Effects of aging on liver microcirculatory function and sinusoidal phenotype.
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ABSTRACT:
SUBMITTER: Maeso-Diaz R
PROVIDER: S-EPMC6260924 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Warm ischemia and reperfusion (WIR) causes hepatic damage and may lead to liver failure, however the mechanisms involved are largely unknown. Here we have characterized the microcirculatory status and endothelial phenotype of livers undergoing WIR, and evaluated the use of simvastatin in WIR injury prevention. Male Wistar rats received simvastatin, or vehicle, 30 min before undergoing 60 min of partial warm ischemia (70%) followed by 2 h or 24 h of reperfusion. Hepatic and systemic hemodynamics, liver injury (AST, ALT, LDH), endothelial function (vasodilatation in response to acetylcholine), KLF2 and nitric oxide pathways, oxidative stress, inflammation (neutrophil and macrophage infiltration) and cell death were evaluated. Profound microcirculatory dysfunction occurred rapidly following WIR. This was evidenced by down-regulation of the KLF2 vasoprotective pathway, impaired vasodilatory capability and endothelial activation, altogether leading to increased hepatic vascular resistance and liver inflammation, with significant leukocyte infiltration, oxidative stress and cell death. Simvastatin preserved the hepatic endothelial phenotype, and blunted the detrimental effects of WIR on liver hemodynamics and organ integrity. In conclusion, WIR-induced injury to liver sinusoidal endothelial cells is mitigated by pre-treatment with Simvastatin probably through a KLF2-dependent mechanism.
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Project description:BackgroundBased on the gut-liver axis theory, a leaky gut can aggravate liver injury. However, clinical studies suggest that although gut mucosa damage is commonly observed in inflammatory bowel disease (IBD), it seldom leads to severe liver injury. We hypothesize that there is a hepatic barrier in the gut-liver axis, which protects the liver against gut-derived invasive factors.MethodsColitis was induced by dextran sulfate sodium (DSS) in eight different liver injury models in Sprague-Dawley rats. Liver sinusoidal endothelial cell (LSEC) injury was evaluated by a scanning and transmission electron microscope. Neutrophils were depleted by injection of anti-rat polymorphonuclear serum. Two pneumonia models were also induced to investigate the mechanism of neutrophil recruitment and activation. LSECs isolated from rat liver were used to investigate the effect on neutrophil recruitment and activation.ResultsAmong eight liver injury models, DSS colitis had no effect on liver injury in three models with normal LSECs. In the other five models with LSEC rupture, liver injury was significantly exacerbated by colitis, and increased hepatic neutrophil accumulation was observed. When neutrophils were depleted, colitis-induced liver injury was significantly attenuated. In pneumonia, liver injury, and colitis models, the level of CXCL1 correlated with the recruitment of neutrophils in different tissues, while DSS colitis and LSEC injury synergistically contributed to increased CXCL1 expression in the liver. In colitis-induced liver injury, neutrophils were activated in the liver. Injured LSECs showed both structural and functional changes, with significantly increased expression of CXCL1 and TNF-α under the stimulation of lipopolysaccharide (LPS). The combination of gut-derived LPS and LSEC-derived TNF-α led to the activation of neutrophils, characterized by enhanced production of reactive oxygen species, pro-inflammatory cytokines, and the formation of neutrophil extracellular traps.ConclusionLSECs constitute a vitally important barrier in the gut-liver axis, defending the liver against colitis-induced injury. When LSECs are damaged, they can turn into a pro-inflammatory pattern under the stimulation of LPS. LSEC injury and colitis-derived LPS synergistically contribute to the recruitment and activation of hepatic neutrophils. Neutrophils play a pivotal role as a downstream effector in colitis-induced liver injury.
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Project description:Aging-associated transcriptome changes in liver sinusoidal endothelial cells. RNA was prepared from liver sinusoidal endothelial cells of the male 8 weeks and 24 months old C57BL/6J mice.RNA samples were then subjected to RNA-sequencing and gene expression profiling analysis.
2022-10-29 | GSE216592 | GEO
Project description:Microcirculatory disturbance is thought to be involved in the pathogenesis of acute liver injury (ALI). The current study examined the pathophysiologic role of hepatic microcirculatory disturbance in patients with ALI and in mouse models of ALI. Using serum aminotransferase (ALT)/lactate dehydrogenase (LDH) ratio as a hypoxic marker, 279 patients with ALI were classified into the low ALT/LDH ratio (ALT/LDH ≤1.5) and high ALT/LDH ratio group (ALT/LDH >1.5). In the low ALT/LDH ratio group, serum ALT, LDH, fibrinogen degradation products and prothrombin time-international normalized ratio were increased relative to the high ALT/LDH ratio group. Histologically, hepatic expression of tissue factor (TF) and hypoxia-related proteins was enhanced in the low ALT/LDH ratio group, and this was accompanied by sinusoidal fibrin deposition. Sinusoidal hypercoagulation and intrahepatic hypoxia was also analyzed in two different mouse models of ALI; Concanavalin A (ConA) mice and Galactosamine/tumor necrosis factor (TNF)-α (G/T) mice. Serum ALT/LDH ratio in ConA mice was significantly lower compared with G/T mice. Pimonidazole staining revealed the upregulation of hypoxia-related proteins in ConA mice. Recombinant human soluble thrombomodulin improved liver damage in ConA mice in association with reduced sinusoidal hypercoagulation and intrahepatic hypoxia. The present study provides evidence that serum ALT/LDH ratio aids in the identification of patients with ALI and intrahepatic hypoxia as a result of microcirculatory disturbance. The results facilitate the improved understanding of the pathogenesis of ALI, thereby offering a novel therapeutic strategy against ALI, which arises from sinusoidal hypercoagulation.
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Project description:Hepatic macrophages are a remarkably heterogeneous population consisting of self-renewing tissue-resident phagocytes, termed Kupffer cells (KCs), and recruited macrophages derived from peritoneal cavity as well as the bone marrow. KCs are located in the liver sinusoid where they scavenge the microbe from the portal vein to maintain liver homeostasis. Liver injury may trigger hepatic recruitment of peritoneal macrophages and monocyte-derived macrophages. Studies describing macrophage accumulation have shown that hepatic macrophages are involved in the initiation and progression of various liver diseases. They act as tolerogenic antigen-presenting cells to inhibit T-cell activation by producing distinct sets of cytokines, chemokines, and mediators to maintain or resolve inflammation. Furthermore, by releasing regenerative growth factors, matrix metalloproteinase arginase, they promote tissue repair. Recent experiments found that KCs and recruited macrophages may play different roles in the development of liver disease. Given that hepatic macrophages are considerably plastic populations, their phenotypes and functions are likely switching along disease progression. In this review, we summarize current knowledge about the role of tissue-resident macrophages and recruited macrophages in pathogenesis of alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), viral hepatitis, and hepatocellular carcinoma (HCC).
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Project description:The liver is a key metabolic organ that maintains whole-body nutrient homeostasis. Aging-induced liver function alterations contribute to systemic susceptibility to aging-related diseases. However, the molecular mechanisms of liver aging remain insufficiently understood. In this study, we performed bulk RNA-Seq and single-cell RNA-Seq analyses to investigate the underlying mechanisms of the aging-induced liver function changes. We found that liver inflammation, glucose intolerance, and liver fat deposition were aggravated in old mice. Aging significantly increased pro-inflammation in hepatic macrophages. Furthermore, we found that Kupffer cells (KCs) were the major driver to induce pro-inflammation in hepatic macrophages during aging. In KCs, aging significantly increased pro-inflammatory levels; in monocyte-derived macrophages (MDMs), aging had a limited effect on pro-inflammation but led to a functional quiescence in antigen presentation and phagosome process. In addition, we identified an aging-responsive KC-specific (ARKC) gene set that potentially mediates aging-induced pro-inflammation in KCs. Interestingly, FOXO1 activity was significantly increased in the liver of old mice. FOXO1 inhibition by AS1842856 significantly alleviated glucose intolerance, hepatic steatosis, and systemic inflammation in old mice. FOXO1 inhibition significantly attenuated aging-induced pro-inflammation in KCs partially through downregulation of ARKC genes. However, FOXO1 inhibition had a limited effect on aging-induced functional quiescence in MDMs. These results indicate that aging induces pro-inflammation in liver mainly through targeting KCs and FOXO1 is a key player in aging-induced pro-inflammation in KCs. Thus, FOXO1 could be a potential therapeutic target for the treatment of age-associated chronic diseases.
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Project description:Hepatic immune function is compromised during cirrhosis. This study investigated the immune features of liver sinusoidal endothelial cells (LSECs) in two experimental models of cirrhosis. Dendritic cells, hepatic macrophages, and LSECs were isolated from carbon tetrachloride and bile duct-ligated rats. Gene expression of innate receptors, bacterial internalization, co-stimulatory molecules induction, and CD4+ T cell activation and differentiation were evaluated. Induced bacterial peritonitis and norfloxacin protocols on cirrhotic rats were also carried out. LSECs demonstrated an active immunosurveillance profile, as shown by transcriptional modulation of different scavenger and cell-adhesion genes, and their contribution to bacterial internalization. LSECs significantly increased their expression of CD40 and CD80 and stimulated CD4+ T cell activation marker CD71 in both models. The pro-inflammatory Th17 subset was expanded in CCl4-derived LSECs co-cultures. In the bile duct ligation (BDL) model, CD4+ T cell differentiation only occurred under induced bacterial peritonitis conditions. Differentiated pro-inflammatory Th cells by LSECs in both experimental models were significantly reduced with norfloxacin treatment, whereas Foxp3 tolerogenic Th CD4+ cells were expanded. Conclusion: LSECs' participation in the innate-adaptive immune progression, their ability to stimulate pro-inflammatory CD4+ T cells expansion during liver damage, and their target role in norfloxacin-induced immunomodulation granted a specific competence to this cell population in cirrhosis.
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Project description:Healthy liver sinusoidal endothelial cells (LSECs) maintain liver homeostasis, while LSEC dysfunction was suggested to coincide with defenestration. Here, we have revisited the relationship between LSEC pro-inflammatory response, defenestration, and impairment of LSEC bioenergetics in non-alcoholic fatty liver disease (NAFLD) in mice. We characterized inflammatory response, morphology as well as bioenergetics of LSECs in early and late phases of high fat diet (HFD)-induced NAFLD. LSEC phenotype was evaluated at early (2-8 week) and late (15-20 week) stages of NAFLD progression induced by HFD in male C57Bl/6 mice. NAFLD progression was monitored by insulin resistance, liver steatosis and obesity. LSEC phenotype was determined in isolated, primary LSECs by immunocytochemistry, mRNA gene expression (qRT-PCR), secreted prostanoids (LC/MS/MS) and bioenergetics (Seahorse FX Analyzer). LSEC morphology was examined using SEM and AFM techniques. Early phase of NAFLD, characterized by significant liver steatosis and prominent insulin resistance, was related with LSEC pro-inflammatory phenotype as evidenced by elevated ICAM-1, E-selectin and PECAM-1 expression. Transiently impaired mitochondrial phosphorylation in LSECs was compensated by increased glycolysis. Late stage of NAFLD was featured by prominent activation of pro-inflammatory LSEC phenotype (ICAM-1, E-selectin, PECAM-1 expression, increased COX-2, IL-6, and NOX-2 mRNA expression), activation of pro-inflammatory prostaglandins release (PGE2 and PGF2?) and preserved LSEC bioenergetics. Neither in the early nor in the late phase of NAFLD, were LSEC fenestrae compromised. In the early and late phases of NAFLD, despite metabolic and pro-inflammatory burden linked to HFD, LSEC fenestrae and bioenergetics are functionally preserved. These results suggest prominent adaptive capacity of LSECs that might mitigate NAFLD progression.
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Project description:Vascular remodelling during liver damage involves loss of healthy liver sinusoidal endothelial cell (LSEC) phenotype via capillarisation. Hedgehog (Hh) signalling regulates vascular development and increases during liver injury. This study therefore examined its role in capillarisation.Primary LSEC were cultured for 5 days to induce capillarisation. Pharmacological, antibody-mediated and genetic approaches were used to manipulate Hh signalling. Effects on mRNA and protein expression of Hh-regulated genes and capillarisation markers were evaluated by quantitative reverse transcription PCR and immunoblot. Changes in LSEC function were assessed by migration and tube forming assay, and gain/loss of fenestrae was examined by electron microscopy. Mice with acute or chronic liver injury were treated with Hh inhibitors; effects on capillarisation were assessed by immunohistochemistry.Freshly isolated LSEC expressed Hh ligands, Hh receptors and Hh ligand antagonist Hhip. Capillarisation was accompanied by repression of Hhip and increased expression of Hh-regulated genes. Treatment with Hh agonist further induced expression of Hh ligands and Hh-regulated genes, and upregulated capillarisation-associated genes; whereas Hh signalling antagonist or Hh ligand neutralising antibody each repressed expression of Hh target genes and capillarisation markers. LSEC isolated from Smo(loxP/loxP) transgenic mice that had been infected with adenovirus expressing Cre-recombinase to delete Smoothened showed over 75% knockdown of Smoothened. During culture, Smoothened-deficient LSEC had inhibited Hh signalling, less induction of capillarisation-associated genes and retention of fenestrae. In mice with injured livers, inhibiting Hh signalling prevented capillarisation.LSEC produce and respond to Hh ligands, and use Hh signalling to regulate complex phenotypic changes that occur during capillarisation.
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