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Trauma Research Center Milestones



 1990       Sublethal endotoxin or IL-1 induce cardiac reprogramming/preconditioning by enhancing endogenous defenses. [1, 2]

In trauma patients, human portal blood is sterile and contains no endotoxin. [3]
Early enteral is superior to parenteral alimentation in the injured patient. [4, 5]

 1992 TWO HIT HYPOTHESIS: Post-injury systemic inflammation predisposes cells/organs to an altered response (protected or vulnerable) to a second stress. [6-8]

Post-injury alpha-adrenergic agonists reprogram ("precondition") cells to tolerate subsequent insult. [9]
Age, Injury Severity Score, 6 Units PRBC/12 hours, base deficit and lactate levels are early independent predictors of multiple organ failure (MOF). [10]

 1994 Phospholipase A2 (PLA2) is proximal mediator of disseminated injury after trauma. [11, 12]

The six isomers of protein kinase C in the human heart create a signaling language that dictates a cell's response to a subsequent insult. [13, 14]
Major torso trauma (first hit) primes and activates PMNs within 6 hours after injury leading to an early window during which a second hit activates exuberant PMN O2- release, rendering the injured patient at high risk for MOF. [15]


MOF presents in two patterns, early versus late, that have unique risk factors and clinical course. [16]
Neutrophils are critical in LPS induced acute lung injury and pulmonary vasomotor dysfunction.
Post-traumatic mediators delay neutrophil apoptosis. [18-20]

 1997 Oral sulfonylurea (oral hypoglycemic) agents block cardiac KATP channels, prevent myocardial preconditioning and explain the paradoxical increased cardiovascular mortality in diabetic patients on oral agents when compared to insulin. [21]

Metabolic therapy attenuates post-ischemic mitochondrial dysfunction. [22]
Plasma and lipids from stored blood cause acute lung injury.
[23, 24]
Soluble PLA2 is released into the systemic circulation following femoral fracture in patients. [25]


Liposome delivery of proteins such as I-kB and Hsp 72 to cells and tissues can be used to therapeutically manipulate inflammatory signal transduction. [26, 27]
Hemorrhagic shock releases factors into the mesenteric lymph not the portal circulation that prime neutrophils. [28]


IL-18 is preformed cytokine that primes neutrophil NADPH oxidase and contributes to ischemic myocardial injury and endotoxin mediated tissue injury. [29-31]


Neutrophils contain a membrane M-type sPLA(2)-R that activates p38 MAPK. [32]
The injured child is resistant to multiple organ failure.
Neutrophil mediated endothelial cell damage is dependent on endothelial activation, chemokine release, PMN adhesion, and lysophosphatidylcholines activation of the oxidase. [34]


Transfusion related acute lung injury (TRALI), like the acute respiratory distress syndrome, may be a 2-event phenomenon with both recipient predisposition and factors in the stored units playing major roles. [35] The importance of these results is highlighted by the fact that the FDA posted these results in a webcast.
Platelet-induced TRALI may be the result of two events: 1) the clinical condition of the patient and 2) the infusion of lipids in stored PLTs. [36]


Review of the Trauma database (1,344) trauma patients at risk for postinjury MO) shows that Lung dysfunction occurs in 94% patients with 1 or more organ dysfunctions and 99% of 605 patients with 2 or more organ dysfunctions. Lung dysfunction precedes heart, liver, and kidney dysfunction by 0.6, 4.8 and 5.5 +/- 0.5 days. [37]
The incidence, severity, and attendant mortality of postinjury MOF has decreased over the last 12 years despite an increased MOF risk. Improvements in MOF outcomes can be attributed to improvements in trauma and critical care and are associated with decreased use of blood transfusion during resuscitation.
Two different etiologies of TRALI are  proposed. The first is a single antibody-mediated event involving the transfusion of anti-HLA class I and class II antibodies into patients whose leukocytes express the cognate antigens. The second is a 2-event model. [39]


CHC is required for certain TNF-alpha-induced, inflammatory signaling pathways.  RNAi of clathrin significantly impairs phosphorylation of both I kappaB alpha and p65. [40]
PAF signaling in neutrophils involves clathrin mediated endocytosis, beta-arrestin-1 recruitment of a p38 MAPK signalosome, and actin bundle formation.
Initiated a US multicenter prehospital trial in which severely injured patients with major blood loss are resuscitated with stored RBCs whereas the study group receives HBOC (up to 6 units) in the first 12 hours.
HMGB1 can interact with both TLR2 and TLR4. [43]


Post shock mesenteric lymph is depleted of gelsolin and can activate NF-kB in endothelial cells. [44, 45]
Military-civilian collaboration in trauma care.
Nucleo-cytoplasmic traffic of NF-kB and I-kB. [47]


Splanchnic ischemia/reperfusion activates gut PLA(2)-mediated release of AA into the lymph where it is delivered to the lungs, provoking LTB(4) production and subsequent PMN-mediated lung injury. [48]
1:1 FFP:RBC reduces coagulopathy, but may increase mortality.
PAF involves clathrin mediated endocytosis induces membrane translocation of p40(phox)-p67(phox) localizing to gp91(phox).
HMGB1 release is an early event following traumatic injury in humans.
HMGB1 acquires proinflammatory activity through binding to proinflammatory mediators, such as IL-1beta. [52]


Packed red blood cell supernates induce T(regs), but this induction is not altered by leukoreduction or prolonged storage. [53]
PAF priming of PMNs requires clathrin-mediated endocytosis that is inhibited when PMNs are pretreated with either amantadine or rimantadine.
Patients resuscitated with PolyHeme, without stored blood for up to 6 U in 12 hours postinjury, had outcomes comparable with those for the standard of care. Although there were more adverse events in the PolyHeme group, the benefit-to-risk ratio of PolyHeme is favorable when blood is needed but not available.
Hypertonic saline inhibits TNFa-induced NF-kB activation in pulmonary epithelial cells.  [56]



  1. Brown JM, White CW, Terada LS, Grosso MA, Shanley PF, Mulvin DW, Banerjee A, Whitman GJ, Harken AH, Repine JE: Interleukin 1 pretreatment decreases ischemia/reperfusion injury. Proc Natl Acad Sci U S A 1990; 87(13): 5026-30.
  2. Brown JM, Grosso MA, Terada LS, Whitman GJ, Banerjee A, White CW, Harken AH, Repine JE: Endotoxin pretreatment increases endogenous myocardial catalase activity and decreases ischemia-reperfusion injury of isolated rat hearts. Proc Natl Acad Sci U S A 1989; 86(7): 2516-20.
  3. Moore FA, Moore EE, Poggetti R, McAnena OJ, Peterson VM, Abernathy CM, Parsons PE: Gut bacterial translocation via the portal vein: a clinical perspective with major torso trauma. J Trauma 1991; 31(5): 629-36; discussion 636-8.
  4. Moore FA, Feliciano DV, Andrassy RJ, McArdle AH, Booth FV, Morgenstein-Wagner TB, Kellum JM, Jr., Welling RE, Moore EE: Early enteral feeding, compared with parenteral, reduces postoperative septic complications. The results of a meta-analysis. Ann Surg 1992; 216(2): 172-83.
  5. Moore EE, Moore FA: Immediate enteral nutrition following multisystem trauma: a decade perspective. J Am Coll Nutr 1991; 10(6): 633-48.
  6. Moore FA, Moore EE, Poggetti RS, Read RA: Postinjury shock and early bacteremia. A lethal combination. Arch Surg 1992; 127(8): 893-7; discussion 897-8.
  7. Moore FA, Moore EE: Evolving concepts in the pathogenesis of postinjury multiple organ failure. Surg Clin North Am 1995; 75(2): 257-77.
  8. Koike K, Moore FA, Moore EE, Poggetti RS, Tuder RM, Banerjee A: Endotoxin after gut ischemia/reperfusion causes irreversible lung injury. J Surg Res 1992; 52(6): 656-62.
  9. Banerjee A, Locke-Winter C, Rogers KB, Mitchell MB, Brew EC, Cairns CB, Bensard DD, Harken AH: Preconditioning against myocardial dysfunction after ischemia and reperfusion by an alpha 1-adrenergic mechanism. Circ Res 1993; 73(4): 656-70.
  10. Sauaia A, Moore FA, Moore EE, Haenel JB, Read RA, Lezotte DC: Early predictors of postinjury multiple organ failure. Arch Surg 1994; 129(1): 39-45.
  11. Anderson BO, Moore EE, Banerjee A: Phospholipase A2 regulates critical inflammatory mediators of multiple organ failure. J Surg Res 1994; 56(2): 199-205.
  12. Koike K, Moore EE, Moore FA, Kim FJ, Carl VS, Banerjee A: Gut phospholipase A2 mediates neutrophil priming and lung injury after mesenteric ischemia-reperfusion. Am J Physiol 1995; 268(3 Pt 1): G397-403.
  13. Banerjee A, Gamboni-Robertson F, Mitchell MB, Rehring TF, Butler K, Cleveland J, Meldrum DR, Shapiro JI, Meng XZ: Stress-induced cardioadaptation reveals a code linking hormone receptors and spatial redistribution of PKC isoforms. Ann N Y Acad Sci 1996; 793: 226-39.
  14. Mitchell MB, Meng X, Ao L, Brown JM, Harken AH, Banerjee A: Preconditioning of isolated rat heart is mediated by protein kinase C. Circ Res 1995; 76(1): 73-81.
  15. Botha AJ, Moore FA, Moore EE, Kim FJ, Banerjee A, Peterson VM: Postinjury neutrophil priming and activation: an early vulnerable window. Surgery 1995; 118(2): 358-64; discussion 364-5.
  16. Moore FA, Sauaia A, Moore EE, Haenel JB, Burch JM, Lezotte DC: Postinjury multiple organ failure: a bimodal phenomenon. J Trauma 1996; 40(4): 501-10; discussion 510-2.
  17. Sheridan BC, McIntyre RC, Agrafojo J, Meldrum DR, Meng X, Fullerton DA: Neutrophil depletion attenuates endotoxin-induced dysfunction of cGMP- mediated pulmonary vasorelaxation. Am J Physiol 1996; 271(5 Pt 1): L820-8.
  18. Biffl WL, Moore EE, Moore FA, Barnett CC, Jr.: Interleukin-6 delays neutrophil apoptosis via a mechanism involving platelet-activating factor. J Trauma 1996; 40(4): 575-8; discussion 578-9.
  19. Biffl WL, Moore EE, Moore FA, Barnett CC, Jr.: Interleukin-6 suppression of neutrophil apoptosis is neutrophil concentration dependent. J Leukoc Biol 1995; 58(5): 582-4.
  20. Biffl WL, Moore EE, Zallen G, Johnson JL, Gabriel J, Offner PJ, Silliman CC: Neutrophils are primed for cytotoxicity and resist apoptosis in injured patients at risk for multiple organ failure. Surgery 1999; 126(2): 198-202.
  21. Cleveland JC, Jr., Meldrum DR, Cain BS, Banerjee A, Harken AH: Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium. Two paradoxes revisited. Circulation 1997; 96(1): 29-32.
  22. Meldrum DR, Dinarello CA, Shames BD, Cleveland JC, Jr., Cain BS, Banerjee A, Meng X, Harken AH: Ischemic preconditioning decreases postischemic myocardial tumor necrosis factor-alpha production. Potential ultimate effector mechanism of preconditioning. Circulation 1998; 98(19 Suppl): II214-8; discussion II218-9.
  23. Silliman CC, Voelkel NF, Allard JD, Elzi DJ, Tuder RM, Johnson JL, Ambruso DR: Plasma and lipids from stored packed red blood cells cause acute lung injury in an animal model. J Clin Invest 1998; 101(7): 1458-67.
  24. Silliman CC, Paterson AJ, Dickey WO, Stroneck DF, Popovsky MA, Caldwell SA, Ambruso DR: The association of biologically active lipids with the development of transfusion-related acute lung injury: a retrospective study. Transfusion 1997; 37(7): 719-26.
  25. Gago LA, Moore EE, Partrick DA, Sauaia A, Davis CM, Toal TR, Jr., Silliman CC: Secretory phospholipase A2 cleavage of intravasated bone marrow primes human neutrophils. J Trauma 1998; 44(4): 660-4.
  26. Meldrum DR, Meng X, Shames BD, Pomerantz B, Donnahoo KK, Banerjee A, Harken AH: Liposomal delivery of heat-shock protein 72 into the heart prevents endotoxin-induced myocardial contractile dysfunction. Surgery 1999; 126(2): 135-41.
  27. Selzman CH, Shames BD, Reznikov LL, Miller SA, Meng X, Barton HA, Werman A, Harken AH, Dinarello CA, Banerjee A: Liposomal delivery of purified inhibitory-kappaB alpha inhibits tumor necrosis factor-alpha-induced human vascular smooth muscle proliferation. Circ Res 1999; 84(8): 867-75.
  28. Zallen G, Moore EE, Tamura DY, Johnson JL, Biffl WL, Silliman CC: Hypertonic saline resuscitation abrogates neutrophil priming by mesenteric lymph. J Trauma 2000; 48(1): 45-8.
  29. Netea MG, Fantuzzi G, Kullberg BJ, Stuyt RJ, Pulido EJ, McIntyre RC, Jr., Joosten LA, Van der Meer JW, Dinarello CA: Neutralization of IL-18 reduces neutrophil tissue accumulation and protects mice against lethal Escherichia coli and Salmonella typhimurium endotoxemia. J Immunol 2000; 164(5): 2644-9.
  30. Pomerantz BJ, Reznikov LL, Harken AH, Dinarello CA: Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1beta. Proc Natl Acad Sci U S A 2001; 98(5): 2871-6.
  31. Wyman TH, Dinarello CA, Banerjee A, Gamboni-Robertson F, Hiester AA, England KM, Kelher M, Silliman CC: Physiological levels of interleukin-18 stimulate multiple neutrophil functions through p38 MAP kinase activation. J Leukoc Biol 2002; 72(2): 401-9.
  32. Silliman CC, Moore EE, Zallen G, et al.: Presence of the M-type sPLA(2) receptor on neutrophils and its role in elastase release and adhesion. Am J Physiol Cell Physiol 2002; 283(4): C1102-13.
  33. Calkins CM, Bensard DD, Moore EE, McIntyre RC, Silliman CC, Biffl W, Harken AH, Partrick DA, Offner PJ: The injured child is resistant to multiple organ failure: a different inflammatory response? J Trauma 2002; 53(6): 1058-63.
  34. Wyman TH, Bjornsen AJ, Elzi DJ, Smith CW, England KM, Kelher M, Silliman CC: A two-insult in vitro model of PMN-mediated pulmonary endothelial damage: requirements for adherence and chemokine release. Am J Physiol Cell Physiol 2002; 283(6): C1592-603.
  35. Silliman CC, Boshkov LK, Mehdizadehkashi Z, Elzi DJ, Dickey WO, Podlosky L, Clarke G, Ambruso DR: Transfusion-related acute lung injury: epidemiology and a prospective analysis of etiologic factors. Blood 2003; 101(2): 454-62.
  36. Silliman CC, Bjornsen AJ, Wyman TH, Kelher M, Allard J, Bieber S, Voelkel NF: Plasma and lipids from stored platelets cause acute lung injury in an animal model. Transfusion 2003; 43(5): 633-40.
  37. Ciesla, D.J., Moore, E.E., Johnson, J.L., Burch, J.M., Cothren, C.C., Sauaia, A. (2005) The role of the lung in postinjury multiple organ failure. Surgery 138, 749-57; discussion 757-8.
  38. Ciesla, D.J., Moore, E.E., Johnson, J.L., Burch, J.M., Cothren, C.C., Sauaia, A. (2005) A 12-year prospective study of postinjury multiple organ failure: has anything changed? Arch Surg 140, 432-8; discussion 438-40.
  39. Silliman, C.C., Ambruso, D.R., Boshkov, L.K. (2005) Transfusion-related acute lung injury. Blood 105, 2266-73.
  40. Escobar, G.A., McIntyre, R.C., Jr., Moore, E.E., Gamboni-Robertson, F., Banerjee, A. (2006) Clathrin heavy chain is required for TNF-induced inflammatory signaling. Surgery 140, 268-72.
  41. McLaughlin, N.J., Banerjee, A., Kelher, M.R., Gamboni-Robertson, F., Hamiel, C., Sheppard, F.R., Moore, E.E., Silliman, C.C. (2006) Platelet-activating factor-induced clathrin-mediated endocytosis requires beta-arrestin-1 recruitment and activation of the p38 MAPK signalosome at the plasma membrane for actin bundle formation. J Immunol 176, 7039-50.
  42. Moore, E.E., Cheng, A.M., Moore, H.B., Masuno, T., Johnson, J.L. (2006) Hemoglobin-based oxygen carriers in trauma care: scientific rationale for the US multicenter prehosptial trial. World J Surg 30, 1247-57.
  43. Park, J.S., Gamboni-Robertson, F., He, Q., Svetkauskaite, D., Kim, J.Y., Strassheim, D., Sohn, J.W., Yamada, S., Maruyama, I., Banerjee, A., Ishizaka, A., Abraham, E. (2006) High mobility group box 1 protein interacts with multiple Toll-like receptors. Am J Physiol Cell Physiol 290, C917-24.
  44. Damle, S.S., Moore, E.E., Nydam, T.L., Banerjee, M., Gamboni-Robertson, F., Su, X., Banerjee, A. (2007) Postshock mesenteric lymph induces endothelial NF-kappaB activation. J Surg Res 143, 136-40.
  45. Jordan, J.R., Moore, E.E., Damle, S.S., Eckels, P., Johnson, J.L., Roach, J.P., Redzic, J.S., Hansen, K.C., Banerjee, A. (2007) Gelsolin is depleted in post-shock mesenteric lymph. J Surg Res 143, 130-5.
  46. Moore, E.E., Knudson, M.M., Schwab, C.W., Trunkey, D.D., Johannigman, J.A., Holcomb, J.B. (2007) Military-civilian collaboration in trauma care and the senior visiting surgeon program. N Engl J Med 357, 2723-7.
  47. Walsh, M.D., Jr., Hamiel, C.R., Banerjee, A., Cheng, A.M., Escobar, G., McIntyre, R.C., Jr. (2008) Exportin 1 inhibition attenuates nuclear factor-kappaB-dependent gene expression. Shock 29, 160-6.
  48. Jordan, J.R., Moore, E.E., Sarin, E.L., Damle, S.S., Kashuk, S.B., Silliman, C.C., Banerjee, A. (2008) Arachidonic acid in postshock mesenteric lymph induces pulmonary synthesis of leukotriene B4. J Appl Physiol 104, 1161-6.
  49. Kashuk, J.L., Moore, E.E., Johnson, J.L., Haenel, J., Wilson, M., Moore, J.B., Cothren, C.C., Biffl, W.L., Banerjee, A., Sauaia, A. (2008) Postinjury life threatening coagulopathy: is 1:1 fresh frozen plasma:packed red blood cells the answer? J Trauma 65, 261-70; discussion 270-1.
  50. McLaughlin, N.J., Banerjee, A., Khan, S.Y., Lieber, J.L., Kelher, M.R., Gamboni-Robertson, F., Sheppard, F.R., Moore, E.E., Mierau, G.W., Elzi, D.J., Silliman, C.C. (2008) Platelet-activating factor-mediated endosome formation causes membrane translocation of p67phox and p40phox that requires recruitment and activation of p38 MAPK, Rab5a, and phosphatidylinositol 3-kinase in human neutrophils. J Immunol 180, 8192-203.
  51. Peltz, E.D., Moore, E.E., Eckels, P.C., Damle, S.S., Tsuruta, Y., Johnson, J.L., Sauaia, A., Silliman, C.C., Banerjee, A., Abraham, E. (2009) Hmgb1 Is Markedly Elevated within Six Hours of Mechanical Trauma in Humans. Shock. . 32 17-22
  52. Sha, Y., Zmijewski, J., Xu, Z., Abraham, E. (2008) HMGB1 develops enhanced proinflammatory activity by binding to cytokines. J Immunol 180, 2531-7.
  53. Baumgartner, J.M., Silliman, C.C., Moore, E.E., Banerjee, A., McCarter, M.D. (2009) Stored red blood cell transfusion induces regulatory T cells. J Am Coll Surg 208, 110-9.
  54. Eckels, P.C., Banerjee, A., Moore, E., McLaughlin, N.J., Gries, L., Kelher, M.R., England, K.M., Gamboni-Robertson, F., Khan, S.Y., Silliman, C.C. (2009) Amantadine Inhibits Platelet-Activating Factor Induced Clathrin-Mediated Endocytosis in Human Neutrophils. Am J Physiol Cell Physiol.
  55. Moore, E.E., Moore, F.A., Fabian, T.C., Bernard, A.C., Fulda, G.J., Hoyt, D.B., Duane, T.M., Weireter, L.J., Jr., Gomez, G.A., Cipolle, M.D., Rodman, G.H., Jr., Malangoni, M.A., Hides, G.A., Omert, L.A., Gould, S.A. (2009) Human polymerized hemoglobin for the treatment of hemorrhagic shock when blood is unavailable: the USA multicenter trial. J Am Coll Surg 208, 1-13.
  56. Nydam, T.L., Moore, E.E., McIntyre, R.C., Jr., Wright, F.L., Gamboni-Robertson, F., Eckels, P.C., Banerjee, A. (2009) Hypertonic saline attenuates TNF-alpha-induced NF-kappaB activation in pulmonary epithelial cells. Shock 31, 466-72.