW. Effect of endotoxin on lipid order and motion in erythrocyte membranes. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1994;1225(2):231-4

134. Yerer MB, Yapislar H, Aydogan S, Yalcin O, Baskurt O. Lipid peroxidation and deformability of red blood cells in experimental sepsis in rats: The protective effects of melatonin. Clinical Hemorheology and Microcirculation 2004;30(2):77-82

135. Snyder LM, Fortier NL, Trainor J, Jacobs J, Leb L, Lubin B, et al. Effect of hydrogen peroxide exposure on normal human erythrocyte deformability, morphology, surface characteristics, and spectrin-hemoglobin cross-linking. Journal of Clinical Investigation 1985;76(5):1975-7

136. Mal A, Chatterjee IB. Mechanism of autoxidation of oxyhaemoglobin. Journal of Biosciences 1991;16(1-2):55-70

137. Bunn, HF, Forget BG. in: Hemoglobin. Molecular and General Clinical Aspects. Philadelphia: Saunders 1986:634-662

138. Kikugawa K, Sasahara T, Sasaki T, Kurechi T. Factors influencing the autoxidation of hemoglobin A. Chemical & Pharmaceutical Bulletin 1981;29(5):1382-9

139. Goldman D, Bateman RM, Ellis CG. Effect of sepsis on skeletal muscle oxygen consumption and tissue oxygenation: interpreting capillary oxygen transport data using a mathematical model. American Journal of Physiology-Heart and Circulatory Physiology 2004;287(6)

140. Spies CD, Reinhart K, Witt I, Meier-Hellmann A, Hannemann L, Bredle DL, et al. Influence of N-acetylcysteine on indirect indicators of tissue oxygenation in septic shock patients: Results from a prospective, randomized, double-blind study. Critical Care Medicine 1994;22:1738-46

141 Spapen H, Zhang H, Demanet C, Vleminckx W, Vincent JL, Huyghens L. Does N-acetyl- L-cysteine influence cytokine response during early human septic shock? Chest 1998;113:1616-24

142. Rank N, Michel C, Haertel C, Lenhart A, Welte M, Meier-Hellmann A, et al. N-acetylcysteine increases liver blood flow and improves liver function in septic shock patients: Results of a prospective, randomized, double-blind study. Critical Care Medicine 2000;28:3799-807

143. Ortolani O, Conte A, De Gaudio AR, Moraldi E, Cantini Q, Novelli G. The effect of glutathione and N-acetylcysteine on lipoperoxidative damage in patients with early septic shock. American Journal of Respiratory and Critical Care Medicine 2000;161:1907-11

144. Zimmermann T, Albrecht S, Kühne H, Vogelsang U, Grützmann R, Kopprasch S. Selenium administration in patients with sepsis syndrome. A prospective randomized study. Medizinische Klinik 1997;92(3):3-4

145. Angstwurm MW, Schottdorf J, Schopohl J, Gaertner R. Selenium replacement in patients with severe systemic inflammatory response syndrome improves clinical outcome. Critical Care Medicine 1999;27:1807-13

146. Mahmud H, Qadri SM, Föller M, Lang F. Inhibition of suicidal erythrocyte death by vitamin C. Nutrition 2010;26(6):671-6

147. Gadek JE, DeMichele SJ, Karlstad MD, Pacht ER, Donahoe M, Albertson TE, et al. Effect of enteral feeding with eicosapentaenoic acid, gammalinolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Critical Care Medicine 1999;27:1409-20

148. Pontes-Arruda A, Albuquerque Aragão AM, Albuquerque JD. Effects of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock. Critical Care Medicine 2006;34:2325-33

149. Hollenberg SM, Cunnion RE, Zimmerberg J. Nitric oxide synthase inhibition reverses arteriolar hyporesponsiveness to catecholamines in septic rats. American Journal of Physiology 1993;264:H660-3

150. Hollenberg SM, Piotrowski MJ, Parrillo JE. Nitric oxide synthase inhibition reverses arteriolar hyporesponsiveness to endothelin- 1 in septic rats. American Journal of Physiology 1997;272:R969-74

151. Frost MT, Wang Q, Moncada S, Singer M. Hypoxia accelerates nitric oxidedependent inhibition of mitochondrial complex I in activated macrophages. American journal of physiology. Regulatory, integrative and comparative physiology 2005;288:R394- 400

152. Scott JA, Mehta S, Duggan M, Bihari A, Mc- Cormack DG. Functional inhibition of constitutive nitric oxide synthase in a rat model of sepsis. American Journal of Respiratory and Critical Care Medicine 2002;165:1426- 32

153. Starzyk D, Korbut R, Gryglewski RJ. The role of nitric oxide in regulation of deformability of red blood cells in acute phase of endotoxaemia in rats. Journal of Physiology and Pharmacology 1997:48:731-735

154. Vincent J-L, Zhang H, Szabo C, Preiser J-C. Effects of Nitric Oxide in Septic Shock. American Journal of Respiratory and Critical Care Medicine 2000;161(6):1781-5

155. Fernandes D, Assreuy J. Nitric oxide and vascular reactivity in sepsis. Shock 2008;30 Suppl 1:10-3

156. Winkler MS, Kluge S, Holzmann M, Moritz E, Robbe L, Bauer A, et al. Markers of nitric oxide are associated with sepsis severity: an observational study. Critical Care 2017;21(1)

157. Knowles RG, Moncada S. Nitric oxide synthases in mammals. Biochemical Journal. 1994;298(2):249-58

158. Takatani Y, Ono K, Suzuki H, Inaba M, Sawada M, Matsuda N. Inducible nitric oxide synthase during the late phase of sepsis is associated with hypothermia and immune cell migration. Laboratory Investigation 2018;98(5):629-39

159. Caironi P, Masson S, Mauri T, Bottazzi B, Leone R, Magnoli M, et al. Pentraxin 3 in patients with severe sepsis or shock: the ALBIOS trial. European Journal of Clinical Investigation 2016;47(1):73-83

160. Carrizzo A, Lenzi P, Procaccini C, Damato A, Biagioni F, Ambrosio M et al. Pentraxin 3 Induces Vascular Endothelial Dysfunction Through a P-selectin/Matrix Metalloproteinase- 1 Pathway. Circulation 2015;131:1495-505

161. Lange M, Hamahata A, Traber DL, Nakano Y, Traber LD, Enkhbaatar P: Specific inhibition of nitric oxide synthases at different time points in a murine model of pulmonary sepsis. Biochemical and Biophysical Research Communications 2011;404(3):877-881

162. Nardi GM, Scheschowitsch K, Ammar D, de Oliveira SK, Arruda TB, Assreuy J: Neuronal nitric oxide synthase and its interaction with soluble guanylate cyclase is a key factor for the vascular dysfunction of experimental sepsis. Critical Care Medicine 2014;42(6):e391-e400

163. Gusarov I, Shatalin K, Starodubtseva M, Nudler E. Endogenous Nitric Oxide Protects Bacteria Against a Wide Spectrum of Antibiotics. Science 2009;325(5946):1380- 4

164. Gusarov I, Nudler E. NO-mediated cytoprotection: Instant adaptation to oxidative stress in bacteria. Proceedings of the National Academy of Sciences 2005;102(39):13855-60

165. Nagababu E, Ramasamy S, Abernethy DR, Rifkind JM. Active nitric oxide produced in the red cell under hypoxic conditions by deoxyhemoglobin-mediated nitrite reduction.The Journal of Biological Chemistry 2003;278:46349-46356

166. Jubelin B, Gierman J. Erythrocytes may synthesize their own nitric oxide. Journal of Hypertension 1996;9(12):1214-9

167. Carvalho A, Martins-Silva J, Saldanha C. Amperometric measurements of nitric oxide in erythrocytes. Biosensors & Bioelectronics 2004;20:505-508

168. Kleinbongard P. Red blood cells express a functional endothelial nitric oxide synthase. Blood 2006 ;107(7):2943-51

169. Silva-Herdade AS, Andolina G, Faggio C, Calado Â, Saldanha C. Erythrocyte deformability- A partner of the inflammatory response. Microvascular Research 2016;107:34-38

170. Korbut R, Gryglewski RJ. The effect of prostacyclin and nitric oxide on deformability of red blood cells in septic shock inrats. Journal of Physiology and Pharmacology 1996;47:591-599

171. Battinelli E, Willoughby SR, Foxall T, Valeri CR, Loscalzo J. Induction of platelet formation from megakaryocytoid cells by nitric oxide. Proceedings of the National of Sciences 2001;98(25):14458-63

172. Shiga T, Maeda N, Kon K. Erythrocyte rheology. Critical Reviews in Oncology/Hematology 1990;10(1):9-48

173. Falkmarken NHD, Arihan O, Iskit AB. Comparison of endothelin and nitric oxide synthase blockerson hemorheological parameters in endotoxemic rats. Turkish Journal Of Medical Sciences 2017;47:1045-52

174. Petrov V, Amery A, Lijnen P. Role of cyclic GMP in atrial-natriuretic-peptide stimulation of erythrocyte Na /H exchange. European Journal of Biochemistry 1994;221(1):195-9

175. Petrov V, Lijnen P. Regulation of human erythrocyte Na /H exchange by soluble and particulate guanylate cyclase. Ameri- can Journal of Physiology-Cell Physiology1996;271(5)

176. Caramelo C, Riesco A, Outeirino J, Millas I, Blum G, Monzu B, et al. Effects of Nitric Oxide on Red Blood Cells: Changes in Erythrocyte Resistance to Hypotonic Hemolysis and Potassium Efflux by Experimental Maneuvers That Decrease Nitric Oxide. Biochemical and Biophysical Research Communications 1994;199(2):447-54

177. Adragna N, Lauf P. Role of Nitrite, a Nitric Oxide Derivative, in K-Cl Cotransport Activation of Low-Potassium Sheep Red Blood Cells. Journal of Membrane Biology 1998;166(3):157-67

178. Grzelak A. Peroxynitrite Activates K -Cl− Cotransport In Human Erythrocytes. Cell Biology International 2001;25(11):1163-5

179. Elias MDO, Lima WTD, Vannuchi YB, Marcourakis T, Silva ZLD, Trezena AG, et al. Nitric oxide modulates Na, K -ATPase activity through cyclic GMP pathway in proximal rat trachea. European Journal of Pharmacology 1999;367(2-3):307-14

180. Pernollet M-G, Lantoine F, Devynck M-A. Nitric Oxide Inhibits ATP-Dependent CA2 Uptake into Platelet Membrane Vesicles. Biochemical and Biophysical Research Communications 1996;222(3):780-5

181. Korbut R, Gryglewski RJ. Nitric oxide from polymorphonuclear leukocytes modulates red blood cell deformability in vitro. European Journal of Pharmacology 1993;234(1):17-22

182. Avontuur JAM, Nolthenius RPT, Bodegom JWV, Bruining HA. Prolonged inhibition of nitric oxide synthesis in severe septic shock. Critical Care Medicine 1998;26(4):660-7

183. Andresen M, Dougnac A, Diaz O, Hernandez G, Castillo L, Bugedo G, et al. Use of methylene blue in patients with refractory septic shock: impact on hemodynamics and gas exchange. Journal of Critical Care 1998;13:164-8

184. Preiser JC, Lejeune P, Roman A, Carlier E, De Backer D, Leeman M, et al. Methylene blue administration in septic shock: a clinical trial. Critical Care Medicine 1995;23:259-64

185. Watson D, Grover R, Anzueto A, Lorente J, Smithies M, Bellomo R, et al. Cardiovascular effects of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) in patients with septic shock: results of a randomized, double-blind, placebocontrolled multicenter study (study no. 144-002). Critical Care Medicine2004;32:13-20

186. Bakker J, Grover R, McLuckie A, Holzapfel L, Andersson J, Lodato R, et al. Administration of the nitric oxide synthase inhibitor NGmethyl- L-arginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis: results of a randomized, double-blind, placebocontrolled multicenter study (study no. 144-002). Critical Care Medicine 2004;32:1-12

187. Lorenz E. TLR2 and TLR4 expression during bacterial infections. Current Pharmaceutical Design 2006;12:4185-93

188. Loughran PA, Lei Z, Xu L, Deng M, Billiar TR. Nitric Oxide in Sepsis and Hemorrhagic Shock: Beneficial or Detrimental? Nitric Oxide 2017;289-300.

189. Boerma EC, Koopmans M, Konijn A, Kaiferova K, Bakker AJ, van Roon EN, et al. Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis/septic shock after a strict resuscitation protocol: a double-blind randomized placebo controlled trial. Critical Care Medicine 2010;38:93-100

190. Spronk PE, Ince C, Gardien MJ, Mathura KR, Oudemans-van Straaten HM, Zandstra DF. Nitroglycerin in septic shock after intravascular volume resuscitation. Lancet 2002;360:1395-6

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