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      NAFLD Aggravates Septic Shock Due to Inadequate Adrenal Response and 11β-HSDs Dysregulation in Rats

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          Abstract

          Background: Non-alcoholic fatty liver disease (NAFLD) is linked with metabolic syndrome. Previous studies showed that obesity may disrupt adrenal function and adversely affect its counter-regulations against shock. This study hence evaluated adrenal function abnormalities in NAFLD with shock. Methods: Sprague-Dawley rats were fed with regular chow-diet (control) or high fat diet (HFD, 60% energy derived from fat). Blood tests were performed at the end of the 4th, 6th and 8th week, respectively. Experiments were performed at the end of the 8th week. Results: HFD rats developed NAFLD. HFD rats had 27% and 51% increase in plasma corticosterone at the 6th and 8th week in usual status. However, HFD rats had 5 times more reduction of mean arterial pressure in response to lipopolysaccharide-induced sepsis as compared to control rats. The corticosterone increment ratio was also lower in HFD rats, even after ACTH administration. 11β-HSD system tended to generate more corticosterone in HFD rats under hemodynamic stable status without shock and the trend was lost in HFD rats with septic shock. Conclusion: Rats with NAFLD had profound septic shock due to inadequate corticosterone response. This is, at least partly, due to 11β-HSDs dysregulation in sepsis.

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          Most cited references 25

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          Immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study.

          Within the last few years, increasing evidence of relative adrenal insufficiency in septic shock evoked a reassessment of hydrocortisone therapy. To evaluate the effects of hydrocortisone on the balance between proinflammatory and antiinflammation, 40 patients with septic shock were randomized in a double-blind crossover study to receive either the first 100 mg of hydrocortisone as a loading dose and 10 mg per hour until Day 3 (n = 20) or placebo (n = 20), followed by the opposite medication until Day 6. Hydrocortisone infusion induced an increase of mean arterial pressure, systemic vascular resistance, and a decline of heart rate, cardiac index, and norepinephrine requirement. A reduction of plasma nitrite/nitrate indicated inhibition of nitric oxide formation and correlated with a reduction of vasopressor support. The inflammatory response (interleukin-6 and interleukin-8), endothelial (soluble E-selectin) and neutrophil activation (expression of CD11b, CD64), and antiinflammatory response (soluble tumor necrosis factor receptors I and II and interleukin-10) were attenuated. In peripheral blood monocytes, human leukocyte antigen-DR expression was only slightly depressed, whereas in vitro phagocytosis and the monocyte-activating cytokine interleukin-12 increased. Hydrocortisone withdrawal induced hemodynamic and immunologic rebound effects. In conclusion, hydrocortisone therapy restored hemodynamic stability and differentially modulated the immunologic response to stress in a way of antiinflammation rather than immunosuppression.
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            Sinusoidal Endothelial Dysfunction Precedes Inflammation and Fibrosis in a Model of NAFLD

            Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Most morbidity associated with the metabolic syndrome is related to vascular complications, in which endothelial dysfunction is a major pathogenic factor. However, whether NAFLD is associated with endothelial dysfunction within the hepatic vasculature is unknown. The aims of this study were to explore, in a model of diet-induced overweight that expresses most features of the metabolic syndrome, whether early NAFLD is associated with liver endothelial dysfunction. Wistar Kyoto rats were fed a cafeteria diet (CafD; 65% of fat, mostly saturated) or a control diet (CD) for 1 month. CafD rats developed features of the metabolic syndrome (overweight, arterial hypertension, hypertryglyceridemia, hyperglucemia and insulin resistance) and liver steatosis without inflammation or fibrosis. CafD rats had a significantly higher in vivo hepatic vascular resistance than CD. In liver perfusion livers from CafD rats had an increased portal perfusion pressure and decreased endothelium-dependent vasodilation. This was associated with a decreased Akt-dependent eNOS phosphorylation and NOS activity. In summary, we demonstrate in a rat model of the metabolic syndrome that shows features of NAFLD, that liver endothelial dysfunction occurs before the development of fibrosis or inflammation.
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              Adrenal insufficiency in patients with cirrhosis and septic shock: Effect of treatment with hydrocortisone on survival.

              Relative adrenal insufficiency is frequent in patients with severe sepsis and is associated with hemodynamic instability, renal failure, and increased mortality. This study prospectively evaluated the effects of steroids on shock resolution and hospital survival in a series of 25 consecutive patients with cirrhosis and septic shock (group 1). Adrenal function was evaluated by the short corticotropin test within the first 24 hours of admission. Patients with adrenal insufficiency were treated with stress doses of intravenous hydrocortisone (50 mg/6 h). Data were compared to those obtained from the last 50 consecutive patients with cirrhosis and septic shock admitted to the same intensive care unit in whom adrenal function was not investigated and who did not receive treatment with steroids (group 2). Incidence of adrenal insufficiency in group 1 was 68% (17 patients). Adrenal dysfunction was frequent in patients with advanced cirrhosis (Child C: 76% vs. Child B: 25%, P = .08). Resolution of septic shock (96% vs. 58%, P = .001), survival in the intensive care unit (68% vs. 38%, P = .03), and hospital survival (64% vs. 32%, P = .003) were significantly higher in group 1. The main causes of death in group 1 were hepatorenal syndrome or liver failure (7 of 9 patients). In contrast, refractory shock caused most of the deaths in group 2 (20 of 34 patients). In conclusion, relative adrenal insufficiency is very frequent in patients with advanced cirrhosis and septic shock. Hydrocortisone administration in these patients is associated with a high frequency of shock resolution and high survival rate.
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                Author and article information

                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                28 April 2020
                May 2020
                : 12
                : 5
                Affiliations
                [1 ]Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei 100, Taiwan; hchuang2@ 123456vghtpe.gov.tw (H.-C.H.); fylee@ 123456vghtpe.gov.tw (F.-Y.L.); ccchang7@ 123456vghtpe.gov.tw (C.-C.C.); clchuang@ 123456vghtpe.gov.tw (C.-L.C.); mchou@ 123456vghtpe.gov.tw (M.-C.H.); yhhuang@ 123456vghtpe.gov.tw (Y.-H.H.)
                [2 ]Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; derickskylark@ 123456gmail.com
                [3 ]Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
                [4 ]Division of Gastroenterology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 320-338, Taiwan; mhtsai@ 123456cgmh.org.tw
                Author notes
                [* ]Correspondence: sjhsu@ 123456vghtpe.gov.tw ; Tel.: +886-2-28712121 (ext. 2014)
                [†]

                These authors contributed equally to this work.

                Article
                pharmaceutics-12-00403
                10.3390/pharmaceutics12050403
                7285211
                32354071
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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