Mechanism of Hepatocellular Dysfunction During Early Sepsis

Wang, Haichao; Ba, Zheng F.; Chaudry, Irshad H.

doi:10.1001/archsurg.1997.01430280038005

Cited by 86 publications

(18 citation statements)

References 27 publications

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“…Some studies show that circulating TNF-α may contribute to hepatocellular dysfunction in early sepsis [37] and that TNF-α concentrations in plasma are a predictor of mortality in septic mice [38]. On the other hand, TNF-α blockade using antibodies failed to protect mice undergoing CLP [39, 40], meanwhile protection was observed following recombinant human TNF-α injections in septic rats [41].…”

Section: Discussionmentioning

confidence: 99%

Resuscitation fluid composition affects hepatic inflammation in a murine model of early sepsis

Patrick

Grin

Kraus

et al. 2017

ICMx

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BackgroundFluid resuscitation is a crucial therapy for sepsis, and the use of balanced fluids and/or isotonic albumin may improve patient survival. We have previously demonstrated that resuscitation with normal saline results in increased hepatic leukocyte recruitment in a murine model of sepsis. Given that clinical formulations of albumin are in saline, our objectives were to develop a novel balanced electrolyte solution specifically for sepsis and to determine if supplementing this solution with albumin would improve the inflammatory response in sepsis.MethodsWe developed two novel buffered electrolyte solutions that contain different concentrations of acetate and gluconate, named Seplyte L and Seplyte H, and administered these solutions with or without 5% albumin. Normal saline with or without albumin and Ringer’s lactate served as controls. Sepsis was induced by cecal ligation and puncture (CLP), and the liver microvasculature was imaged in vivo at 6 h after CLP to quantify leukocyte recruitment. Hepatic cytokine expression and plasma cell-free DNA (cfDNA) concentrations were also measured.ResultsSeptic mice receiving either Seplyte fluid showed significant reductions in hepatic post-sinusoidal leukocyte rolling and adhesion compared to normal saline. Hepatic cytokine concentrations varied in response to different concentrations of acetate and gluconate in the novel resuscitation fluids but were unaffected by albumin. All Seplyte fluids significantly increased hepatic TNF-α levels at 6 h compared to control fluids. However, Seplyte H exhibited a similar cytokine profile to the control fluids for all other cytokines, whereas mice given Seplyte L had significantly elevated IL-6, IL-10, KC (CXCL1), and MCP-1 (CCL2). Plasma cfDNA was generally increased during sepsis, but resuscitation fluid composition did not significantly affect cfDNA concentrations.ConclusionsElectrolyte concentrations and buffer constituents of resuscitation fluids can modulate hepatic cytokine production and leukocyte recruitment in septic mice, while the effects of albumin are modest during early sepsis. Therefore, crystalloid fluid choice should be an important consideration for resuscitation in sepsis, and the effects of fluid composition on inflammation in other organ systems should be studied to better understand the physiological impact of this vital sepsis therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s40635-017-0118-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Resuscitation fluid composition affects hepatic inflammation in a murine model of early sepsis

Patrick

Grin

Kraus

et al. 2017

ICMx

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“…The cecum was then exposed, ligated just distal to the ileocecal valve to avoid intestinal obstruction, punctured twice with an 18-gauge needle, and returned to the abdominal cavity. The incision was closed in layers and the animals were resuscitated with 3 ml/100 g BW normal saline subcutaneously immediately after CLP [12]. This model of sepsis is associated with an early, hyperdynamic phase (i.e., 2–10 h after CLP; characterized by an increased cardiac output and tissue perfusion, decreased vascular resistance, and hyperglycemia), which is followed by a late, hypodynamic phase (16 h after CLP and later; characterized by reduced cardiac output and tissue perfusion, increased vascular resistance, and hypoglycemia) [5], [13], [14].…”

Section: Methodsmentioning

confidence: 99%

“…Kupffer cells were isolated from normal and septic rats as previously described elsewhere with some modifications [12]. Briefly, under isoflurane anesthesia, following a midline incision the inferior vena cava was cannulated and the portal vein was severed.…”

Section: Methodsmentioning

confidence: 99%

Pivotal Role of the α2A-Adrenoceptor in Producing Inflammation and Organ Injury in a Rat Model of Sepsis

et al. 2009

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BackgroundNorepinephrine (NE) modulates the responsiveness of macrophages to proinflammatory stimuli through the activation of adrenergic receptors (ARs). Being part of the stress response, early increases of NE in sepsis sustain adverse systemic inflammatory responses. The intestine is an important source of NE release in the early stage of cecal ligation and puncture (CLP)-induced sepsis in rats, which then stimulates TNF-α production in Kupffer cells (KCs) through the activation of the α2-AR. It is important to know which of the three α2-AR subtypes (i.e., α2A, α2B or α2C) is responsible for the upregulation of TNF-α production. The aim of this study was to determine the contribution of α2A-AR in this process.Methodology/Principal FindingsAdult male rats underwent CLP and KCs were isolated 2 h later. Gene expression of α2A-AR was determined. In additional experiments, cultured KCs were incubated with NE with or without BRL-44408 maleate, a specific α2A-AR antagonist, and intraportal infusion of NE for 2 h with or without BRL-44408 maleate was carried out in normal animals. Finally, the impact of α2A-AR activation by NE was investigated under inflammatory conditions (i.e., endotoxemia and CLP). Gene expression of the α2A-AR subtype was significantly upregulated after CLP. NE increased the release of TNF-α in cultured KCs, which was specifically inhibited by the α2A-AR antagonist BRL-44408. Equally, intraportal NE infusion increased TNF-α gene expression in KCs and plasma TNF-α which was also abrogated by co-administration of BRL-44408. NE also potentiated LPS-induced TNF-α release via the α2A-AR in vitro and in vivo. This potentiation of TNF-α release by NE was mediated through the α2A-AR coupled Gαi protein and the activation of the p38 MAP kinase. Treatment of septic animals with BRL-44408 suppressed TNF-α, prevented multiple organ injury and significantly improved survival from 45% to 75%.Conclusions/SignificanceOur novel finding is that hyperresponsiveness to α2-AR stimulation observed in sepsis is primarily due to an increase in α2A-AR expression in KCs. This appears to be in part responsible for the increased proinflammatory response and ensuing organ injury in sepsis. These findings provide important feasibility information for further developing the α2A-AR antagonist as a new therapy for sepsis.

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“…Their results are corroborated by the observation that in vivo TNF-␣ and IL-6 are up-regulated before the onset of hepatocellular dysfunction. 37 However, the exact contribution of cytokines versus ROS to liver cell damage in vivo will be hard to determine because cytokines stimulate ROS production from KCs as well as PMNs.…”

Section: Inflammatory Mediators and Liver Function In Sepsismentioning

confidence: 99%

The Hepatic Microvascular Responses to Sepsis

Ring

Stremmel²

2000

Semin Thromb Hemost

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The liver is believed to play a major role in the initiation of multiorgan failure, the most lethal complication in the clinical course of sepsis. Microbes and their virulence factors enter the hepatic circulation where they first activate sinusoidal endothelial cells and Kupffer cells to produce proinflammatory mediators, including TNF-alpha, IL-1, IL-6, reactive oxygen metabolites, and eicosanoids. These mediators cause not only microbial killing, but also structural and functional liver damage concerning mainly the parenchymal cells. Leukocytes are targeted to the liver sinusoids by chemoattractants and, like platelets, tether to the sinusoidal endothelial cells, which are in a procoagulant state of inflammatory activation. Clogging of the sinusoids by these cells leads to a decrease of blood flow through the sinusoids, which is further aggravated by endothelin-1 effectuating the constriction of hepatic stellate cells in the sinusoids. In contrast, both nitric oxide (NO) and carbon monoxide (CO) act as antagonists of endothelin-1 by mediating relaxation of sinusoidal vessels. By maintaining an adequate sinusoidal perfusion, both NO and CO are hepatoprotective during the early, hyperdynamic phase of sepsis characterized by an increased cardiac output and moderate peripheral vasodilation. However, during the late, hypodynamic phase of sepsis, massive overproduction of NO by the inducible NO synthase leads to circulatory collapse, which inevitably includes breakdown of the liver circulation.

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Mechanism of Hepatocellular Dysfunction During Early Sepsis

Cited by 86 publications

References 27 publications

Resuscitation fluid composition affects hepatic inflammation in a murine model of early sepsis

Resuscitation fluid composition affects hepatic inflammation in a murine model of early sepsis

Pivotal Role of the α2A-Adrenoceptor in Producing Inflammation and Organ Injury in a Rat Model of Sepsis

The Hepatic Microvascular Responses to Sepsis

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