Pathogenesis of multiple organ failure in sepsis

Critical Reviews in Immunology

Volumn 35, Issue 4, 2015, Pages 277-291

  Rossaint, Jan ^a   Zarbock, Alexander ^a  

^a UNIVERSITY HOSPITAL MÜNSTER   (Germany)

Author keywords

Multi organ dysfunction syndrome; Multi organ failure; Sepsis

Indexed keywords

CD4 ANTIGEN; CD8 ANTIGEN; INTERLEUKIN 22; TOLL LIKE RECEPTOR 2; TOLL LIKE RECEPTOR 4; TOLL LIKE RECEPTOR 5; TOLL LIKE RECEPTOR 9;

ACUTE KIDNEY FAILURE; ADAPTIVE IMMUNITY; B LYMPHOCYTE; BACTERIAL INFECTION; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; ENDOTHELIAL DYSFUNCTION; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; INFLAMMATION; INTRACELLULAR SIGNALING; MULTIPLE ORGAN FAILURE; NONHUMAN; PATHOGENESIS; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; SEPSIS; T LYMPHOCYTE; TH1 CELL; TH17 CELL; TH2 CELL; THROMBOCYTE ACTIVATION; ANIMAL; COMPLICATION; CYTOTOXICITY; IMMUNOLOGY; MOLECULARLY TARGETED THERAPY; SIGNAL TRANSDUCTION;

ANIMALS; CYTOTOXICITY, IMMUNOLOGIC; HUMANS; INFLAMMATION; MOLECULAR TARGETED THERAPY; MULTIPLE ORGAN FAILURE; SEPSIS; SIGNAL TRANSDUCTION;

EID: 84954441780     PISSN: 10408401     EISSN: None     Source Type: Journal    
DOI: 10.1615/CritRevImmunol.2015015461     Document Type: Review

References (102)

1. Cohen J, Vincent JL, Adhikari NK, Machado FR, Angus DC, Calandra T, Jaton K, Giulieri S, Delaloye J, Opal S, Tracey K, van der Poll T, Pelfrene E. Sepsis: a roadmap for future research. Lancet Infect Dis. 2015;15:581-614.
2. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303-10.
3. Wilhelms SB, Huss FR, Granath G, Sjoberg F. Assessment of incidence of severe sepsis in Sweden using different ways of abstracting International Classification of Diseases codes: difficulties with methods and interpretation of results. Crit Care Med. 2010;38:1442-9.
4. Flaatten H. Epidemiology of sepsis in Norway in 1999. Crit Care. 2004;8:R180-4.
5. Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA. 2014;311:1308-16.
6. Vincent JL, Marshall JC, Namendys-Silva SA, Francois B, Martin-Loeches I, Lipman J, Reinhart K, Antonelli M, Pickkers P, Njimi H, Jimenez E, Sakr Y, investigators I. Assessment of the worldwide burden of critical illness: the intensive care over nations (ICON) audit. Lancet Respir Med. 2014;2:380-6.
7. Vincent JL, Opal SM, Marshall JC, Tracey KJ. Sepsis definitions: time for change. Lancet. 2013;381:774-5.
8. Ramirez M. Multiple organ dysfunction syndrome. Curr Problem Pediatr Adolesc Health Care. 2013;43:273-7.
9. Le Gall JR, Klar J, Lemeshow S, Saulnier F, Alberti C, Artigas A, Teres D. The Logistic Organ Dysfunction system. A new way to assess organ dysfunction in the intensive care unit. ICU Scoring Group. JAMA. 1996;276:802-10.
10. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Medicine. 1996;22:707-10.
11. Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, Sibbald WJ. Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med. 1995;23:1638-52.
12. Shapiro N, Howell MD, Bates DW, Angus DC, Ngo L, Talmor D. The association of sepsis syndrome and organ dysfunction with mortality in emergency department patients with suspected infection. Ann Emerg Med. 2006;48:583-90, 90 e1.
13. Alberti C, Brun-Buisson C, Burchardi H, Martin C, Goodman S, Artigas A, Sicignano A, Palazzo M, Moreno R, Boulme R, Lepage E, Le Gall R. Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Intensive Care Med. 2002;28:108-21.
14. Janeway CA, Jr., Medzhitov R. Introduction: the role of innate immunity in the adaptive immune response. Semin Immunol. 1998;10:349-50.
15. Majcherczyk PA, Langen H, Heumann D, Fountoulakis M, Glauser MP, Moreillon P. Digestion of Streptococcus pneumoniae cell walls with its major peptidoglycan hydrolase releases branched stem peptides carrying proinflammatory activity. J Biol Chem. 1999;274:12537-43.
16. Morath S, Geyer A, Hartung T. Structure-function relationship of cytokine induction by lipoteichoic acid from Staphylococcus aureus. J Exper Med. 2001;193:393-7.
17. Eaves-Pyles T, Murthy K, Liaudet L, Virag L, Ross G, Soriano FG, Szabo C, Salzman AL. Flagellin, a novel mediator of Salmonella-induced epithelial activation and systemic inflammation: I kappa B alpha degradation, induction of nitric oxide synthase, induction of proinflammatory mediators, and cardiovascular dysfunction. J Immunol. 2001;166:1248-60.
18. Herwald H, Morgelin M, Olsen A, Rhen M, Dahlback B, Muller-Esterl W, Bjorck L. Activation of the contact-phase system on bacterial surfaces—a clue to serious complications in infectious diseases. Nature Med. 1998;4:298-302.
19. Sparwasser T, Miethke T, Lipford G, Borschert K, Hacker H, Heeg K, Wagner H. Bacterial DNA causes septic shock. Nature. 1997;386:336-7.
20. Bauer S, Kirschning CJ, Hacker H, Redecke V, Hausmann S, Akira S, Wagner H, Lipford GB. Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc Nat Acad Sci U S A. 2001;98:9237-42.
21. Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science. 1990;249:1431-3.
22. Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature. 2000;406:782-7.
23. Vasselon T, Detmers PA. Toll receptors: a central element in innate immune responses. Infect Immun. 2002;70:1033-41.
24. Medzhitov R, Preston-Hurlburt P, Janeway CA, Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997;388:394-7.
25. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282:2085-8.
26. Bowie A, O’Neill LA. The interleukin-1 receptor/Toll-like receptor superfamily: signal generators for pro-inflammatory interleukins and microbial products. J Leukocyte Biol. 2000;67:508-14.
27. Opal SM, Huber CE. Bench-to-bedside review: Toll-like receptors and their role in septic shock. Crit Care. 2002;6:125-36.
28. Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T, Takeda K, Akira S. Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components. Immunity. 1999;11:443-51.
29. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature. 2001;410:1099-103.
30. Ozinsky A, Underhill DM, Fontenot JD, Hajjar AM, Smith KD, Wilson CB, Schroeder L, Aderem A. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Nat Acad Sci U S A. 2000;97:13766-71.
31. Lorenz E, Mira JP, Cornish KL, Arbour NC, Schwartz DA. A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect Immun. 2000;68:6398-401.
32. Lorenz E, Mira JP, Frees KL, Schwartz DA. Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med. 2002;162:1028-32.
33. Tang D, Kang R, Coyne CB, Zeh HJ, Lotze MT. PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol Revs. 2012;249:158-75.
34. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104-7.
35. Abraham E, Singer M. Mechanisms of sepsis-induced organ dysfunction. Crit Care Med. 2007;35:2408-16.
36. Ojeda Ojeda M, Larrondo Muguercia H, Magdariaga Figuerola A, Sanchez Valdivia A, Rodriguez Alonso I, Valenzuela Silva C, Garcia Iglesias E, Dominguez Alonso E, Buurman WA, Arana Rosainz Mde J. Temporal trends of circulating nitric oxide and pro-inflammatory cytokine responses ex vivo in intra-abdominal sepsis: results from a cohort study. Inflam Res. 2011;60:289-97.
37. Santos SS, Brunialti MK, Rigato O, Machado FR, Silva E, Salomao R. Generation of nitric oxide and reactive oxygen species by neutrophils and monocytes from septic patients and association with outcomes. Shock. 2012;38:18-23.
38. Szabo C, Modis K. Pathophysiological roles of peroxynitrite in circulatory shock. Shock. 2010; 34 Suppl 1:4-14.
39. Losser MR, Damoisel C, Payen D. Bench-to-bedside review: glucose and stress conditions in the intensive care unit. Crit Care. 2010;14:231.
40. Levy B, Gibot S, Franck P, Cravoisy A, Bollaert PE. Relation between muscle Na+K+ ATPase activity and raised lactate concentrations in septic shock: a prospective study. Lancet. 2005;365:871-5.
41. Opal SM, van der Poll T. Endothelial barrier dysfunction in septic shock. J Intern Med. 2015;277:277-93.
42. Hollenberg SM, Cunnion RE. Endothelial and vascular smooth muscle function in sepsis. J Crit Care. 1994;9:262-80.
43. Kumar P, Shen Q, Pivetti CD, Lee ES, Wu MH, Yuan SY. Molecular mechanisms of endothelial hyperpermeability: implications in inflammation. Expert Revs Molec Med. 2009;11:e19.
44. Dixon B. The role of microvascular thrombosis in sepsis. Anaesthesia and Intensive Care. 2004;32:619-29.
45. Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA. The sepsis seesaw: tilting toward immunosuppression. Nature Med. 2009;15:496-7.
46. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. New Engl J Med. 2003;348:138-50.
47. Hotchkiss RS, Nicholson DW. Apoptosis and caspases regulate death and inflammation in sepsis. Nature Revs Immunol. 2006;6:813-22.
48. Hotchkiss RS, Opal S. Immunotherapy for sepsis—a new approach against an ancient foe. New England Journal of Medicine. 2010;363:87-9.
49. Jiang H, Chess L. Regulation of immune responses by T cells. New Engl J Med. 2006;354:1166-76.
50. Kasten KR, Tschop J, Adediran SG, Hildeman DA, Caldwell CC. T cells are potent early mediators of the host response to sepsis. Shock. 2010;34:327-36.
51. Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a primer. Critical Care Medicine. 2009;37:291-304.
52. Littman DR, Rudensky AY. Th17 and regulatory T cells in mediating and restraining inflammation. Cell. 2010;140:845-58.
53. van de Veerdonk FL, Teirlinck AC, Kleinnijenhuis J, Kullberg BJ, van Crevel R, van der Meer JW, Joosten LA, Netea MG. Mycobacterium tuberculosis induces IL-17A responses through TLR4 and dectin-1 and is critically dependent on endogenous IL-1. J Leukocyte Biol. 2010;88:227-32.
54. Chen Z, O’Shea JJ. Th17 cells: a new fate for differentiating helper T cells. Immunol Res. 2008;41:87-102.
55. Chizzolini C, Chicheportiche R, Alvarez M, de Rham C, Roux-Lombard P, Ferrari-Lacraz S, Dayer JM. Prostaglandin E2 synergistically with interleukin-23 favors human Th17 expansion. Blood. 2008;112:3696-703.
56. Lavoie PM, Huang Q, Jolette E, Whalen M, Nuyt AM, Audibert F, Speert DP, Lacaze-Masmonteil T, Soudeyns H, Kollmann TR. Profound lack of interleukin (IL)-12/IL-23p40 in neonates born early in gestation is associated with an increased risk of sepsis. J Infect Dis. 2010;202:1754-63.
57. Opal SM. New perspectives on immunomodulatory therapy for bacteraemia and sepsis. Int J Antimicrob Agents. 2010;36 Suppl 2:S70-3.
58. Venet F, Bohe J, Debard AL, Bienvenu J, Lepape A, Monneret G. Both percentage of gamma-delta T lymphocytes and CD3 expression are reduced during septic shock. Crit Care Med. 2005;33:2836-40.
59. Akira S, Takeda K. Toll-like receptor signalling. Nat Revs Immunol. 2004;4:499-511.
60. Osuchowski MF, Welch K, Siddiqui J, Remick DG. Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. J Immunol. 2006;177:1967-74.
61. Meisel C, Schefold JC, Pschowski R, Baumann T, Hetzger K, Gregor J, Weber-Carstens S, Hasper D, Keh D, Zuckermann H, Reinke P, Volk HD. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med. 2009;180:640-8.
62. Trapnell BC. A novel biomarker-guided immunomodulatory approach for the therapy of sepsis. Am J Respir Crit Care Med. 2009;180:585-6.
63. Dinarello CA. Anti-inflammatory agents: present and future. Cell. 2010;140:935-50.
64. Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I, Kroczek RA. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature. 1999;397:263-6.
65. Wang S, Zhu G, Chapoval AI, Dong H, Tamada K, Ni J, Chen L. Costimulation of T cells by B7-H2, a B7-like molecule that binds ICOS. Blood. 2000;96:2808-13.
66. Okazaki T, Honjo T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol. 2006;27:195-201.
67. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Ann Rev Immunol. 2008;26:677-704.
68. Huang X, Venet F, Wang YL, Lepape A, Yuan Z, Chen Y, Swan R, Kherouf H, Monneret G, Chung CS, Ayala A. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc Nat Acad Sci U S A. 2009;106:6303-8.
69. Brahmamdam P, Inoue S, Unsinger J, Chang KC, McDunn JE, Hotchkiss RS. Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis. J Leukocyte Biol. 2010;88:233-40.
70. Albring JC, Sandau MM, Rapaport AS, Edelson BT, Satpathy A, Mashayekhi M, Lathrop SK, Hsieh CS, Stelljes M, Colonna M, Murphy TL, Murphy KM. Targeting of B and T lymphocyte associated (BTLA) prevents graft-versus-host disease without global immunosuppression. J Exper Med. 2010;207:2551-9.
71. Watanabe N, Gavrieli M, Sedy JR, Yang J, Fallarino F, Loftin SK, Hurchla MA, Zimmerman N, Sim J, Zang X, Murphy TL, Russell JH, Allison JP, Murphy KM. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nature Immunol. 2003;4:670-9.
72. Vendel AC, Calemine-Fenaux J, Izrael-Tomasevic A, Chauhan V, Arnott D, Eaton DL. B and T lymphocyte attenuator regulates B cell receptor signaling by targeting Syk and BLNK. J Immunol. 2009;182:1509-17.
73. Hurchla MA, Sedy JR, Gavrieli M, Drake CG, Murphy TL, Murphy KM. B and T lymphocyte attenuator exhibits structural and expression polymorphisms and is highly Induced in anergic CD4+ T cells. J Immunol. 2005;174:3377-85.
74. Sedy JR, Gavrieli M, Potter KG, Hurchla MA, Lindsley RC, Hildner K, Scheu S, Pfeffer K, Ware CF, Murphy TL, Murphy KM. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nature Immunol. 2005;6:90-8.
75. Chemnitz JM, Lanfranco AR, Braunstein I, Riley JL. B and T lymphocyte attenuator-mediated signal transduction provides a potent inhibitory signal to primary human CD4 T cells that can be initiated by multiple phosphotyrosine motifs. J Immunol. 2006;176:6603-14.
76. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322:271-5.
77. Zhu X, Marcus WD, Xu W, Lee HI, Han K, Egan JO, Yovandich JL, Rhode PR, Wong HC. Novel human interleukin-15 agonists. J Immunol. 2009;183:3598-607.
78. Davidson GH, Hamlat CA, Rivara FP, Koepsell TD, Jurkovich GJ, Arbabi S. Long-term survival of adult trauma patients. JAMA. 2011;305:1001-7.
79. Hasegawa A, Iwasaka H, Hagiwara S, Asai N, Nishida T, Noguchi T. Alternate day calorie restriction improves systemic inflammation in a mouse model of sepsis induced by cecal ligation and puncture. J Surg Res. 2012;174:136-41.
80. Christaki E, Opal SM, Keith JC, Jr., Kessinian N, Palardy JE, Parejo NA, Lavallie E, Racie L, Mounts W, Malamas MS, Mewshaw RE, Harris HA, Vlasuk GP. Estrogen receptor beta agonism increases survival in experimentally induced sepsis and ameliorates the genomic sepsis signature: a pharmacogenomic study. J Infect Dis. 2010;201:1250-7.
81. Cohen I, Rider P, Carmi Y, Braiman A, Dotan S, White MR, Voronov E, Martin MU, Dinarello CA, Apte RN. Differential release of chromatin-bound IL-1alpha discriminates between necrotic and apoptotic cell death by the ability to induce sterile inflammation. Proc Nat Acad Sci. 2010;107:2574-9.
82. Chen CJ, Kono H, Golenbock D, Reed G, Akira S, Rock KL. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat Med. 2007;13:851-6.
83. Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Ann Rev Immunol. 2009;27:519-50.
84. Werman A, Werman-Venkert R, White R, Lee JK, Werman B, Krelin Y, Voronov E, Dinarello CA, Apte RN. The precursor form of IL-1alpha is an intracrine proinflammatory activator of transcription. Proc Nat Acad Sci U S A. 2004;101:2434-9.
85. Secor D, Li F, Ellis CG, Sharpe MD, Gross PL, Wilson JX, Tyml K. Impaired microvascular perfusion in sepsis requires activated coagulation and P-selectin-mediated platelet adhesion in capillaries. Intensive Care Med. 2010;36:1928-34.
86. Shibazaki M, Kawabata Y, Yokochi T, Nishida A, Takada H, Endo Y. Complement-dependent accumulation and degradation of platelets in the lung and liver induced by injection of lipopolysaccharides. Infect Immun. 1999;67:5186-91.
87. Singer G, Urakami H, Specian RD, Stokes KY, Granger DN. Platelet recruitment in the murine hepatic microvasculature during experimental sepsis: role of neutrophils. Microcirculation. 2006;13:89-97.
88. Rossaint J, Zarbock A. Platelets in leucocyte recruitment and function. Cardiovascular Res. 2015; 107:386-95.
89. Herter JM, Rossaint J, Zarbock A. Platelets in inflammation and immunity. J Thrombosis Haemostasis. 2014;12:1764-75.
90. Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF. Neutrophils in development of multiple organ failure in sepsis. Lancet. 2006;368:157-69.
91. Peters MJ, Dixon G, Kotowicz KT, Hatch DJ, Heyderman RS, Klein NJ. Circulating platelet-neutrophil complexes represent a subpopulation of activated neutrophils primed for adhesion, phagocytosis and intracellular killing. Brit J Hematology. 1999;106:391-9.
92. Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, Patel KD, Chakrabarti S, McAvoy E, Sinclair GD, Keys EM, Allen-Vercoe E, Devinney R, Doig CJ, Green FH, Kubes P. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nature Med. 2007;13:463-9.
93. Rossaint J, Herter JM, Van Aken H, Napirei M, Doring Y, Weber C, Soehnlein O, Zarbock A. Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap-mediated sterile inflammation. Blood. 2014;123:2573-84.
94. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A. Neutrophil extracellular traps kill bacteria. Science. 2004;303:1532-5.
95. McDonald B, Urrutia R, Yipp BG, Jenne CN, Kubes P. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host & Microbe. 2012;12:324-33.
96. Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Revs Immunol. 2013;13:34-45.
97. Kitchens CS. Thrombocytopenia and thrombosis in disseminated intravascular coagulation (DIC). Hematology. 2009:240-6.
98. Coopersmith CM, Stromberg PE, Dunne WM, Davis CG, Amiot DM, 2nd, Buchman TG, Karl IE, Hotchkiss RS. Inhibition of intestinal epithelial apoptosis and survival in a murine model of pneumonia-induced sepsis. JAMA. 2002;287:1716-21.
99. Haimovitz-Friedman A, Cordon-Cardo C, Bayoumy S, Garzotto M, McLoughlin M, Gallily R, Edwards CK, 3rd, Schuchman EH, Fuks Z, Kolesnick R. Lipopolysaccharide induces disseminated endothelial apoptosis requiring ceramide generation. J Exper Med. 1997;186:1831-41.
100. Sharron M, Hoptay CE, Wiles AA, Garvin LM, Geha M, Benton AS, Nagaraju K, Freishtat RJ. Platelets induce apoptosis during sepsis in a contact-dependent manner that is inhibited by GPIIb/IIIa blockade. PLoS One. 2012;7:e41549.
101. Freishtat RJ, Natale J, Benton AS, Cohen J, Sharron M, Wiles AA, Ngor WM, Mojgani B, Bradbury M, Degnan A, Sachdeva R, Debiase LM, Ghimbovschi S, Chow M, Bunag C, Kristosturyan E, Hoffman EP. Sepsis alters the megakaryocyte-platelet transcriptional axis resulting in granzyme B-mediated lymphotoxicity. Am J Respir Crit Care Med. 2009;179:467-73.
102. Kraemer BF, Campbell RA, Schwertz H, Cody MJ, Franks Z, Tolley ND, Kahr WH, Lindemann S, Seizer P, Yost CC, Zimmerman GA, Weyrich AS. Novel anti-bacterial activities of beta-defensin 1 in human platelets: suppression of pathogen growth and signaling of neutrophil extracellular trap formation. PLoS Pathogens. 2011;7:e1002355.