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A two-compartment mathematical model of endotoxin-induced inflammatory and physiologic alterations in swine.

ABSTRACT: To gain insights into individual variations in acute inflammation and physiology.Large-animal study combined with mathematical modeling.Academic large-animal and computational laboratories.Outbred juvenile swine.Four swine were instrumented and subjected to endotoxemia (100 µg/kg), followed by serial plasma sampling.Swine exhibited various degrees of inflammation and acute lung injury, including one death with severe acute lung injury (PaO(2)/FIO(2) ratio ?200 and static compliance ?10 L/cm H(2)O). Plasma interleukin-1?, interleukin-4, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-?, high mobility group box-1, and NO(2)/NO(3) were significantly (p ? .05) elevated over the course of the experiment. Principal component analysis was used to suggest principal drivers of inflammation. Based in part on principal component analysis, an ordinary differential equation model was constructed, consisting of the lung and the blood (as a surrogate for the rest of the body), in which endotoxin induces tumor necrosis factor-? in monocytes in the blood, followed by the trafficking of these cells into the lung leading to the release of high mobility group box-1, which in turn stimulates the release of interleukin-1? from resident macrophages. The ordinary differential equation model also included blood pressure, PaO(2), and FIO(2), and a damage variable that summarizes the health of the animal. This ordinary differential equation model could be fit to both inflammatory and physiologic data in the individual swine. The predicted time course of damage could be matched to the oxygen index in three of the four swine.The approach described herein may aid in predicting inflammation and physiologic dysfunction in small cohorts of subjects with diverse phenotypes and outcomes.

SUBMITTER: Nieman G

PROVIDER: S-EPMC3308118 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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A two-compartment mathematical model of endotoxin-induced inflammatory and physiologic alterations in swine.

Nieman Gary G Brown David D Sarkar Joydeep J Kubiak Brian B Ziraldo Cordelia C Dutta-Moscato Joyeeta J Vieau Christopher C Barclay Derek D Gatto Louis L Maier Kristopher K Constantine Gregory G Billiar Timothy R TR Zamora Ruben R Mi Qi Q Chang Steve S Vodovotz Yoram Y

Critical care medicine 20120401 4

<h4>Objective</h4>To gain insights into individual variations in acute inflammation and physiology.<h4>Design</h4>Large-animal study combined with mathematical modeling.<h4>Setting</h4>Academic large-animal and computational laboratories.<h4>Subjects</h4>Outbred juvenile swine.<h4>Interventions</h4>Four swine were instrumented and subjected to endotoxemia (100 µg/kg), followed by serial plasma sampling.<h4>Measurements and main results</h4>Swine exhibited various degrees of inflammation and acut ...[more]

PMID: 22425816

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Project description:The acute respiratory distress syndrome (ARDS), affects up to 150,000 patients per year in the United States. We and other groups have demonstrated that bone marrow derived mesenchymal stromal stem cells prevent ARDS induced by systemic and local administration of endotoxin (lipopolysaccharide (LPS)) in mice.A study was undertaken to determine the effects of the diverse populations of bone marrow derived cells on the pathophysiology of ARDS, using a unique ex-vivo swine preparation, in which only the ventilated lung and the liver are perfused with autologous blood. Six experimental groups were designated as: 1) endotoxin alone, 2) endotoxin + total fresh whole bone marrow nuclear cells (BMC), 3) endotoxin + non-hematopoietic bone marrow cells (CD45 neg), 4) endotoxin + hematopoietic bone marrow cells (CD45 positive), 5) endotoxin + buffy coat and 6) endotoxin + in vitro expanded swine CD45 negative adherent allogeneic bone marrow cells (cultured CD45neg). We measured at different levels the biological consequences of the infusion of the different subsets of cells. The measured parameters were: pulmonary vascular resistance (PVR), gas exchange (PO2), lung edema (lung wet/dry weight), gene expression and serum concentrations of the pro-inflammatory cytokines IL-1?, TNF-? and IL-6.Infusion of freshly purified autologous total BMCs, as well as non-hematopoietic CD45(-) bone marrow cells significantly reduced endotoxin-induced pulmonary hypertension and hypoxemia and reduced the lung edema. Also, in the groups that received BMCs and cultured CD45neg we observed a decrease in the levels of IL-1? and TNF-? in plasma. Infusion of hematopoietic CD45(+) bone marrow cells or peripheral blood buffy coat cells did not protect against LPS-induced lung injury.We conclude that infusion of freshly isolated autologous whole bone marrow cells and the subset of non-hematopoietic cells can suppress the acute humoral and physiologic responses induced by endotoxemia by modulating the inflammatory response, mechanisms that do not involve engraftment or trans-differentiation of the cells. These observations may have important implications for the design of future cell therapies for ARDS.

Project description:Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis--the growth of new microvessels from existing microvasculature. Angiogenesis is a complex process involving numerous molecular species, and to better understand it, a systems biology approach is necessary. In vivo preclinical experiments in the area of angiogenesis are typically performed in mouse models; this includes drug development targeting VEGF. Thus, to quantitatively interpret such experimental results, a computational model of VEGF distribution in the mouse can be beneficial. In this paper, we present an in silico model of VEGF distribution in mice, determine model parameters from existing experimental data, conduct sensitivity analysis, and test the validity of the model. The multiscale model is comprised of two compartments: blood and tissue. The model accounts for interactions between two major VEGF isoforms (VEGF(120) and VEGF(164)) and their endothelial cell receptors VEGFR-1, VEGFR-2, and co-receptor neuropilin-1. Neuropilin-1 is also expressed on the surface of parenchymal cells. The model includes transcapillary macromolecular permeability, lymphatic transport, and macromolecular plasma clearance. Simulations predict that the concentration of unbound VEGF in the tissue is approximately 50-fold greater than in the blood. These concentrations are highly dependent on the VEGF secretion rate. Parameter estimation was performed to fit the simulation results to available experimental data, and permitted the estimation of VEGF secretion rate in healthy tissue, which is difficult to measure experimentally. The model can provide quantitative interpretation of preclinical animal data and may be used in conjunction with experimental studies in the development of pro- and anti-angiogenic agents. The model approximates the normal tissue as skeletal muscle and includes endothelial cells to represent the vasculature. As the VEGF system becomes better characterized in other tissues and cell types, the model can be expanded to include additional compartments and vascular elements.

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A two-compartment mathematical model of endotoxin-induced inflammatory and physiologic alterations in swine.

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A two-compartment mathematical model of endotoxin-induced inflammatory and physiologic alterations in swine.

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