Inflammation ensues from both infectious and non-infectious causes. It is a complex, multi-scale biological response to stress that is also required for proper healing of injured tissue. Despite the volume of information concerning the cellular and molecular processes involved in inflammation, there exists a significant gap between the knowledge of mechanistic pathophysiology and the development of effective clinical therapeutic regimens for sepsis, trauma, burns, and other acute inflammatory conditions. Various groups, most recently the NIH in its Roadmap Initiative, have suggested that systems biology approaches should be used to gain basic insights into the biology of inflammation.
Our group’s research has been focused first on studying mechanisms of inflammation and second on gaining a systems-level perspective into this central physiological and pathological process.
Our systems biology work is carried out in a highly interdisciplinary environment, under the auspices of the Center for Inflammation and Regenerative Modeling (CIRM) which I direct at the McGowan Institute for Regenerative Medicine. The CIRM includes collaborating investigators from the departments of Surgery, Critical Care Medicine, Mathematics, and various departments in the School of Health and Rehabilitation Sciences, with data obtained in my own laboratory at the Department of Surgery as well as in collaborating laboratories. We have created various types of computational simulations of the interlinked inflammation / healing responses. The methods we use include statistical data reduction and modeling techniques; modeling using ordinary differential equations, partial differential equations, and agent-based methods; novel parameter estimation algorithms; studies involving molecular, cellular, and whole-animal manipulations; and clinical studies. The central factor in all of our simulations is the positive feedback loop of inflammation→tissue damage/dysfunction→inflammation, a process now known to be driven by “alarm/danger” signals.
We have used these simulations to gain insights into the pathology of sepsis, trauma, and wound healing. We have begun work on simulating how chronic inflammation leads to cancer and how immunotherapy might affect an established cancer. We have begun to simulate various aspects of post-spinal cord injury inflammation and subsequent complications, including urinary tract infections. We have also simulated the pathology of various lung diseases, including COPD. We have focused on mathematical modeling of the process of inflammatory preconditioning, in which the response to a secondary insult is altered by the first. These simulations have included basic insights, simulated clinical trials, and patient-specific models. We also continue to work on the activation of the cytokine transforming growth factor-β1 by nitric oxide as well as by extracellular β-nicotinamide adenine dinucleotide (NAD+), the latter study including also in silico modeling to help uncover novel biological mechanisms. NAD+ is also being studied in vivo as an anti-inflammatory compound. We have recently begun work with colleagues in the Department of Mathematics to create mathematical models of the complex, multi-species transfer of immune factors that includes the TGF-β1 and both mammalian and mosquito inducible nitric oxide synthases. We have also initiated a project on the control of inflammation through a bioreactor, in which cells are transfected with constructs sensitive to a given cytokine and that produce that cytokine’s endogenous inhibitor. With colleagues in the Department of Urology (now at William Beaumont Hospital), we have characterized the inflammatory response in rats subjected to experimental cystitis. We are now working with Dr. Rob Squires at Children’s Hospital on modeling the inflammatory response in Pediatric Acute Liver Failure, as part of a large UO1 grant that was recently renewed.
Namas, R.*; Almahmoud, K.*; Mi, Q.; Ghuma, A.; Namas, R.; Zaaqoq, A.; Sperry, J.; Zamora, R.; Billiar, T.R.; Vodovotz, Y. Individual-specific principal component analysis of circulating inflammatory mediators predicts early organ dysfunction in trauma patients. J. Crit. Care. 2016. 36:146-153. *Co-first authors.
Almahmoud, K.; Namas, R.; Zaaqoq, A.M.; Abdul-Malak, O.; Namas, R.; Zamora, R.; Sperry, J.; Billiar, T.R.; Vodovotz, Y. Prehospital hypotension is associated with altered inflammation dynamics and worse outcomes following blunt trauma in humans. Crit. Care Med. 2015. 43:1395-1404.
Almahmoud, K.; Namas, R.A.; Abdul-Malak, O.; Zaaqoq, A.M.; Zamora, R.; Zuckerbraun, B.; Sperry, J.; Peitzman, A.B.; Billiar, T.R.; Vodovotz, Y. Impact of injury severity on dynamic inflammation networks following blunt trauma. Shock. 2015. 44:105-109.
Day, J.; Metes, D.; Vodovotz, Y. Mathematical modeling of early cellular innate and adaptive immune responses to ischemia-reperfusion injury and solid organ allotransplantation. Frontiers in Immunology. 2015. 6:484.
Ziraldo, C.; Solovyev, A.; Allegretti, A.; n, S.; Henzel, M.K.; Sowa, G.A.; Brienza, D.; An, G.; Mi, Q.; Vodovotz, Y. A Computational, tissue-realistic model of pressure ulcer formation in individuals with spinal cord injury. PLoS Comp. Biol. 2015. 11:e1004309.
Trauma in silico: Individual-specific mathematical models and virtual clinical populations. Brown D, Namas, RA, Almahmoud K, Zaaqoq A, Sarkar J, Barclay DA, Yin Y, Ghuma A, Abboud A, Constantine G, Nieman G, Zamora R, Chang SC, Billiar TR, Vodovotz Y. Sci Transl Med. 2015 April; 7 (285): ra61 | Abstract | Full Text
Complex Systems and Computational Biology Approaches to Acute Inflammation. An, G.; Vodovotz, Y., eds. New York, NY: New York, NY: Springer. 2013. http://dx.doi.org/10.1007/978-1-4614-8008-2
Solovyev, A.; Mi, Q.; Tzen, Y-T.; Brienza, D.; Vodovotz, Y. Hybrid equation- / agent-based model of ischemia-induced hyperemia and pressure ulcer formation predicts greater propensity to ulcerate in subjects with spinal cord injury. PLoS Comput. Biol. 2013. 9:e1003070.
Namas, R.A.; Bartels, J.; Hoffman, R.; Barclay, D.; Billiar, T.R.; Zamora, R.; Vodovotz, Y. Combined in silico, in vivo, and in vitrostudies shed insights into the acute inflammatory response in middle-aged mice. 2013. PLoS ONE. 2013. 8: e67419.
Price, I.; Ermentrout, B.; Zamora, R.; Wang, B.; Azhar, N.; Mi, Q.; Constantine, G.; Faeder, J.; Luckhart, S.; Vodovotz, Y. In vivo, in vitro, and in silico studies suggest a conserved immune module that may regulate malaria parasite transmission from mammals to mosquitoes. J. Theoretical Biol. 2013. 334:173-186. Article featured on Malaria Nexus (http://www.malarianexus.com/)
Azhar, N.; Ziraldo, C.; Barclay, D.; Rudnick, D.; Squires, R.; Vodovotz, Y. Analysis of serum inflammatory mediators identifies unique dynamic networks associated with death and spontaneous survival in pediatric acute liver failure. PLoS ONE. 2013. 8:e78202.
Ziraldo, C.*; Vodovotz, Y.*; Namas, R.A.; Mi, Q.; Barclay, D.; Almahmoud, K.; Jefferson, B.S.; Chen, G.; Billiar, T.R.; Zamora, R. Central role for MCP-1/CCL2 in injury-induced inflammation revealed by in vitro, in silico, and clinical studies. PLoS ONE. 2013. 8:e79804. *Co-first authors.
Vodovotz, Y.; An, G.; Androulakis, I.P. A systems engineering perspective on homeostasis and disease. Frontiers Bioengineering Biotechnol. 2013. 1 (Article 6): 1-8.
Emr, B.; Sadowsky, D.; Azhar, N.; Gatto, L.; An, G.; Nieman, G.; Vodovotz, Y. Removal of inflammatory ascites is associated with dynamic modification of local and systemic inflammation along with prevention of acute lung injury: In vivo and in silico studies. Shock. 2014. 41:317-323.
Vodovotz, Y.; Billiar, T.R. In silico modeling: Methods and applications to trauma and sepsis. Crit. Care Med. 2013. 41:2008-2014.
Zaaqoq, A.M.; Namas, R.; Almahmoud, K.; Krishnan, S.; Azhar, N.; Mi, Q.; Zamora, R.; Brienza, D.M.; Billiar, T.R.; Vodovotz, Y. IP-10, a potential driver of neurally-controlled IL-10 and morbidity in human blunt trauma. Crit Care Med, 2014, 42:1487-2497.
Translational Systems Biology: Concepts and Practice for the Future of Biomedical Research. An, G. and Vodovotz, Y. New York, NY: Elsevier. 2014. ISBN: 9780123978844. (http://store.elsevier.com/Translational-Systems-Biology/Yoram-Vodovotz/isbn-9780123978844/ )