The acute inflammatory response in trauma / hemorrhage and traumatic brain injury: current state and emerging prospects

R Namas, A Ghuma, L Hermus, R Zamora, D O Okonkwo, T R Billiar, Y Vodovotz, R Namas, A Ghuma, L Hermus, R Zamora, D O Okonkwo, T R Billiar, Y Vodovotz

Abstract

Traumatic injury/hemorrhagic shock (T/HS) elicits an acute inflammatory response that may result in death. Inflammation describes a coordinated series of molecular, cellular, tissue, organ, and systemic responses that drive the pathology of various diseases including T/HS and traumatic brain injury (TBI). Inflammation is a finely tuned, dynamic, highly-regulated process that is not inherently detrimental, but rather required for immune surveillance, optimal post-injury tissue repair, and regeneration. The inflammatory response is driven by cytokines and chemokines and is partially propagated by damaged tissue-derived products (Damage-associated Molecular Patterns; DAMP's). DAMPs perpetuate inflammation through the release of pro-inflammatory cytokines, but may also inhibit anti-inflammatory cytokines. Various animal models of T/HS in mice, rats, pigs, dogs, and non-human primates have been utilized in an attempt to move from bench to bedside. Novel approaches, including those from the field of systems biology, may yield therapeutic breakthroughs in T/HS and TBI in the near future.

Keywords: Hemorrhagic Shock; Inflammation; Systems Biology; Trauma; Traumatic Brain Injury.

Figures

Figure 1
Figure 1
The ‘one-hit’ and ‘two-hit’ paradigm of traumatic injury. ‘One hit’ represents the initial, massive tissue injury and shock and SIRS along with remote organ injury. The ‘second hit’ refers to the less intense SIRS that normally resolves but leaves the patient vulnerable to a secondary inflammatory hit that can reactivate the SIRS and precipitate late MODS.
Figure 2
Figure 2
The inflammatory response to tissue injury. Traumatic injury signals various cell types to produce cytokines, chemokines, and DAMPs. In turn, DAMPs re-activate and further propagate the production of inflammatory mediators, setting in motion a positive feedback loop of inflammation→damage→inflammation.
Figure 3
Figure 3
The spectrum of cytokines, chemokines, and DAMPs in T/HS and TBI. The inflammatory response generated in response to T/HS or TBI can be assessed by measuring a panoply of cytokines, chemokines, DAMPs, and ultimate markers of endorgan damage. Some of these biomarkers may also be candidates for therapeutic intervention.
Figure 4
Figure 4
A vision for the future of drug design for T/HS and TBI. The future of rational drug design for T/HS and TBI may involve the use of in silico (computer simulated) that would be based on a mechanistic understanding of the inflammatory response as well as pharmacokinetic and pharmacodynamic principles and used to determine the optimal properties, dosage, timing, and inclusion/exclusion criteria for a given drug candidate's clinical trial. Key aspects of these simulations would be tested iteratively in cell culture experiments and pre-clinical animal models, streamlining the process (and reducing the time and cost) of clinical trial design and implementation.

References

    1. Kauvar DS, Wade CE. The epidemiology and modern management of traumatic hemorrhage: US and international perspectives. Crit Care. 2005;9(Suppl 5):S1–9.
    1. Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma. 2006;60:S3–11.
    1. Moore FA, Moore EE, Sauaia A. Postinjury multiple-organ failure in Trauma. In: Mattox KL, Feliciano DV, Moore EE, editors. New York, NY: McGraw-Hill; 1999. pp. 1427–59.
    1. Harbrecht BG, Doyle HR, Clancy KD, Townsend RN, Billiar TR, Peitzman AB. The impact of liver dysfunction on outcome in patients with multiple injuries. Am Surg. 2001;67:122–6.
    1. Harbrecht BG, Zenati MS, Doyle HR, et al. Hepatic dysfunction increases length of stay and risk of death after injury. J Trauma. 2002;53:517–23.
    1. Bone RC. Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS) Ann Intern Med. 1996;125:680–87.
    1. Peitzman AB, Billiar TR, Harbrecht BG, Kelly E, Udekwu AO, Simmons RL. Hemorrhagic shock. Curr Probl Surg. 1995;32:925–02.
    1. Clark JA, Coopersmith CM. Intestinal crosstalk: a new paradigm for understanding the gut as the “motor” of critical illness. Shock. 2007;28:384–93.
    1. Rotstein OD. Modeling the two-hit hypothesis for evaluating strategies to prevent organ injury after shock/resuscitation. J Trauma. 2003;54:S203–6.
    1. DeLong WG, Jr, Born CT. Cytokines in patients with polytrauma. Clin Orthop Relat Res. 2004;422:57–65.
    1. Vodovotz Y, Csete M, Bartels J, Chang S, An G. Translational systems biology of inflammation. PLoS Comput Biol. 2008;4:1–6.
    1. Nathan C. Points of control in inflammation. Nature. 2002;420:846–52.
    1. Santos CC, Zhang H, Liu M, Slutsky AS. Bench-to-bedside review: Biotrauma and modulation of the innate immune response. Crit Care. 2005;9:280–86.
    1. Alverdy J, Zaborina O, Wu L. The impact of stress and nutrition on bacterial-host interactions at the intestinal epithelial surface. Curr Opin Clin Nutr Metab Care. 2005;8:205–9.
    1. Matzinger P. The danger model: a renewed sense of self. Science. 2002;296:301–5.
    1. Vincent JL, Ferreira F, Moreno R. Scoring systems for assessing organ dysfunction and survival. Crit Care Clin. 2000;16:353–66.
    1. Rosenberg AL. Recent innovations in intensive care unit risk-prediction models. Curr Opin Crit Care. 2002;8:321–30.
    1. Schlag G, Redl H. Mediators of injury and inflammation. World J Surg. 1996;20:406–10.
    1. Jarrar D, Chaudry IH, Wang P. Organ dysfunction following hemorrhage and sepsis: mechanisms and therapeutic approaches. Int J Mol Med. 1999;4:575–83.
    1. Smith RM, Giannoudis PV. Trauma and the immune response. J R Soc Med. 1998;91:417–20.
    1. Catania RA, Chaudry IH. Immunological consequences of trauma and shock. Ann Acad Med Singapore. 1999;28:120–32.
    1. Moore FA, Moore EE. Evolving concepts in the pathogenesis of postinjury multiple organ failure. Surg Clin North Am. 1995;75:257–77.
    1. Moore FA, Moore EE, Read RA. Postinjury multiple organ failure: role of extrathoracic injury and sepsis in adult respiratory distress syndrome. New Horiz. 1993;1:538–49.
    1. Youn YK, LaLonde C, Demling R. The role of mediators in the response to thermal injury. World J Surg. 1992;16:30–6.
    1. Chaudry IH, Ayala A, Ertel W, Stephan RN. Hemorrhage and resuscitation: immunological aspects. Am J Physiol. 1990;259(4 Pt 2):R663–78.
    1. DiPiro JT. Isakson P: Interleukin 4. Adv Neuroimmunol. 1992;2:55–65.
    1. Marcu AC, Paccione KE, Barbee RW, et al. Androstenetriol immunomodulation improves survival in a severe trauma hemorrhage shock model. J Trauma. 2007;63:662–9.
    1. Letterio J. J, Vodovotz Y., Bogdan C. TGF-b and IL-10: Inhibitory Cytokines Regulating Immunity and the Response to Infection. In: Henderson B., Higgs G., editors. Novel Cytokine Inhibitors. Basel: Birkhauser Verlag; 2000. pp. 217–42.
    1. Karakozis S, Hinds M, Cook JW, Kim D, Provido H, Kirkpatrick JR. The effects of interleukin-10 in hemorrhagic shock. J Surg Res. 2000;90:109–12.
    1. Foëx BA, Lamb WR, Roberts TE, et al. Early cytokine response to multiple injury. Injury. 1993;24:373–6.
    1. Schinkel C, Faist E, Zimmer S, et al. Kinetics of circulating adhesion molecules and chemokines after mechanical trauma and burns. Eur J Surg. 1996;162:763–8.
    1. Lomas-Niera JL, Perl M, Chung CS, Ayala A. Shock and hemorrhage: an overview of animal models. Shock. 2005;24:33–39.
    1. Wiggers CJ. The present status of the shock problem. Physioly Rev. 1942;22:74–123.
    1. Fry DE, Hanschen SR, Ratcliff DJ, Garrison RN. The effects of heparin on hemorrhagic shock. Circulation and Shock. 1984;13:60–61.
    1. Call DR, Remick DG. Low molecular weight heparin is associated with greater cytokine production in a stimulated whole blood model. Shock. 1998;10:192–97.
    1. DeLong WG, Jr, Born CT. Cytokines in patients with polytrauma. Clin Orthop Relat Res. 2004;422:57–65.
    1. Abraham E, Jesmok G, Tuder R, Allbee J, Chang YH. Contribution of tumor necrosis factor-alpha to pulmonary cytokine expression and lung injury after hemorrhage and resuscitation. Crit Care Med. 1995;23(8):1319–26.
    1. Franceschi C, Bonafè M, Valensin S. Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space. Vaccine. 2000;18:1717–20.
    1. Franceschi C, Bonafè M, Valensin S, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244–54.
    1. Schröder AK, Rink L. Neutrophil immunity of the elderly. Mech. Ageing Dev. 2003;124:419–25.
    1. Plackett TP, Boehmer ED, Faunce DE, Kovacs EJ. Aging and innate immune cells. J Leukoc Biol. 2004;76:291–99.
    1. Fagiolo U, Cossarizza A, Scala E, et al. Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol. 1993;23:2375–78.
    1. Clark JA, Peterson TC. Cytokine production and aging: overproduction of IL-8 in elderly males in response to lipopolysaccharide. Mechanisms of Ageing and Development. 1994;77:127–39.
    1. Mariani E, Meneghetti A, Neri S, et al. Chemokine production by natural killer cells from nonagenarians. Eur J Immunol. 2002;32:1524–29.
    1. Zhang X, Fujii H, Kishimoto H, LeRoy E, Surh CD, Sprent J. Aging leads to disturbed homeostasis of memory phenotype CD8(+) cells. J Exp Med. 2002;195:283–93.
    1. Tateda K, Matsumoto T, Miyazaki S, Yamaguchi K. Lipopolysaccharide-Induced Lethality and Cytokine Production in Aged Mice. Infect Immun. 1996;64:769–74.
    1. Saito H, Sherwood E., Varma TK, Evers BM. Effects of aging on mortality, hypothermia, and cytokine induction in mice with endotoxemia or sepsis. Mechanisms of Ageing and Development. 2003;124:1047–58.
    1. Gebhard F, Nussler AK, Rosch M, et al. Early posttraumatic increase in production of nitric oxide in humans. Shock. 1998;10:237–42.
    1. Hsieh CH, Frink M, Hsieh YC, et al. The role of MIP-1 alpha in the development of systemic inflammatory response and organ injury following trauma hemorrhage. J Immunol. 2008;181:2806–12.
    1. Maurer M, von Stebut E. Macrophage inflammatory protein-1. Int. J. Biochem Cell Biol. 2004;36:1882–86.
    1. Lier H, Krep H, Schroeder S, Stuber F. Preconditions of hemostasis in trauma: a review. The influence of acidosis, hypocalcemia, anemia, and hypothermia on functional hemostasis in trauma. J Trauma. 2008;65:951–60.
    1. Angele MK, Ayala A, Monfils BA, Cioffi WG, Bland KI, Chaudry IH. Testosterone and/or low estradiol:normally required but harmful immunologically for males after trauma-hemorrhage. J Trauma. 1998;44:78–85.
    1. Catania RA, Angele MK, Ayala A, Cioffi WG, Bland KI, Chaudry IH. Dehydroepiandrosterone restores immune function following trauma-haemorrhage by a direct effect on T lymphocytes. Cytokine. 1999;11:443–50.
    1. Angele MK, Schwacha MG, Ayala A, Chaudry IH. Effect of gender and sex hormones on immune responses following shock. Shock. 2000;14:81–90.
    1. Marcu AC, Kielar ND, Paccione KE, et al. Androstenetriol improves survival in a rodent model of traumatic shock. Resuscitation. 2006;71:379–86.
    1. Sperry JL, Friese RS, Frankel HL, et al. Inflammation and the Host Response to Injury Investigators. Male gender is associated with excessive IL-6 expression following severe injury. J Trauma. 2008;64:572–8. discussion 578-9.
    1. Migeon BR. The role of X inactivation and cellular mosaicism in women's health and sex-specific diseases. JAMA. 2006;295:1428–33.
    1. Spolarics Z. The X-files of inflammation: cellular mosaicism of Xlinked polymorphic genes and the female advantage in the host response to injury and infection. Shock. 2007;27:597–04.
    1. Highlights of Mathematical Physics (American Mathematical Society, Providence, RI) 2002.
    1. The Economy As an Evolving Complex System. New York, NY: Oxford University Press; 2005. III: Current Perspectives and Future Directions (Santa Fe Institute Studies on the Sciences of Complexity)
    1. Kot M. Cambridge, UK: Cambridge University Press; 2001. Elements of Mathematical Ecology.
    1. Crame C.J. West Sussex, UK: John Wiley and Sons; 2004. Essentials of Computational Chemistry: Theories and Models.
    1. Kitano H. Systems biology: a brief overview. Science. 2002;295:1662–64.
    1. Arkin A.P. Synthetic cell biology. Curr. Opin. Biotechnol. 2001;12:638–44.
    1. Csete ME, Doyle JC. Reverse engineering of biological complexity. Science. 2002;295:1664–69.
    1. Aderem A, Smith KD. A systems approach to dissecting immunity and inflammation. Semin Immunol. 2004;16:55–67.
    1. Ge H, Walhout AJ, Vidal M. Integrating'omic' information: a bridge between genomics and systems biology. Trends Genet. 2003;19:551–60.
    1. Bagci EZ, Vodovotz Y, Billiar TR, Ermentrout GB, Bahar I. Bistability in apoptosis: Roles of Bax, Bcl-2 and mitochondrial permeability transition pores. Biophys J. 2006;90:1546–59.
    1. Fussenegger M, Bailey JE, Varner J. A mathematical model of caspase function in apoptosis. Nat Biotechnol. 2000;18:768–74.
    1. Cobb JP, Buchman TG, Karl IE, Hotchkiss RS. Molecular biology of multiple organ dysfunction syndrome: injury, adaptation, and apoptosis. Surg. Infect. (Larchmt.) 2000;1:207–15.
    1. Blinov ML, Yang J, Faeder JR, Hlavacek WS. Depicting signaling cascades. Nat Biotechnol. 2006;24:137–38.
    1. An G, Faeder J, Vodovotz Y. Translational systems biology: Introduction of an engineering approach to the pathophysiology of the burn patient. J. Burn Care Res. 2008;29:277–85.
    1. Seely AJ, Christou NV. Multiple organ dysfunction syndrome: exploring the paradigm of complex nonlinear systems. Crit Care Med. 2000;28:2193–200.
    1. Kumar R, Clermont G, Vodovotz Y, Chow CC. The dynamics of acute inflammation. J Theoretical Biol. 2004;230:145–55.
    1. Reynolds A, Rubin J, Clermont G, Day J, Vodovotz Y, Bard Ermentrout G. A reduced mathematical model of the acute inflammatory response: I. Derivation of model and analysis of anti-inflammation. J. Theor Biol. 2006;242:220–36.
    1. Day J, Rubin J, Vodovotz Y, Chow CC, Reynolds A, Clermont G. A reduced mathematical model of the acute inflammatory response II. Capturing scenarios of repeated endotoxin administration. J Theor Biol. 2006;242:237–56.
    1. An G. Agent-based computer simulation and SIRS: building a bridge between basic science and clinical trials. Shock. 2001;16:266–73.
    1. Chow CC, Clermont G, Kumar R, et al. The acute inflammatory response in diverse shock states. Shock. 2005;24:74–84.
    1. Prince JM, Levy RM, Bartels J, et al. In silico and in vivo approach to elucidate the inflammatory complexity of CD14-deficient mice. Mol Med. 2006;12:88–96.
    1. Lagoa CE, Bartels J, Baratt A, et al. The role of initial trauma in the host's response to injury and hemorrhage: Insights from a comparison of mathematical simulations and hepatic transcriptomic analysis. Shock. 2006;26:592–600.
    1. An G, Hunt CA, Clermont G, Neugebauer E, Vodovotz Y. Challenges and rewards on the road to translational systems biology in acute illness: Four case reports from interdisciplinary teams. J. Crit. Care. 2007;22:169–75.
    1. Vodovotz Y, Clermont G, Chow C, An G. Mathematical models of the acute inflammatory response. Curr. Opin. Crit Care. 2004;10:383–90.
    1. Clermont G, Bartels J, Kumar R, Constantine G, Vodovotz Y, Chow C. In silico design of clinical trials: a method coming of age. Crit Care Med. 2004;32:2061–70.
    1. Kumar R, Chow CC, Bartels JD, Clermont G, Vodovotz Y. A mathematical simulation of the inflammatory response to anthrax infection. Shock. 2008;29:104–11.
    1. An G. In-silico experiments of existing and hypothetical cytokine-directed clinical trials using agent based modeling. Crit Care Med. 2004;32:2050–60.
    1. Vodovotz Y, Chow CC, Bartels J, et al. In silico models of acute inflammation in animals. Shock. 2006;26:235–44.
    1. Nathan C, Sporn M. Cytokines in context. J Cell Biol. 1991;113:981–6.
    1. Vodovotz Y. Deciphering the complexity of acute inflammation using mathematical models. Immunologic Res. 2006;36:237–45.
    1. Katsanos GS, Anogeianaki A, Orso C, et al. Mast cells and chemokines. J Biol Regul Homeost Agents. 2008;22:145–51.
    1. Fahey TJ, 3rd, Tracey KJ, Tekamp-Olson P, et al. Macrophage inflammatory protein 1 modulates macrophage function. J Immunol. 1992;148:2764–9.
    1. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007;81:1–5.
    1. Janeway CA, Jr, Medzhitov R. Innate immune recognition. Annu. Rev. Immunol. 2002;20:197–16.
    1. Ulloa L, Tracey KJ. The “cytokine profile”: a code for sepsis. Trends Mol Med. 2005;11:56–63.
    1. Foell D, Wittkowski H, Vogl T, Roth J. S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol. 2007;81:28–37.
    1. Yao YM, Bahrami S, Redl H, Fuerst S, Schlag G. IL-6 release after intestinal ischemia/reperfusion in rats is under partial control of TNF. J Surg Res. 1997;70:21–6.
    1. Foëx BA. Systemic responses to trauma. Br Med Bull. 1999;55:726–43.
    1. Endo S, Inada K, Yamada Y, et al. Plasma endotoxin and cytokine concentrations in patients with hemorrhagic shock. Crit Care Med. 1994;22:949–55.
    1. Kim JY, Park JS, Strassheim D, et al. HMGB1 contributes to the development of acute lung injury after hemorrhage. Am J Physiol Lung Cell Mol Physiol. 2005;288:L958–65.
    1. Yang R, Harada T, Mollen KP, et al. Anti-HMGB1 neutralizing antibody ameliorates gut barrier dysfunction and improves survival after hemorrhagic shock. Mol Med. 2006;12:105–14.
    1. Cinat ME, Waxman K, Granger GA, Pearce W, Annas C, Daughters K. Trauma causes sustained elevation of soluble tumor necrosis factor receptors. J Am Coll Surg. 1994;179:529–37.
    1. Hensler T, Sauerland S, Bouillon B, et al. Association between injury pattern of patients with multiple injuries and circulating levels of soluble tumor necrosis factor receptors, interleukin-6 and interleukin-10, and polymorphonuclear neutrophil elastase. J Trauma. 2002;52:962–70.
    1. Martin C, Boisson C, Haccoun M, Thomachot L, Mege JL. Patterns of cytokine evolution (tumor necrosis factor-alpha and interleukin-6) after septic shock, hemorrhagic shock, and severe trauma. Crit Care Med. 1997;25:1813–9.
    1. Levy RM, Mollen KP, Prince JM, et al. Systemic inflammation and remote organ injury following trauma require HMGB1. Am J Physiol Regul Integr Comp Physiol. 2007;293:R1538–44.
    1. Wang H, Bloom O, Zhang M, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science. 1999;285(5425):248–51.
    1. Ombrellino M, Wang H, Ajemian MS, et al. Increased serum concentrations of high-mobility-group protein 1 in haemorrhagic shock. Lancet. 1999;354(9188):1446–7.
    1. Okonkwo DO, Stone JR. Basic science of closed head injuries and spinal cord injuries. Clin Sports Med. 2003;22:467–81.
    1. Buchman TG, Cobb JP, Lapedes AS, Kepler TB. Complex systems analysis: a tool for shock research. Shock. 2001;16:248–51.
    1. Ghirnikar RS, Lee YL, Eng LF. Inflammation in traumatic brain injury: role of cytokines and chemokines. Neurochem Res. 1998;23:329–40.
    1. Zamora R, Vodovotz Y, Billiar TR. Inducible nitric oxide synthase and inflammatory diseases. Mol Med. 2000;6:347–73.
    1. Hierholzer C, Harbrecht B, Menezes JM, et al. Essential role of induced nitric oxide in the initiation of the inflammatory response after hemorrhagic shock. J Exp Med. 1998;187:917–28.
    1. Jin T, Xu X, Hereld D. Chemotaxis, chemokine receptors and human disease. Cytokine. 2008;44:1–8.
    1. Viola A, Luster AD. Chemokines and their receptors: drug targets in immunity and inflammation. Annu Rev Pharmacol Toxicol. 2008;48:171–97.
    1. Vodovotz Y, Constantine G, Rubin J, Csete M, Voit EO, An G. Mechanistic simulations of inflammation: Current state and future prospects. Math Biosci. 2009;217:1–10.
    1. Kochanek PM, Berger RP, Bayir H, Wagner AK, Jenkins LW, Clark RS. Biomarkers of primary and evolving damage in traumatic and ischemic brain injury: diagnosis, prognosis, probing mechanisms, and therapeutic decision making. Curr Opin Crit Care. 2008;14:135–41.
    1. Zeytun A, van Velkinburgh JC, Pardington PE, Cary RR, Gupta G. Pathogen-specific innate immune response. Adv Exp Med Biol. 2007;598:342–57.
    1. Yang H, Ochani M, Li J, et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci U S A. 2004;101:296–1.
    1. Handrigan MT, Bentley TB, Oliver JD, Tabaku LS, Burge JR, Atkins JL. Choice of fluid influences outcome in prolonged hypotensive resuscitation after hemorrhage in awake rats. Shock. 2005;23:337–43.
    1. Torres A, Bentley T, Bartels J, et al. Mathematical Modeling of Post-hemorrhage Inflammation in Mice: Studies Using a Novel, Computer-controlled, Closed-loop Hemorrhage Apparatus. Shock. 2008 Nov 11; Epub ahead of print.
    1. Keramaris NC, Kanakaris NK, Tzioupis C, Kontakis G, Giannoudis PV. Translational research: from benchside to bedside. Injury. 2008;39:643–50.
    1. Nathan C, Xie QW. Nitric oxide synthases: Roles, tolls, and controls. Cell. 1994;78:915–18.
    1. Namas R, Ghuma A, Barclay D, Zamora R, Ochoa J, Billiar TR, Vodovotz Y. Manuscript in preparation.
    1. Ideker T, Galitski T, Hood L. A new approach to decoding life: systems biology. Annu Rev Genomics Hum Genet. 2001;2:343–72.
    1. Kitano H. Computational systems biology. Nature. 2002;420(6912):206–10.
    1. Ge H, Walhout AJ, Vidal M. Integrating'omic' information: a bridge between genomics and systems biology. Trends Genet. 2003;19(10):551–60.
    1. Lindon JC, Holmes E, Bollard ME, Stanley EG, Nicholson JK. Metabonomics technologies and their applications in physiological monitoring, drug safety assessment and disease diagnosis. Biomarkers. 2004;9:1–31.
    1. Mesarovic MD, Sreenath SN, Keene JD. Search for organising principles: understanding in systems biology. Syst.Biol. Stevenage. 2004;1:19–27.
    1. Weston AD, Hood L. Systems biology, proteomics, and the future of health care: toward predictive, preventative, and personalized medicine. J Proteome Res. 2004;3:179–96.
    1. Bruggeman FJ, Westerhoff HV. The nature of systems biology. Trends Microbiol. 2007;15:45–50.
    1. Sieberts SK, Schadt EE. Moving toward a system genetics view of disease. Mamm. Genome. 2007;18:389–1.
    1. Ross J. From the Determination of Complex Reaction Mechanisms to Systems Biology. Annu Rev. Biochem. 2008;77:479–94.
    1. Southern J, Pitt-Francis J, Whiteley J, et al. Multi-scale computational modelling in biology and physiology. Prog Biophys Mol Biol. 2008;96:60–89.
    1. Chung TP, Laramie JM, Province M, Cobb JP. Functional genomics of critical illness and injury. Crit Care Med. 2002;30(1 Suppl):51–S57.
    1. Cobb JP, O'Keefe GE. Injury research in the genomic era. Lancet. 2004;363(9426):2076–83.
    1. Calvano SE, Xiao W, Richards DR, et al. A network-based analysis of systemic inflammation in humans. Nature. 2005;437:1032–37.
    1. von Gertten C, Flores Morales A, Holmin S, Mathiesen T, Nordqvist AC. Genomic responses in rat cerebral cortex after traumatic brain injury. BMC Neurosci. 2005;6:69.
    1. Brownstein BH, Logvinenko T, Lederer JA, et al. Commonality and differences in leukocyte gene expression patterns among three models of inflammation and injury. Physiol Genomics. 2006;24:298–9.
    1. Edmonds B, Tseng G, Vodovotz Y, Billiar TR. Manuscript in preparation.
    1. Wang KK, Ottens A, Haskins W, et al. Proteomics studies of traumatic brain injury. Int Rev Neurobiol. 2004;61:215–40.
    1. Wang KK, Ottens AK, Liu MC, et al. Proteomic identification of biomarkers of traumatic brain injury. Expert Rev Proteomics. 2005;2:603–14.
    1. Liu T, Qian WJ, Gritsenko MA, et al. High dynamic range characterization of the trauma patient plasma proteome. Mol Cell Proteomics. 2006;5:1899–13.
    1. Ottens AK, Kobeissy FH, Fuller BF, et al. Novel neuroproteomic approaches to studying traumatic brain injury. Prog Brain Res. 2007;161:401–18.
    1. Prieto DA, Ye X, Veenstra TD. Proteomic analysis of traumatic brain injury: the search for biomarkers. Expert Rev Proteomics. 2008;5:283–91.
    1. Li NY, Verdolini K, Clermont G, et al. A patient-specific in silico model of inflammation and healing tested in acute vocal fold injury. PLoS ONE. 2008;3:e2789.
    1. Sarkar J, Chang S, Namas R, Ghuma A, Zenati M, Ochoa J, Billiar TR, Vodovotz Y. Manuscript in preparation.
    1. Mi Q, Solovyev A, Namas R, Ghuma A, Constantine G, Okonkwo D, Vodovotz Y. Manuscript in preparation.
    1. Rutland-Brown W, Langlois JA, Thomas KE, Xi YL. Incidence of traumatic brain injury in the United States, 2003. Head trauma rehabilitation. 2006;21:544–48.
    1. Sosin DM, Sniezek JE, Waxweiler RJ. Trends in death associated with traumatic brain injury, through 1992. Success and failure. JAMA 1995. 1979;273:1778–80.
    1. Perel P, Edwards P, Wentz R, Roberts I. Systematic review of prognostic models in traumatic brain injury. BMC Med Inform Decis Mak. 2006;6(38)
    1. Hukkelhoven CW, Steyerberg EW, Rampen AJ, et al. Patient age and outcome following severe traumatic brain injury: an analysis of 5600 patients. J Neurosurg. 2003;99:666–73.
    1. .
    1. .
    1. Morganti-Kossmann MC, Satgunaseelan L, Bye N, Kossmann T. Modulation of immune response by head injury. Injury. 2007;38:1392–400.
    1. Colicos MA, Dash PK. Apoptotic morphology of dentate gyrus granule cells following experimental cortical impact injury in rats: possible role in spatial memory deficits. Brain Res. 1996;739(1-2):120–31.
    1. Hausmann R, Biermann T, Wiest I, Tübel J, Betz P. Neuronal apoptosis following human brain injury. Int J Legal Med. 2004;118:32–6.
    1. Morganti-Kossmann MC, Rancan M, Otto VI, Stahel PF, Kossmann T. Role of cerebral inflammation after traumatic brain injury: a revisited concept. Shock. 2001;16:165–77.
    1. Ransohoff RM, Tani M. Do chemokines mediate leukocyte recruitment in post-traumatic CNS inflammation? Trends Neurosci. 1998;21:154–9.
    1. Benveniste EN. Cytokine actions in the central nervous system. Cytokine Growth Factor Rev. 1998;9:259–75.
    1. Fan L, Young PR, Barone FC, Feuerstein GZ, Smith DH, McIntosh TK. Experimental brain injury induces expression of interleukin-1 beta mRNA in the rat brain. Brain Res Mol Brain Res. 1995;30:125–30.
    1. Aloisi F, Care A, Borsellino G, et al. Production of hemolymphopoietic cytokines (IL-6, IL-8, colony-stimulating factors) by normal human astrocytes in response to IL-1 beta and tumor necrosis factor-alpha. J Immunol. 1992;149:2358–66.
    1. Chung IY, Benveniste EN. Tumor necrosis factor-alpha production by astrocytes. Induction by lipopolysaccharide, IFNgamma, and IL-1 beta. J Immunol. 1990;144:2999–7.
    1. Fan L, Young PR, Barone FC, Feuerstein GZ, Smith DH, McIntosh TK. Experimental brain injury induces differential expression of tumor necrosis factoralpha mRNA in the CNS. Brain Res Mol Brain Res. 1996;36:287–91.
    1. Kita T, Liu L, Tanaka N, Kinoshita Y. The expression of tumor necrosis factor-alpha in the rat brain after fluid percussive injury. Int J Legal Med. 1997;110:305–11.
    1. Kamm K, Vanderkolk W, Lawrence C, Jonker M, Davis AT. The effect of traumatic brain injury upon the concentration and expression of interleukin-1beta and interleukin-10 in the rat. J Trauma. 2006;60:152–7.
    1. Shohami E, Novikov M, Bass R, Yamin A, Gallily R. Closed head injury triggers early production of TNF alpha and IL-6 by brain tissue. J Cereb Blood Flow Metab. 1994;14:615–9.
    1. Taupin V, Toulmond S, Serrano A, Benavides J, Zavala F. Increase in IL-6, IL-1 and TNF levels in rat brain following traumatic lesion; Influence of preand post-traumatic treatment with Ro5 4864, a peripheral-type (p site) benzodiazepine ligand. J Neuroimmunol. 1993;42:177–85.
    1. Knoblach SM, Faden AI. Interleukin-10 improves outcome and alters proinflammatory cytokine expression after experimental traumatic brain injury. Exp Neurol. 1998;153:143–51.
    1. Chiaretti A, Genovese O, Aloe L, et al. Interleukin 1beta and interleukin 6 relationship with paediatric head trauma severity and outcome. Childs Nerv Syst. 2005;21:18593.
    1. Shiozaki T, Hayakata T, Tasaki O, et al. Cerebrospinal fluid concentrations of anti-inflammatory mediators in earlyphase severe traumatic brain injury. Shock. 2005;23:406–10.
    1. Narayan RK, Michel ME, Ansell B, et al. Clinical trials in head injury. J Neurotrauma. 2002;19:503–57.
    1. Csuka E, Morganti-Kossmann MC, Lenzlinger PM, Joller H, Trentz O, Kossmann T. IL-10 levels in cerebrospinal fluid and serum of patients with severe traumatic brain injury: relationship to IL-6, TNFalpha, TGF-beta1 and blood-brain barrier function. J Neuroimmunol. 1999;101:211–21.
    1. Schmidt OI, Morganti-Kossmann MC, Heyde CE, et al. Tumor necrosis factor-mediated inhibition of interleukin-18 in the brain: a clinical and experimental study in head-injured patients and in a murine model of closed head injury. J Neuroinflamm. 2004;1:13.
    1. Kossmann T, Hans V, Imhof HG, Trentz O, Morganti-Kossmann MC. Interleukin-6 released in human cerebrospinal fluid following traumatic brain injury may trigger nerve growth factor production in astrocytes. Brain Res. 1996;713:143–52.
    1. Morganti-Kossmann MC, Hans VH, Lenzlinger PM, et al. TGFbeta is elevated in the CSF of patients with severe traumatic brain injuries and parallels blood-brain barrier function. J Neurotrauma. 1999;16:617–28.
    1. Hensler T, Sauerland S, Riess P, et al. The effect of additional brain injury on systemic interleukin (IL)-10 and IL-13 levels in trauma patients. Inflamm Res. 2000;49:524–8.
    1. Shimonkevitz R, Bar-Or D, Harris L, Dole K, McLaughlin L, Yukl R. Transient monocyte release of interleukin-10 in response to traumatic brain injury. Shock. 1999;12:10–6.
    1. Morales DM, Marklund N, Lebold D, et al. Experimental models of traumatic brain injury: Do we really need to build a better mousetrap? Neuroscience. 2005;136:971–89.
    1. Finnie JW, Blumbergs PC. Traumatic Brain Injury. Vet Pathol. 2002;39:679–89.
    1. Park HK, Fernandez I, I, Dujovny M, Diaz FG. Experimental animal models of traumatic brain injury: medical and biomechanical mechanism. Crit Rev Neurosurg. 1999;9:44–52.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅