Modeling the acute inflammatory response

Summary

Principal Investigator: Gilles Clermont
Abstract: The acute inflammatory response is a cascade of cellular and molecular events that takes place in the body after a traumatic injury or an infection. This response involves the immune, endocrine and neurological systems and aims to eliminate damaging agents and restore the body back to equilibrium. The clinical manifestation of this response is called the systemic inflammatory response syndrome (SIRS) or sepsis in the case of infection. There are approximately three-quarters of a million cases of SIRS severe enough to warrant hospitalization in the United States each year. Although much has been learned in the last several years on the molecular and cellular mechanisms of SIRS, this knowledge has not translated into improved outcome prediction or treatments. We hypothesize that a major reason effective treatments have not been developed is that a good understanding of the global dynamical behavior of the acute inflammatory response is lacking. We propose to address this shortcoming by developing biologically accurate mathematical models of the acute inflammatory response. These models will be tested and calibrated with carefully designed animal experiments in an iterative procedure that relies heavily on detailed statistical analysis. More specifically, we propose to 1) develop a hierarchy of mathematical models, each designed to address a specific set of questions; 2) refine and validate the mathematical models through an iterative process of experimentation, statistical analysis, and model development; and 3) analyze the various modes of behavior in the mathematical models and use these modes to make predictions of outcomes in different experimental scenarios. The long-term goal of this study is to provide a rational basis for the design of therapies to combat SIRS as well as to aid in patient management.
Funding Period: 2002-08-01 - 2007-07-31
more information: NIH RePORT

Top Publications

  1. pmc In silico modeling: methods and applications to trauma and sepsis
    Yoram Vodovotz
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
    Crit Care Med 41:2008-14. 2013
  2. ncbi Using nonlinear model predictive control to find optimal therapeutic strategies to modulate inflammation
    Judy Day
    Mathematical Biosciences Institute, The Ohio State University, 1735 Neil Ave, 377 Jennings Hall, Columbus, OH 43210, United States
    Math Biosci Eng 7:739-63. 2010
  3. ncbi Toward computational identification of multiscale "tipping points" in acute inflammation and multiple organ failure
    Gary An
    Department of Surgery, University of Chicago, Chicago, IL 60637, USA
    Ann Biomed Eng 40:2414-24. 2012
  4. pmc Sepsis: from pattern to mechanism and back
    Gary An
    Department of Surgery, University of Chicago, Chicago, IL 60637, USA
    Crit Rev Biomed Eng 40:341-51. 2012
  5. pmc A three-dimensional mathematical and computational model of necrotizing enterocolitis
    Jared Barber
    Department of Mathematics, 301 Thackeray Hall, University of Pittsburgh, Pittsburgh, PA 15260, USA
    J Theor Biol 322:17-32. 2013
  6. pmc A mathematical model of pulmonary gas exchange under inflammatory stress
    Angela Reynolds
    Department of Mathematics, 301 Thackeray, University of Pittsburgh, Pittsburgh, PA 15260, USA
    J Theor Biol 264:161-73. 2010
  7. pmc Translational systems approaches to the biology of inflammation and healing
    Yoram Vodovotz
    Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Immunopharmacol Immunotoxicol 32:181-95. 2010
  8. ncbi Systems biology and inflammation
    Yoram Vodovotz
    Center for Inflammation and Regenerative Modeling, McGowan Institute of Regenerative Medicine and Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
    Methods Mol Biol 662:181-201. 2010
  9. pmc Translational systems biology of inflammation and healing
    Yoram Vodovotz
    Department of Surgery Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Wound Repair Regen 18:3-7. 2010
  10. ncbi Equation-based models of dynamic biological systems
    Silvia Daun
    Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
    J Crit Care 23:585-94. 2008

Scientific Experts

  • Yoram Vodovotz
  • Gary C An
  • Jeffrey S Upperman
  • Gilles Clermont
  • Judy Day
  • Angela Reynolds
  • Jonathan Rubin
  • Carson C Chow
  • Rukmini Kumar
  • John Bartels
  • Timothy R Billiar
  • Mitchell P Fink
  • Jared Barber
  • G Bard Ermentrout
  • Silvia Daun
  • Baris Hancioglu
  • Claudio E Lagoa
  • Jose M Prince
  • Arie Baratt
  • Claudio Lagoa
  • C Harold Horvat
  • Ivan Yotov
  • Mark Tronzo
  • John D Bartels
  • David Swigon
  • Ryan M Levy
  • John M Kane
  • Sanna M Goyert
  • George Tseng
  • Joyce Wei
  • David Gallo
  • Binnie Betten
  • Gregory Constantine
  • Zacharia Tawadrous

Detail Information

Publications28

  1. pmc In silico modeling: methods and applications to trauma and sepsis
    Yoram Vodovotz
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
    Crit Care Med 41:2008-14. 2013
    ..To familiarize clinicians with advances in computational disease modeling applied to trauma and sepsis...
  2. ncbi Using nonlinear model predictive control to find optimal therapeutic strategies to modulate inflammation
    Judy Day
    Mathematical Biosciences Institute, The Ohio State University, 1735 Neil Ave, 377 Jennings Hall, Columbus, OH 43210, United States
    Math Biosci Eng 7:739-63. 2010
    ..These results imply that a combination of computational modeling and NMPC may be of practical use in suggesting novel immuno-modulatory strategies for the treatment of intensive care patients...
  3. ncbi Toward computational identification of multiscale "tipping points" in acute inflammation and multiple organ failure
    Gary An
    Department of Surgery, University of Chicago, Chicago, IL 60637, USA
    Ann Biomed Eng 40:2414-24. 2012
    ....
  4. pmc Sepsis: from pattern to mechanism and back
    Gary An
    Department of Surgery, University of Chicago, Chicago, IL 60637, USA
    Crit Rev Biomed Eng 40:341-51. 2012
    ....
  5. pmc A three-dimensional mathematical and computational model of necrotizing enterocolitis
    Jared Barber
    Department of Mathematics, 301 Thackeray Hall, University of Pittsburgh, Pittsburgh, PA 15260, USA
    J Theor Biol 322:17-32. 2013
    ....
  6. pmc A mathematical model of pulmonary gas exchange under inflammatory stress
    Angela Reynolds
    Department of Mathematics, 301 Thackeray, University of Pittsburgh, Pittsburgh, PA 15260, USA
    J Theor Biol 264:161-73. 2010
    ....
  7. pmc Translational systems approaches to the biology of inflammation and healing
    Yoram Vodovotz
    Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Immunopharmacol Immunotoxicol 32:181-95. 2010
    ..This plethora of computational and intertwined experimental/engineering approaches is the cornerstone of Translational Systems Biology approaches for inflammatory diseases...
  8. ncbi Systems biology and inflammation
    Yoram Vodovotz
    Center for Inflammation and Regenerative Modeling, McGowan Institute of Regenerative Medicine and Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
    Methods Mol Biol 662:181-201. 2010
    ..This chapter reviews the existing, translational applications of computational simulations and related approaches as applied to inflammation...
  9. pmc Translational systems biology of inflammation and healing
    Yoram Vodovotz
    Department of Surgery Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Wound Repair Regen 18:3-7. 2010
    ..We suggest that computational simulations are the cornerstone of Translational Systems Biology approaches for inflammatory diseases...
  10. ncbi Equation-based models of dynamic biological systems
    Silvia Daun
    Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
    J Crit Care 23:585-94. 2008
    ..Equation-based modeling, although potentially an integrative approach, is complementary to and extends the potential of traditional statistically based approaches to inference...
  11. pmc Mechanistic simulations of inflammation: current state and future prospects
    Yoram Vodovotz
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Math Biosci 217:1-10. 2009
    ..Here we discuss the state of this emerging field. We note several common features of inflammation models, as well as challenges and prospects for future studies...
  12. pmc Translational systems biology of inflammation
    Yoram Vodovotz
    Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
    PLoS Comput Biol 4:e1000014. 2008
    ..Future advances in understanding complex medical problems are highly dependent on methodological advances and integration of the computational systems biology community with biologists and clinicians...
  13. ncbi A reduced mathematical model of the acute inflammatory response: I. Derivation of model and analysis of anti-inflammation
    Angela Reynolds
    Department of Mathematics, 301 Thackeray, University of Pittsburgh, Pittsburgh, PA 15260, USA
    J Theor Biol 242:220-36. 2006
    ..Further, we offer a clinical correlation between model predictions and potential therapeutic interventions based on modulation of immunity by anti-inflammatory agents...
  14. ncbi A reduced mathematical model of the acute inflammatory response II. Capturing scenarios of repeated endotoxin administration
    Judy Day
    Department of Mathematics, 301 Thackeray, University of Pittsburgh, Pittsburgh, PA 15260, USA
    J Theor Biol 242:237-56. 2006
    ....
  15. ncbi In silico models of acute inflammation in animals
    Yoram Vodovotz
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Shock 26:235-44. 2006
    ..Mathematical modeling may provide insights into the complex dynamics of acute inflammation in a manner that can be tested in vivo using many fewer animals than has been possible previously...
  16. pmc In silico and in vivo approach to elucidate the inflammatory complexity of CD14-deficient mice
    Jose M Prince
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Mol Med 12:88-96. 2006
    ....
  17. ncbi The role of initial trauma in the host's response to injury and hemorrhage: insights from a correlation of mathematical simulations and hepatic transcriptomic analysis
    Claudio E Lagoa
    Department of Surgery, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA
    Shock 26:592-600. 2006
    ..Mathematical simulations and DNA microarrays, both systems biology tools, may provide valuable insight into the complex global physiological interactions that occur in response to trauma and hemorrhagic shock...
  18. ncbi A dynamical model of human immune response to influenza A virus infection
    Baris Hancioglu
    Department of Mathematics, 301 Thackeray, University of Pittsburgh, Pittsburgh, PA 15260, USA
    J Theor Biol 246:70-86. 2007
    ..This behavior is robust to a wide range of parameter values. The absence of antibody response leads to recurrence of disease and appearance of a chronic state with nontrivial constant viral load...
  19. ncbi Mathematical modeling in necrotizing enterocolitis--a new look at an ongoing problem
    Jeffrey S Upperman
    Department of Pediatric Surgery, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA
    J Pediatr Surg 42:445-53. 2007
    ..We suggest that a properly validated and calibrated mathematical model of inflammation and its pathologic consequences in NEC will be useful for predicting the physiologic and biologic response in infants suffering from the disease...
  20. ncbi Deciphering the complexity of acute inflammation using mathematical models
    Yoram Vodovotz
    Department of Surgery, University of Pittsburgh, and Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
    Immunol Res 36:237-45. 2006
    ..Modeling may help in understanding the complex interactions among the components of inflammation and response to stress, and therefore aid in the development of novel therapies and diagnostics...
  21. pmc Evidence-based modeling of critical illness: an initial consensus from the Society for Complexity in Acute Illness
    Yoram Vodovotz
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
    J Crit Care 22:77-84. 2007
    ..Accordingly, SCAI identified a need for and carried out a critical appraisal of DMM as currently used in the setting of acute illness...
  22. pmc Challenges and rewards on the road to translational systems biology in acute illness: four case reports from interdisciplinary teams
    Gary An
    Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
    J Crit Care 22:169-75. 2007
    ..However, the development of these groups must overcome domain-specific barriers to communication and understanding...
  23. pmc A mathematical simulation of the inflammatory response to anthrax infection
    Rukmini Kumar
    Department of Physics, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
    Shock 29:104-11. 2008
    ..Rather, our simulations suggest that an optimal strategy would require both vaccination and antibiotic administration...
  24. pmc Translational systems biology: introduction of an engineering approach to the pathophysiology of the burn patient
    Gary An
    Department of Surgery, Northwestern University, Chicago, IL 60611, USA
    J Burn Care Res 29:277-85. 2008
    ....
  25. ncbi The acute inflammatory response in diverse shock states
    Carson C Chow
    Department of Mathematics, University of Pittsburgh, Pittsburgh, Pensylvania 15261, USA
    Shock 24:74-84. 2005
    ....