The hepatocellular uptake and biliary excretion of endotoxin in the rat

Maitra, Shyamal K.; Rachmilewitz, Daniel; Eberle, David; Kaplowitz, Neil

doi:10.1002/hep.1840010506

Cited by 42 publications

(20 citation statements)

References 21 publications

(12 reference statements)

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“…26 This activation of macrophages by LPS results in an up-regulation and secretion of TNF-␣, IL-6, and IL-12p35 and subsequent liver tissue damage. 18,26 To determine if the protection associated with probiotic administration was accompanied by alterations in hepatic cytokines, TNF-␣, IL-6, and IL-12p35 RNA were measured by semiquantitative reverse transcription polymerase chain reaction. Enhanced levels of TNF-␣ and IL-6, but not IL-12p35 RNA, were observed after LPS/GalN injection (Fig.…”

Section: Resultsmentioning

confidence: 99%

Probiotic bacteria prevent hepatic damage and maintain colonic barrier function in a mouse model of sepsis

et al. 2007

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A breakdown in intestinal barrier function and increased bacterial translocation are key events in the pathogenesis of sepsis and liver disease. Altering gut microflora with noninvasive and immunomodulatory probiotic organisms has been proposed as an adjunctive therapy to reduce the level of bacterial translocation and prevent the onset of sepsis. The purpose of this study was to determine the efficacy of a probiotic compound in attenuating hepatic and intestinal injury in a mouse model of sepsis. Wild-type and interleukin-10 (IL-10) gene-deficient 129 Sv/Ev mice were fed the probiotic compound VSL#3 for 7 days. To induce sepsis, the mice were injected with lipopolysaccharide (LPS) and D-galactosamine (GalN) in the presence and absence of the peroxisome proliferator-activated receptor gamma (PPAR␥) inhibitor GW9662. The mice were killed after 6 hours, and their colons were removed for the measurement of the cytokine production and epithelial function. The functional permeability was assessed by the mannitol movement and cyclic adenosine monophosphate-dependent chloride secretion in tissue mounted in Ussing chambers. The livers were analyzed for bacterial translocation, cytokine production, histological injury, and PPAR␥ levels. The tissue levels of tumor necrosis factor alpha, interferon gamma, IL-6, and IL-12p35 ribonucleic acid were measured by semiquantitative reverse transcription polymerase chain reaction. L iver dysfunction and failure contribute to the high mortality rates seen in patients with Gram-negative sepsis. The presence of lipopolysaccharide (LPS) from Gram-negative bacteria in the systemic circulation results in the activation of the innate immune system and the secretion of high levels of proinflammatory cytokines. In animal models, LPS challenge can induce a systemic reaction resulting in a sepsis-like condition characterized by fever, hypotension, and widespread tissue damage. D-Galactosamine (GalN) increases the susceptibility of mice to LPS-induced shock by impairing liver metabolism. 1 Challenging mice with low doses of LPS in conjunction with GalN results in massive liver apoptosis and increased mortality.Tumor necrosis factor alpha (TNF-␣) plays a central role in the overwhelming systemic inflammatory response to LPS. 2 However, the complete blockade of TNF-␣ production does not improve survival in animals or humans 3 The activation of nuclear factor kappa B (NF-B) has been shown to play a key role in the pathogenesis of sepsis and is a pivotal step in the regulation of several immune and proinflammatory genes, including TNF-␣. 4 The modulation of NF-B activity has been proposed as a strategy for reducing the mortality associated with sepsis. Peroxisome proliferator-activated receptor gamma (PPAR␥) is a nuclear hormone receptor and transcription

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Section: Resultsmentioning

confidence: 99%

Probiotic bacteria prevent hepatic damage and maintain colonic barrier function in a mouse model of sepsis

et al. 2007

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“…Lipopolysaccharide is cleared in approximately 1 h (44,45). Circulating neutrophils are activated directly and produce TNF (46) and IL-10 (47)(48)(49).…”

Section: Generation Of a Mathematical Model Of Acute Inflammationmentioning

confidence: 99%

The Acute Inflammatory Response in Diverse Shock States

Chow¹,

Clermont²,

Kumar

et al. 2005

Shock

190

244

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A poorly controlled acute inflammatory response can lead to organ dysfunction and death. Severe systemic inflammation can be induced and perpetuated by diverse insults such as the administration of toxic bacterial products (e.g., endotoxin), traumatic injury, and hemorrhage. Here, we probe whether these varied shock states can be explained by a universal inflammatory system that is initiated through different means and, once initiated, follows a course specified by the cellular and molecular mechanisms of the immune and endocrine systems. To examine this question, we developed a mathematical model incorporating major elements of the acute inflammatory response in C57Bl/6 mice, using input from experimental data. We found that a single model with different initiators including the autonomic system could describe the response to various insults. This model was able to predict a dose range of endotoxin at which mice would die despite having been calibrated only in nonlethal inflammatory paradigms. These results show that the complex biology of inflammation can be modeled and supports the hypothesis that shock states induced by a range of physiologic challenges could arise from a universal response that is differently initiated and modulated.

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“…In endotoxemia, the model assumes that LPS enters the bloodstream, incites a systemwide response (45), and is cleared in approximately 1 h (46,47). Circulating neutrophils are activated directly and produce TNF (48) and IL-10 (49Y51).…”

Section: An In Silico Model Of Mouse Endotoxemiamentioning

confidence: 99%

In Silico Models of Acute Inflammation in Animals

Vodovotz¹,

Chow²,

Bartels³

et al. 2006

Shock

100

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Trauma and hemorrhagic shock elicit an acute inflammatory response, predisposing patients to sepsis, organ dysfunction, and death. Few approved therapies exist for these acute inflammatory states, mainly due to the complex interplay of interacting inflammatory and physiological elements working at multiple levels. Various animal models have been used to simulate these phenomena, but these models often do not replicate the clinical setting of multiple overlapping insults. Mathematical modeling of complex systems is an approach for understanding the interplay among biological interactions. We constructed a mathematical model using ordinary differential equations that encompass the dynamics of cells and cytokines of the acute inflammatory response, as well as global tissue dysfunction. The model was calibrated in C57Bl/6 mice subjected to (1) various doses of lipopolysaccharide (LPS) alone, (2) surgical trauma, and (3) surgery + hemorrhagic shock. We tested the model's predictive ability in scenarios on which it had not been trained, namely, (1) surgery +/- hemorrhagic shock + LPS given at times after the beginning of surgical instrumentation, and (2) surgery + hemorrhagic shock + bilateral femoral fracture. Software was created that facilitated fitting of the mathematical model to experimental data, as well as for simulation of experiments with various inflammatory challenges and associated variations (gene knockouts, inhibition of specific cytokines, etc.). Using this software, the C57Bl/6-specific model was recalibrated for inflammatory analyte data in CD14-/- mice and was used to elucidate altered features of inflammation in these animals. In other experiments, rats were subjected to surgical trauma +/- LPS or to bacterial infection via fibrin clots impregnated with various inocula of Escherichia coli. 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.

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The hepatocellular uptake and biliary excretion of endotoxin in the rat

Cited by 42 publications

References 21 publications

Probiotic bacteria prevent hepatic damage and maintain colonic barrier function in a mouse model of sepsis

Probiotic bacteria prevent hepatic damage and maintain colonic barrier function in a mouse model of sepsis

The Acute Inflammatory Response in Diverse Shock States

In Silico Models of Acute Inflammation in Animals

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