Gender differences in sepsis: Cardiovascular and immunological aspects

Virulence

Volumn 5, Issue 1, 2014, Pages 12-19

  Angele, Martin K ^a   Pratschke, Sebastian ^a   Hubbard, William J ^b   Chaudry, Irshad H ^b  

^a LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

^b UNIVERSITY OF ALABAMA SCHOOL OF MEDICINE   (United States)

Author keywords

Estrogen; Immune depression; Immune modulation; Sex steroids

Indexed keywords

ANDROGEN; ANDROSTENEDIOL; ANTITHROMBIN III; BLOOD CLOTTING FACTOR 9; CASPASE 3; ESTRADIOL; ESTROGEN; ESTROGEN RECEPTOR ALPHA; ESTROGEN RECEPTOR BETA; FLUTAMIDE; GAMMA INTERFERON; INDUCIBLE NITRIC OXIDE SYNTHASE; INTERLEUKIN 1; INTERLEUKIN 10; INTERLEUKIN 12; INTERLEUKIN 1BETA; INTERLEUKIN 2; INTERLEUKIN 6; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; MITOGEN ACTIVATED PROTEIN KINASE P38; PRASTERONE; RAC1 PROTEIN; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE; TESTOSTERONE; TOLL LIKE RECEPTOR 4; TUMOR NECROSIS FACTOR ALPHA; TUMOR NECROSIS FACTOR RECEPTOR ASSOCIATED FACTOR 1; UNINDEXED DRUG;

CARDIOVASCULAR FUNCTION; CARDIOVASCULAR SYSTEM; CELLULAR IMMUNITY; DISEASE ASSOCIATION; HUMAN; IMMUNE RESPONSE; INCIDENCE; INFLAMMATION; MESENCHYMAL STEM CELL; NONHUMAN; PNEUMONIA; REVIEW; RISK FACTOR; SEPSIS; SEPTIC SHOCK; SEX DIFFERENCE; SURVIVAL RATE; X CHROMOSOME;

ESTROGEN; IMMUNE DEPRESSION; IMMUNE MODULATION; SEX STEROIDS;

ANDROGEN RECEPTOR ANTAGONISTS; ANDROGENS; ANIMALS; CARDIOVASCULAR SYSTEM; DEHYDROEPIANDROSTERONE; ESTROGENS; FEMALE; FLUTAMIDE; HUMANS; IMMUNITY, CELLULAR; MALE; MESENCHYMAL STEM CELL TRANSPLANTATION; MICE; SEX FACTORS; SHOCK, SEPTIC;

EID: 84891654164     PISSN: 21505594     EISSN: 21505608     Source Type: Journal    
DOI: 10.4161/viru.26982     Document Type: Review

References (81)

1. Jarrar D, Wang P, Cioffi WG, Bland KI, Chaudry IH. The female reproductive cycle is an important variable in the response to trauma-hemorrhage. Am J Physiol Heart Circ Physiol 2000; 279:H1015-21. PMID:10993763
2. Opal SM, Laterre PF, Francois B, LaRosa SP, Angus DC, Mira JP, Wittebole X, Dugernier T, Perrotin D, Tidswell M, et al.; ACCESS Study Group. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA 2013; 309:1154-62. PMID:23512062; http://dx.doi.org/10.1001/jama.2013.2194
3. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, et al.; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 2013; 39:165-228. PMID:23361625; http://dx.doi.org/10.1007/s00134-012-2769-8
4. Cunnington A, Nadel S. New therapies for sepsis. Curr Top Med Chem 2008; 8:603-14. PMID:18473886; http://dx.doi.org/10.2174/156802608783955601
5. Nadkarni S, McArthur S. Oestrogen and immunomodulation: new mechanisms that impact on peripheral and central immunity. Curr Opin Pharmacol 2013; 13:576-81. PMID:23731522; http://dx.doi.org/10.1016/j.coph.2013.05.007
6. Hernández-Bello R, Nava-Castro K, Muñiz-Hernández S, Nava-Luna P, Trejo-Sánchez I, Tiempos-Guzmán N, Mendoza-Rodríguez Y, Morales-Montor J. Beyond the reproductive effect of sex steroids: their role during immunity to helminth parasite infections. Mini Rev Med Chem 2012; 12:1071-80. PMID:22924485; http://dx.doi.org/10.2174/138955712802762149
7. Pan Z, Chang C. Gender and the regulation of longevity: implications for autoimmunity. Autoimmun Rev 2012; 11:A393-403. PMID:22182796; http://dx.doi.org/10.1016/j.autrev.2011.12.004
8. Nussinovitch U, Shoenfeld Y. The role of gender and organ specific autoimmunity. Autoimmun Rev 2012; 11:A377-85. PMID:22100310; http://dx.doi.org/10.1016/j.autrev.2011.11.001
9. Smyk DS, Rigopoulou EI, Pares A, Billinis C, Burroughs AK, Muratori L, Invernizzi P, Bogdanos DP. Sex differences associated with primary biliary cirrhosis. Clin Dev Immunol 2012; 2012:610504. PMID:22693524; http://dx.doi.org/10.1155/2012/610504
10. Luckey D, Medina K, Taneja V. B cells as effectors and regulators of sex-biased arthritis. Autoimmunity 2012; 45:364-76. PMID:22429183; http://dx.doi.org/10.3109/08916934.2012.665528
11. Saha S, Tieng A, Pepeljugoski KP, Zandamn-Goddard G, Peeva E. Prolactin, systemic lupus erythematosus, and autoreactive B cells: lessons learnt from murine models. Clin Rev Allergy Immunol 2011; 40:8-15. PMID:19937157; http://dx.doi.org/10.1007/s12016-009-8182-6
12. Zandman-Goddard G, Peeva E, Shoenfeld Y. Gender and autoimmunity. Autoimmun Rev 2007; 6:366-72. PMID:17537382; http://dx.doi.org/10.1016/j.autrev.2006.10.001
13. Gaillard RC, Spinedi E. Sex-and stress-steroids interactions and the immune system: evidence for a neuroendocrine-immunological sexual dimorphism. Domest Anim Endocrinol 1998; 15:345-52. PMID:9785038; http://dx.doi.org/10.1016/S0739-7240(98)00028-9
14. Sakiani S, Olsen NJ, Kovacs WJ. Gonadal steroids and humoral immunity. Nat Rev Endocrinol 2013; 9:56-62. PMID:23183675; http://dx.doi.org/10.1038/nrendo.2012.206
15. Panchanathan R, Shen H, Bupp MG, Gould KA, Choubey D. Female and male sex hormones differentially regulate expression of Ifi202, an interferon-inducible lupus susceptibility gene within the Nba2 interval. J Immunol 2009; 183:7031-8. PMID:19890043; http://dx.doi.org/10.4049/jimmunol.0802665
16. Weidler C, Härle P, Schedel J, Schmidt M, Schölmerich J, Straub RH. Patients with rheumatoid arthritis and systemic lupus erythematosus have increased renal excretion of mitogenic estrogens in relation to endogenous antiestrogens. J Rheumatol 2004; 31:489-94. PMID:14994392
17. Chrousos GP. Stress and sex versus immunity and inflammation. Sci Signal 2010; 3:pe36. PMID:20940425; http://dx.doi.org/10.1126/scisignal.3143pe36
18. Offner PJ, Moore EE, Biffl WL. Male gender is a risk factor for major infections after surgery. Arch Surg 1999; 134:935-8, discussion 938-40; PMID:10487586; http://dx.doi.org/10.1001/archsurg.134.9.935
19. McGowan JE Jr., Barnes MW, Finland M. Bacteremia at Boston City Hospital: Occurrence and mortality during 12 selected years (1935-1972), with special reference to hospital-acquired cases. J Infect Dis 1975; 132:316-35. PMID:1159333; http://dx.doi.org/10.1093/infdis/132.3.316
20. Gannon CJ, Pasquale M, Tracy JK, McCarter RJ, Napolitano LM. Male gender is associated with increased risk for postinjury pneumonia. Shock 2004; 21:410-4. PMID:15087816; http://dx.doi.org/10.1097/00024382-200405000-00003
21. Mahmood K, Eldeirawi K, Wahidi MM. Association of gender with outcomes in critically ill patients. Crit Care 2012; 16:R92. PMID:22617003; http://dx.doi.org/10.1186/CC11355
22. Reade MC, Yende S, D'Angelo G, Kong L, Kellum JA, Barnato AE, Milbrandt EB, Dooley C, Mayr FB, Weissfeld L, et al.; Genetic and Inflammatory Markers of Sepsis Investigators. Differences in immune response may explain lower survival among older men with pneumonia. Crit Care Med 2009; 37:1655-62. PMID:19325487; http://dx.doi.org/10.1097/CCM.0b013e31819da853
23. Schröder J, Kahlke V, Staubach KH, Zabel P, Stüber F. Gender differences in human sepsis. Arch Surg 1998; 133:1200-5. PMID:9820351; http://dx.doi.org/10.1001/archsurg.133.11.1200
24. Kisat M, Villegas CV, Onguti S, Zafar SN, Latif A, Efron DT, Haut ER, Schneider EB, Lipsett PA, Zafar H, et al. Predictors of sepsis in moderately severely injured patients: an analysis of the National Trauma Data Bank. Surg Infect (Larchmt) 2013; 14:62-8. PMID:23461696; http://dx.doi.org/10.1089/sur.2012.009
25. Zellweger R, Wichmann MW, Ayala A, Stein S, DeMaso CM, Chaudry IH. Females in proestrus state maintain splenic immune functions and tolerate sepsis better than males. Crit Care Med 1997; 25:106-10. PMID:8989185; http://dx.doi.org/10.1097/00003246-199701000-00021
26. Diodato MD, Knöferl MW, Schwacha MG, Bland KI, Chaudry IH. Gender differences in the inflammatory response and survival following haemorrhage and subsequent sepsis. Cytokine 2001; 14:162-9. PMID:11396994; http://dx.doi.org/10.1006/cyto.2001.0861
27. Gannon CJ, Napolitano LM, Pasquale M, Tracy JK, McCarter RJ. A statewide population-based study of gender differences in trauma: validation of a prior single-institution study. J Am Coll Surg 2002; 195:11-8. PMID:12113534; http://dx.doi.org/10.1016/S1072-7515(02)01187-0
28. Oberholzer A, Keel M, Zellweger R, Steckholzer U, Trentz O, Ertel W. Incidence of septic complications and multiple organ failure in severely injured patients is sex specific. J Trauma 2000; 48:932-7. PMID:10823539; http://dx.doi.org/10.1097/00005373-200005000-00019
29. Frink M, Pape HC, van Griensven M, Krettek C, Chaudry IH, Hildebrand F. Influence of sex and age on mods and cytokines after multiple injuries. Shock 2007; 27:151-6. PMID:17224789; http://dx.doi.org/10.1097/01.shk.0000239767.64786.de
30. Aulock SV, Deininger S, Draing C, Gueinzius K, Dehus O, Hermann C. Gender difference in cytokine secretion on immune stimulation with LPS and LTA. J Interferon Cytokine Res 2006; 26:887-92. PMID:17238831; http://dx.doi.org/10.1089/jir.2006.26.887
31. Wang HE, Shapiro NI, Griffin R, Safford MM, Judd S, Howard G. Inflammatory and endothelial activation biomarkers and risk of sepsis: a nested case-control study. J Crit Care 2013; 28:549-55. PMID:23414982; http://dx.doi.org/10.1016/j.jcrc.2012.11.002
32. Li P, Allen H, Banerjee S, Franklin S, Herzog L, Johnston C, McDowell J, Paskind M, Rodman L, Salfeld J, et al. Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. Cell 1995; 80:401-11. PMID:7859282; http://dx.doi.org/10.1016/0092-8674(95)90490-5
33. Ongaro L, Castrogiovanni D, Giovambattista A, Gaillard RC, Spinedi E. Enhanced proinflammatory cytokine response to bacterial lipopolysaccharide in the adult male rat after either neonatal or prepubertal ablation of biological testosterone activity. Neuroimmunomodulation 2011; 18:254-60. PMID:21430397; http://dx.doi.org/10.1159/000324125
34. Yu HP, Yang S, Choudhry MA, Hsieh YC, Bland KI, Chaudry IH. Mechanism responsible for the salutary effects of flutamide on cardiac performance after trauma-hemorrhagic shock: Upregulation of cardiomyocyte estrogen receptors. Surgery 2005; 138:85-92. PMID:16003321; http://dx.doi.org/10.1016/j.surg.2005.03.006
35. Shimizu T, Yu HP, Hsieh YC, Choudhry MA, Suzuki T, Bland KI, Chaudry IH. Flutamide attenuates proinflammatory cytokine production and hepatic injury following trauma-hemorrhage via estrogen receptorrelated pathway. Ann Surg 2007; 245:297-304. PMID:17245185; http://dx.doi.org/10.1097/01.sla.0000232523.88621.17
36. Hsieh YC, Yang S, Choudhry MA, Yu HP, Bland KI, Schwacha MG, Chaudry IH. Flutamide restores cardiac function after trauma-hemorrhage via an estrogen-dependent pathway through upregulation of PGC-1. Am J Physiol Heart Circ Physiol 2006; 290:H416-23. PMID:16155096; http://dx.doi.org/10.1152/ajpheart.00865.2005
37. Asai K, Hiki N, Mimura Y, Ogawa T, Unou K, Kaminishi M. Gender differences in cytokine secretion by human peripheral blood mononuclear cells: role of estrogen in modulating LPS-induced cytokine secretion in an ex vivo septic model. Shock 2001; 16:340-3. PMID:11699070; http://dx.doi.org/10.1097/00024382-200116050-00003
38. Wichmann MW, Müller C, Meyer G, Adam M, Angele MK, Eisenmenger SJ, Schildberg FW. Different immune responses to abdominal surgery in men and women. Langenbecks Arch Surg 2003; 387:397-401. PMID:12607118
39. Majetschak M, Christensen B, Obertacke U, Waydhas C, Schindler AE, Nast-Kolb D, Schade FU. Sex differences in posttraumatic cytokine release of endotoxin-stimulated whole blood: relationship to the development of severe sepsis. J Trauma 2000; 48:832-9, discussion 839-40; PMID:10823526; http://dx.doi.org/10.1097/00005373-200005000-00006
40. Angele MK, Schwacha MG, Ayala A, Chaudry IH. Effect of gender and sex hormones on immune responses following shock. Shock 2000; 14:81-90. PMID:10947147; http://dx.doi.org/10.1097/00024382-200014020-00001
41. Brunnemer U, Zeckey C, Hildebrand F, Frink M, Mommsen P, van Griensven M, Andruszkow H, Krettek C, Barkhausen T. Androstenediol exerts salutary effects on chemokine response after traumahemorrhage and sepsis in mice. J Orthop Trauma 2011; 25:511-5. PMID:21738064; http://dx.doi.org/10.1097/BOT.0b013e3182251044
42. Drechsler S, Weixelbaumer K, Raeven P, Jafarmadar M, Khadem A, van Griensven M, Bahrami S, Osuchowski MF. Relationship between age/genderinduced survival changes and the magnitude of inflammatory activation and organ dysfunction in post-traumatic sepsis. PLoS One 2012; 7:e51457. PMID:23251540; http://dx.doi.org/10.1371/journal.pone.0051457
43. Scotland RS, Stables MJ, Madalli S, Watson P, Gilroy DW. Sex differences in resident immune cell phenotype underlie more efficient acute inflammatory responses in female mice. Blood 2011; 118:5918-27. PMID:21911834; http://dx.doi.org/10.1182/blood-2011-03-340281
44. Rettew JA, Huet-Hudson YM, Marriott I. Testosterone reduces macrophage expression in the mouse of toll-like receptor 4, a trigger for inflammation and innate immunity. Biol Reprod 2008; 78:432-7. PMID:18003947; http://dx.doi.org/10.1095/biolreprod.107.063545
45. Newsome CT, Flores E, Ayala A, Gregory S, Reichner JS. Improved antimicrobial host defense in mice following poly-(1,6)-β-D-glucopyranosyl-(1,3)-β-D-glucopyranose glucan treatment by a gender-dependent immune mechanism. Clin Vaccine Immunol 2011; 18:2043-9. PMID:21976224; http://dx.doi.org/10.1128/CVI.05202-11
46. Chandra R, Federici S, Haskó G, Deitch EA, Spolarics Z. Female X-chromosome mosaicism for gp91phox expression diversifies leukocyte responses during endotoxemia. Crit Care Med 2010; 38:2003-10. PMID:20657276
47. Cristofaro PA, Opal SM, Palardy JE, Parejo NA, Jhung J, Keith JC Jr., Harris HA. WAY-202196, a selective estrogen receptor-beta agonist, protects against death in experimental septic shock. Crit Care Med 2006; 34:2188-93. PMID:16755255; http://dx.doi.org/10.1097/01.CCM.0000227173.13497.56
48. Choudhry MA, Schwacha MG, Hubbard WJ, Kerby JD, Rue LW, Bland KI, Chaudry IH. Gender differences in acute response to trauma-hemorrhage. Shock 2005; 24(Suppl 1):101-6. PMID:16374381; http://dx.doi.org/10.1097/01.shk.0000191341.31530.5e
49. Wang M, Tsai BM, Reiger KM, Brown JW, Meldrum DR. 17-beta-Estradiol decreases p38 MAPKmediated myocardial inflammation and dysfunction following acute ischemia. J Mol Cell Cardiol 2006; 40:205-12. PMID:16427650; http://dx.doi.org/10.1016/j.yjmcc.2005.06.019
50. Remmers DE, Cioffi WG, Bland KI, Wang P, Angele MK, Chaudry IH. Testosterone: the crucial hormone responsible for depressing myocardial function in males after trauma-hemorrhage. Ann Surg 1998; 227:790-9. PMID:9637542; http://dx.doi.org/10.1097/00000658-199806000-00002
51. Remmers DE, Wang P, Cioffi WG, Bland KI, Chaudry IH. Testosterone receptor blockade after trauma-hemorrhage improves cardiac and hepatic functions in males. Am J Physiol 1997; 273:H2919-25. PMID:9435632
52. Kuebler JF, Toth B, Rue LW 3rd, Wang P, Bland KI, Chaudry IH. Differential fluid regulation during and after soft tissue trauma and hemorrhagic shock in males and proestrus females. Shock 2003; 20:144-8. PMID:12865658; http://dx.doi.org/10.1097/01.shk.0000072127.33223.f1
53. Sperry JL, Minei JP. Gender dimorphism following injury: making the connection from bench to bedside. J Leukoc Biol 2008; 83:499-506. PMID:17895398; http://dx.doi.org/10.1189/jlb.0607360
54. Yu HP, Chaudry IH. The role of estrogen and receptor agonists in maintaining organ function after trauma-hemorrhage. Shock 2009; 31:227-37. PMID:18665049; http://dx.doi.org/10.1097/SHK.0b013e31818347e7
55. Yu HP, Hsieh YC, Suzuki T, Choudhry MA, Schwacha MG, Bland KI, Chaudry IH. The PI3K/ Akt pathway mediates the nongenomic cardioprotective effects of estrogen following trauma-hemorrhage. Ann Surg 2007; 245:971-7. PMID:17522524; http://dx.doi.org/10.1097/01.sla.0000254417.15591.88
56. Sharawy N, Ribback S, Al-Banna N, Lehmann C, Kern H, Wendt M, Cerny V, Dombrowski F, Pavlovic D. Estradiol receptors agonists induced effects in rat intestinal microcirculation during sepsis. Microvasc Res 2013; 85:118-27. PMID:23063870; http://dx.doi.org/10.1016/j.mvr.2012.10.002
57. Zhu H, Shan L, Peng T. Rac1 mediates sex difference in cardiac tumor necrosis factor-alpha expression via NADPH oxidase-ERK1/2/p38 MAPK pathway in endotoxemia. J Mol Cell Cardiol 2009; 47:264-74. PMID:19450605; http://dx.doi.org/10.1016/j.yjmcc.2009.05.002
58. Angele MK, Chaudry IH. Surgical trauma and immunosuppression: pathophysiology and potential immunomodulatory approaches. Langenbecks Arch Surg 2005; 390:333-41. PMID:15995884; http://dx.doi.org/10.1007/s00423-005-0557-4
59. Angele MK, Wichmann MW, Ayala A, Cioffi WG, Chaudry IH. Testosterone receptor blockade after hemorrhage in males. Restoration of the depressed immune functions and improved survival following subsequent sepsis. Arch Surg 1997; 132:1207-14. PMID:9366714; http://dx.doi.org/10.1001/archsurg.1997.01430350057010
60. Wichmann MW, Angele MK, Ayala A, Cioffi WG, Chaudry IH. Flutamide: a novel agent for restoring the depressed cell-mediated immunity following soft-tissue trauma and hemorrhagic shock. Shock 1997; 8:242-8. PMID:9329124; http://dx.doi.org/10.1097/00024382-199710000-00002
61. Lin CY, Hsu CC, Lin MT, Chen SH. Flutamide, an androgen receptor antagonist, improves heatstroke outcomes in mice. Eur J Pharmacol 2012; 688:62-7. PMID:22609231; http://dx.doi.org/10.1016/j.ejphar.2012.05.002
62. Angele MK, Catania RA, Ayala A, Cioffi WG, Bland KI, Chaudry IH. Dehydroepiandrosterone: an inexpensive steroid hormone that decreases the mortality due to sepsis following trauma-induced hemorrhage. Arch Surg 1998; 133:1281-8. PMID:9865644; http://dx.doi.org/10.1001/archsurg.133.12.1281
63. Catania RA, Angele MK, Ayala A, Cioffi WG, Bland K, Chaudry IH. Dehydroepiandrosterone (DHEA) restores immune function following trauma-hemorrhage by a direct effect on T-lymphocytes. Cytokine 1998; 11:443-50; http://dx.doi.org/10.1006/cyto.1998.0458
64. Barkhausen T, Hildebrand F, Krettek C, van Griensven M. DHEA-dependent and organ-specific regulation of TNF-alpha mRNA expression in a murine polymicrobial sepsis and trauma model. Crit Care 2009; 13:R114. PMID:19594900; http://dx.doi.org/10.1186/cc7963
65. Zeckey C, Hildebrand F, Hoevel P, Müller K, Krettek C, Barkhausen T, van Griensven M. Activity of lymphocyte subpopulations in polymicrobial sepsis and DHEA treatment in IL-6 knockout mice. J Innate Immun 2010; 2:469-77. PMID:20375552; http://dx.doi.org/10.1159/000284369
66. Schmitz D, Lendemans S, Oberbeck R. Androstenediol Modulates Sepsis Induced Alterations of Survival and Immune Functions in a Murin Model of Sepsis. Med Chem 2013; (Forthcoming) PMID:23432316
67. Matsuda A, Furukawa K, Suzuki H, Matsutani T, Tajiri T, Chaudry IH. Dehydroepiandrosterone modulates toll-like receptor expression on splenic macrophages of mice after severe polymicrobial sepsis. Shock 2005; 24:364-9. PMID:16205322; http://dx.doi.org/10.1097/01.shk.0000180624.36811.97
68. Frantz MC, Prix NJ, Wichmann MW, van den Engel NK, Hernandez-Richter T, Faist E, Chaudry IH, Jauch KW, Angele MK. Dehydroepiandrosterone restores depressed peripheral blood mononuclear cell function following major abdominal surgery via the estrogen receptors. Crit Care Med 2005; 33:1779-86. PMID:16096456; http://dx.doi.org/10.1097/01.CCM.0000172278.91959.38
69. Szalay L, Shimizu T, Suzuki T, Hsieh YC, Choudhry MA, Schwacha MG, Bland KI, Chaudry IH. Androstenediol administration after trauma-hemorrhage attenuates inflammatory response, reduces organ damage, and improves survival following sepsis. Am J Physiol Gastrointest Liver Physiol 2006; 291:G260-6. PMID:16574990; http://dx.doi.org/10.1152/ajpgi.00390.2005
70. Shimizu T, Choudhry MA, Szalay L. Rue LW, Bland KI, Chaudry IH. Salutary effects of androstenediol on cardiac function and splanchnic perfusion after trauma-hemorrhage. Am J Physiol Regul Integr Comp Physiol 2004; 287:386-90; http://dx.doi.org/10.1152/ajpregu.00214.2004
71. Kiang JG, Peckham RM, Duke LE, Shimizu T, Chaudry IH, Tsokos GC. Androstenediol inhibits the trauma-hemorrhage-induced increase in caspase-3 by downregulating the inducible nitric oxide synthase pathway. J Appl Physiol (1985) 2007; 102:933-41. PMID:17110508; http://dx.doi.org/10.1152/japplphysiol.00919.2006
72. Weil BR, Markel TA, Herrmann JL, Abarbanell AM, Kelly ML, Meldrum DR. Stem cells in sepsis. Ann Surg 2009; 250:19-27. PMID:19561461; http://dx.doi.org/10.1097/SLA.0b013e3181a77b9c
73. Xu J, Woods CR, Mora AL, Joodi R, Brigham KL, Iyer S, Rojas M. Prevention of endotoxin-induced systemic response by bone marrow-derived mesenchymal stem cells in mice. Am J Physiol Lung Cell Mol Physiol 2007; 293:L131-41. PMID:17416739; http://dx.doi.org/10.1152/ajplung.00431.2006
74. Gonzalez-Rey E, Anderson P, González MA, Rico L, Büscher D, Delgado M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 2009; 58:929-39. PMID:19136511; http://dx.doi.org/10.1136/gut.2008.168534
75. Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA. Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol 2007; 179:1855-63. PMID:17641052
76. Mei SH, Haitsma JJ, Dos Santos CC, Deng Y, Lai PF, Slutsky AS, Liles WC, Stewart DJ. Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med 2010; 182:1047-57. PMID:20558630; http://dx.doi.org/10.1164/rccm.201001-0010OC
77. Németh K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 2009; 15:42-9. PMID:19098906; http://dx.doi.org/10.1038/nm.1905
78. Crisostomo PR, Wang M, Herring CM, Morrell ED, Seshadri P, Meldrum KK, Meldrum DR. Sex dimorphisms in activated mesenchymal stem cell function. Shock 2006; 26:571-4. PMID:17117131; http://dx.doi.org/10.1097/01.shk.0000233195.63859.ef
79. Crisostomo PR, Markel TA, Wang M, Lahm T, Lillemoe KD, Meldrum DR. In the adult mesenchymal stem cell population, source gender is a biologically relevant aspect of protective power. Surgery 2007; 142:215-21. PMID:17689688; http://dx.doi.org/10.1016/j.surg.2007.04.013
80. Crisostomo PR, Wang M, Herring CM, Markel TA, Meldrum KK, Lillemoe KD, Meldrum DR. Gender differences in injury induced mesenchymal stem cell apoptosis and VEGF, TNF, IL-6 expression: role of the 55 kDa TNF receptor (TNFR1). J Mol Cell Cardiol 2007; 42:142-9. PMID:17070836; http://dx.doi.org/10.1016/j.yjmcc.2006.09.016
81. Dyson A, Singer M. Animal models of sepsis: why does preclinical efficacy fail to translate to the clinical setting? Crit Care Med 2009; 37(Suppl):S30-7. PMID:19104223; http://dx.doi.org/10.1097/CCM.0b013e3181922bd3