Splanchnic blood flow is greater in septic shock treated with norepinephrine than in severe sepsis
sepsis; hypoxia; transport; General & Internal Medicine; metabolism; dopamine; septic shock; norepinephrine; failure; gut; oxygen consumption; endotoxemia; splanchnic oxygen delivery; splanchnic oxygen consumption; critically ill; extraction; splanchnic blood flow
Objective: To assess global and splanchnic blood flow and oxygen transport in patients with sepsis with and without norepinephrine treatment. Design: Prospective, clinical study. Setting: University hospital intensive care unit. Patients: A convenience sample of 15 septic shock patients treated with norepinephrine and 13 patients with severe sepsis who did not receive norepinephrine. Measurements and main results: There were no differences between the two groups in global haemodynamics and oxygen transport. Splanchnic blood flow and oxygen delivery (splanchnic DO2 303 +/- 43 ml/min per m(2)) and consumption (splanchnic VO2 100 +/- 13 ml/min per m(2)) were much higher in the septic shock group compared with the severe sepsis group (splanchnic DO2 175 +/- 19 ml/min per m(2), splanchnic VO2 61 +/- 6 ml/min per m(2)). Gastric mucosal pH was subnormal in both groups (septic shock 7.29 +/- 0.02, severe sepsis 7.25 +/- 0.02) with no significant difference. No significant differences between groups were detected in lactate values. Conclusion: These data confirm a redistribution of blood flow to the splanchnic region in sepsis that is even more pronounced in patients with septic shock requiring norepinephrine. However, subnormal gastric mucosal pH suggested inadequate oxygenation in parts of the splanchnic region due to factors other than splanchnic hypoperfusion. Progress in this area will depend on techniques that address not only total splanchnic blood flow, but also inter-organ flow distribution, intra-organ distribution, and other microcirculatory or metabolic malfunctions.
MeierHellmann A; Specht M; Hannemann L; Hassel H; Bredle D L; Reinhart K
Intensive Care Medicine
1996
1996-12
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1007/s001340050264" target="_blank" rel="noreferrer noopener">10.1007/s001340050264</a>
MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the
*CYTOKINES; *ETHANOL; *FATTY LIVER; *INFLAMMATION; *LEUKOCYTES; Adult; Alanine Transaminase/blood; Alcoholic/genetics/*metabolism/pathology; Alcoholism/*blood/complications; Animals; Aspartate Aminotransferases/blood; Bilirubin/blood; Binge Drinking/*blood/complications; Case-Control Studies; Central Nervous System Depressants/administration & dosage; Down-Regulation; Ethanol/administration & dosage; Female; Humans; Inbred C57BL; Interleukin-6/genetics/metabolism; Liver Diseases; Male; Mice; MicroRNAs/*blood/*genetics; Middle Aged; NADPH Oxidases/genetics/metabolism; Neutrophils/*metabolism; Reactive Oxygen Species/metabolism; Up-Regulation; Young Adult
OBJECTIVES: Chronic-plus-binge ethanol feeding activates neutrophils and exacerbates liver injury in mice. This study investigates how recent excessive drinking affects peripheral neutrophils and liver injury in alcoholics, and how miR-223, one of the most abundant microRNAs (miRNAs) in neutrophils, modulates neutrophil function and liver injury in ethanol-fed mice. DESIGNS: Three hundred alcoholics with (n=140) or without (n=160) recent excessive drinking and 45 healthy controls were enrolled. Mice were fed an ethanol diet for 10 days followed by a single binge of ethanol. RESULTS: Compared with healthy controls or alcoholics without recent drinking, alcoholics with recent excessive drinking had higher levels of circulating neutrophils, which correlated with serum levels of alanine transaminase (ALT) and aspartate transaminase (AST). miRNA array analysis revealed that alcoholics had elevated serum miR-223 levels compared with healthy controls. In chronic-plus-binge ethanol feeding mouse model, the levels of miR-223 were increased in both serum and neutrophils. Genetic deletion of the miR-223 gene exacerbated ethanol-induced hepatic injury, neutrophil infiltration, reactive oxygen species (ROS) and upregulated hepatic expression of interleukin (IL)-6 and phagocytic oxidase (phox) p47(phox). Mechanistic studies revealed that miR-223 directly inhibited IL-6 expression and subsequently inhibited p47(phox) expression in neutrophils. Deletion of the p47(phox) gene ameliorated ethanol-induced liver injury and ROS production by neutrophils. Finally, miR-223 expression was downregulated, while IL-6 and p47(phox) expression were upregulated in peripheral blood neutrophils from alcoholics compared with healthy controls. CONCLUSIONS: miR-223 is an important regulator to block neutrophil infiltration in alcoholic liver disease and could be a novel therapeutic target for the treatment of this malady.
Li Man; He Yong; Zhou Zhou; Ramirez Teresa; Gao Yueqiu; Gao Yanhang; Ross Ruth A; Cao Haixia; Cai Yan; Xu Ming-Jiang; Feng Dechun; Zhang Ping; Liangpunsakul Suthat; Gao Bin
Gut
2017
2017-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1136/gutjnl-2016-311861" target="_blank" rel="noreferrer noopener">10.1136/gutjnl-2016-311861</a>
Estrogen-related receptor gamma controls hepatic CB1 receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol.
Alcohol-Induced Injury; Alcoholic Liver Disease; Alcoholic/genetics/*metabolism/prevention & control; Animals; Cannabinoid; CB1/*physiology; Cytochrome P-450 CYP2E1 Inhibitors; Cytochrome P-450 CYP2E1/genetics/*metabolism; Enzyme Inhibitors/pharmacology/therapeutic use; Enzymologic/drug effects/physiology; Estrogen/deficiency/genetics/*physiology; Ethanol/pharmacology; Gene Expression Profiling/methods; Gene Expression Regulation; Gene Regulation; Genetic/physiology; Inbred C57BL; Knockout; Liver; Liver Diseases; Liver Metabolism; Liver/metabolism; Male; Mice; Oxidation-Reduction; Oxidative Stress/physiology; Receptor; Receptors; Signal Transduction/drug effects/physiology; Tamoxifen/analogs & derivatives/pharmacology/therapeutic use; Transcription
BACKGROUND: The hepatic endocannabinoid system and cytochrome P450 2E1 (CYP2E1), a key enzyme causing alcohol-induced reactive oxygen species (ROS) generation, are major contributors to the pathogenesis of alcoholic liver disease. The nuclear hormone receptor oestrogen-related receptor gamma (ERRgamma) is a constitutively active transcriptional activator regulating gene expression. OBJECTIVE: To investigate the role of ERRgamma in the alcohol-mediated regulation of CYP2E1 and to examine the possibility to control alcohol-mediated oxidative stress and liver injury through an ERRgamma inverse agonist. DESIGN: For chronic alcoholic hepatosteatosis study, C57BL/6J wild-type and CB1(-/-) mice were administered alcohol for 4 weeks. GSK5182 and chlormethiazole (CMZ) were given by oral gavage for the last 2 weeks of alcohol feeding. Gene expression profiles and biochemical assays were performed using the liver or blood of mice. RESULTS: Hepatic ERRgamma gene expression induced by alcohol-mediated activation of CB1 receptor results in induction of CYP2E1, while liver-specific ablation of ERRgamma gene expression blocks alcohol-induced expression of CYP2E1 in mouse liver. An ERRgamma inverse agonist significantly ameliorates chronic alcohol-induced liver injury in mice through inhibition of CYP2E1-mediated generation of ROS, while inhibition of CYP2E1 by CMZ abrogates the beneficial effects of the inverse agonist. Finally, chronic alcohol-mediated ERRgamma and CYP2E1 gene expression, ROS generation and liver injury in normal mice were nearly abolished in CB1(-/-) mice. CONCLUSIONS: ERRgamma, as a previously unrecognised transcriptional regulator of hepatic CB1 receptor, controls alcohol-induced oxidative stress and liver injury through CYP2E1 induction, and its inverse agonist could ameliorate oxidative liver injury due to chronic alcohol exposure.
Kim Don-Kyu; Kim Yong-Hoon; Jang Hyun-Hee; Park Jinyoung; Kim Jung Ran; Koh Minseob; Jeong Won-Il; Koo Seung-Hoi; Park Tae-Sik; Yun Chul-Ho; Park Seung Bum; Chiang John Y L; Lee Chul-Ho; Choi Hueng-Sik
Gut
2013
2013-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1136/gutjnl-2012-303347" target="_blank" rel="noreferrer noopener">10.1136/gutjnl-2012-303347</a>