Liver Dysfunction and Phosphatidylinositol-3-Kinase Signalling in Early Sepsis: Experimental Studies in Rodent Models of Peritonitis

Recknagel, Peter; Gonnert, Falk A.; Westermann, Martin; Lambeck, Sandro; Lupp, Amelie; Rudiger, Alain; Dyson, Alex; Carré, Jane E.; Kortgen, Andreas; Krafft, Christoph; Popp, Jürgen; Sponholz, Christoph; Fuhrmann, Valentin; Hilger, Ingrid; Claus, Ralf A.; Riedemann, Niels C.; Wetzker, Reinhard; Singer, Mervyn; Trauner, Michael; Bauer, Michael

doi:10.1371/journal.pmed.1001338

Cited by 160 publications

(190 citation statements)

References 55 publications

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“…For example, effector kinases are promising targets for therapy in diverse disease entities ranging from cancer to organ dysfunction in critical care. 1,2 Interventions into kinase function (for example, PI3K) might be limited by deleterious off-target effects, for example, on the immune system. A broad spectrum of approaches, including viruses and non-viral vectors has been applied for delivery to specific cells, but these strategies are still far from satisfactory.…”

Section: Introductionmentioning

confidence: 99%

Cargo–carrier interactions significantly contribute to micellar conformation and biodistribution

et al. 2017

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Strategies to deliver drugs using nanocarriers, which are passively or actively targeted to their alleged site of action might favorably affect benefit-risk profiles of novel therapeutics. Here we tested the hypothesis whether the physico-chemical properties of the cargo as well as the actual conditions during encapsulation interfere during formulation of nanoparticular cargo-carrier systems. On the basis of previous work, a versatile class of nanocarriers is polyether-based ABC triblock terpolymer micelles with diameters below 50 nm. Their tunable chemistry and size allows to systematically vary important parameters. We demonstrate in vivo differences in pharmacokinetics and biodistribution not only dependent on micellar net charge but also on the properties of encapsulated (model) drugs and their localization within the micelles. On the basis of in vitro and in vivo evidence we propose that depending on drug cargo and encapsulation conditions micelles with homogeneous or heterogeneous corona structure are formed, contributing to an altered pharmacokinetic profile as differences in cargo location occur. Thus, these interactions have to be considered when a carrier system is selected to achieve optimal delivery to a given tissue.

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Section: Introductionmentioning

confidence: 99%

Cargo–carrier interactions significantly contribute to micellar conformation and biodistribution

et al. 2017

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“…For example, acyl-GPCs have been suggested in sepsis diagnosis (27) and treatment (28); whereas kynurenine, a known immunosuppressive metabolite, is a biomarker for active tuberculosis infections (29). Increased conjugated bile acids (e.g., taurocholenate and taurolithocholate-3 sulfate) have been identified as sensitive indicators of sepsisinduced cholestasis and poor outcomes (30). We previously observed increases in small-chain, medium-chain, and branchedchain amino acid (BCAA) carnitine esters, consistent with the finding that dysregulated b-oxidation and BCAA degradation precedes sepsis-induced death In light of the lung colonization and injury, lung transcriptomics were assessed across all infectious doses.…”

Section: Metabolomic Analysis In Nhp Plasmamentioning

confidence: 99%

“…These metabolites were selected based on the relationship to the pathophysiology of the disease and their high individual sensitivity. Although taurolithocholate-3-sulfate did not perform as well in diagnosis (AUC, 0.7695) it was included in the panel because of the reported relationship with liver cholestasis and patient outcome (30). The fourmetabolite model performed similarly to 1-stearoyl-GPC alone (AUC, 0.9675 vs. 0.9519) ( Table 1).…”

Section: Identification Of Sepsis Using Metabolomic Differences In Lomentioning

confidence: 99%

Integrative “Omic” Analysis of Experimental Bacteremia Identifies a Metabolic Signature That Distinguishes Human Sepsis from Systemic Inflammatory Response Syndromes

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et al. 2014

Am J Respir Crit Care Med

102

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Rationale: Sepsis is a leading cause of morbidity and mortality. Currently, early diagnosis and the progression of the disease are difficult to make. The integration of metabolomic and transcriptomic data in a primate model of sepsis may provide a novel molecular signature of clinical sepsis.Objectives: To develop a biomarker panel to characterize sepsis in primates and ascertain its relevance to early diagnosis and progression of human sepsis.Methods: Intravenous inoculation of Macaca fascicularis with Escherichia coli produced mild to severe sepsis, lung injury, and death. Plasma samples were obtained before and after 1, 3, and 5 days of E. coli challenge and at the time of killing. At necropsy, blood, lung, kidney, and spleen samples were collected. An integrative analysis of the metabolomic and transcriptomic datasets was performed to identify a panel of sepsis biomarkers. Measurements and Main Results:The extent of E. coli invasion, respiratory distress, lethargy, and mortality was dependent on the bacterial dose. Metabolomic and transcriptomic changes characterized severe infections and death, and indicated impaired mitochondrial, peroxisomal, and liver functions. Analysis of the pulmonary transcriptome and plasma metabolome suggested impaired fatty acid catabolism regulated by peroxisome-proliferator activated receptor signaling. A representative four-metabolite model effectively diagnosed sepsis in primates (area under the curve, 0.966) and in two human sepsis cohorts (area under the curve, 0.78 and 0.82).Conclusions: A model of sepsis based on reciprocal metabolomic and transcriptomic data was developed in primates and validated in two human patient cohorts. It is anticipated that the identified parameters will facilitate early diagnosis and management of sepsis.

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“…The resulting decrease in canalicular bile acid transport can lead to drug-induced cholestasis, which will generally resolve quickly after drug withdrawal (Stieger et al, 2000). Inflammation and TPN repress canalicular ABCB11 expression in rodents (Nishimura et al, 2005;Recknagel et al, 2012). This decrease, which occurs via various (post-) transcriptional mechanisms, can contribute to the development of inflammatory/septic or TPNinduced cholestasis.…”

Section: Abcb11mentioning

confidence: 99%

“…This decrease in ABCC2, which occurs via several (post-) transcriptional mechanisms, provides a molecular explanation for the conjugated hyperbilirubinemia that can be observed under inflammatory conditions (Hinoshita et al, 2001;Zollner et al, 2001;Denson et al, 2002). Septic hyperbilirubinemia, for example, is largely induced by a cytokine-mediated decrease in ABCC2 expression and is considered to be a poor prognostic sign in critically ill patients (Trauner et al, 1997;Recknagel et al, 2012). Hepatic ABCC2 also transports glutathione and bile acids.…”

Section: Abcc2mentioning

confidence: 99%

The Role of Canalicular ABC Transporters in Cholestasis

et al. 2014

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Cholestasis, a hallmark feature of hepatobiliary disease, is characterized by the retention of biliary constituents. Some of these constituents, such as bile acids, inflict damage to hepatocytes and bile duct cells. This damage may lead to inflammation, fibrosis, cirrhosis, and eventually carcinogenesis, sequelae that aggravate the underlying disease and deteriorate clinical outcome. Canalicular ATP-binding cassette (ABC) transporters, which mediate the excretion of individual bile constituents, play a key role in bile formation and cholestasis. The study of these transporters and their regulatory nuclear receptors has revolutionized our understanding of cholestatic disease. This knowledge has served as a template to develop novel treatment strategies, some of which are currently already undergoing phase III clinical trials. In this review we aim to provide an overview of the structure, function, and regulation of canalicular ABC transporters. In addition, we will focus on the role of these transporters in the pathogenesis and treatment of cholestatic bile duct and liver diseases.

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Liver Dysfunction and Phosphatidylinositol-3-Kinase Signalling in Early Sepsis: Experimental Studies in Rodent Models of Peritonitis

Abstract: Experimental studies in a rat model of fecal peritonitis conducted by Michael Bauer and colleagues show that in this model, changes in liver function occur early in the development of sepsis, with potential implications for prognosis and development of new therapeutic approaches.

Cited by 160 publications

References 55 publications

Cargo–carrier interactions significantly contribute to micellar conformation and biodistribution

Cargo–carrier interactions significantly contribute to micellar conformation and biodistribution

Integrative “Omic” Analysis of Experimental Bacteremia Identifies a Metabolic Signature That Distinguishes Human Sepsis from Systemic Inflammatory Response Syndromes

The Role of Canalicular ABC Transporters in Cholestasis

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