Changes of hepatic sinusoids are crucial in the pathogenesis of liver cirrhosis and portal hypertension. Liver injury leads to distinct morphological abnormalities such as loss of sinusoidal ...fenestration, vasoconstriction, and angiogenesis as well as molecular changes. Communication between the two key cells in this hepatic microenvironment—hepatic stellate cells (HSC) and sinusoidal endothelial cells (SEC)—has been studied for many years and several canonical pathways have been elucidated, such as decreased eNOS activity or increased PDGF and TGF-β production leading to activation and migration of HSC. In recent studies, alternative pathways of intercellular communication in liver diseases have been described such as cell-derived extracellular vesicles called exosomes, which deliver cell compounds to their target cells. Moreover, such extracellular vesicles may link injury to inflammation in alcoholic hepatitis. While inflammation leading to liver fibrosis has been studied in detail, in some circumstances pathways other than the known canonical inflammatory pathways may contribute to hepatic fibrogenesis. For example, in congestive hepatopathy, sinusoidal dilatation and fibrosis have been shown to be mediated by non-inflammatory mechanisms and associated with sinusoidal thrombi. A recently developed murine model further enables experimental studies of this disease entity. Increasing knowledge about these alternative disease pathways in liver injury, inflammation, and fibrosis may reveal possible target molecules for future therapies. This article builds upon a seminar given at the recent 3rd JSGE International Topic Conference in Sendai, Japan, and reviews the areas outlined above.
Abstract Cellular crosstalk is a process through which a message is transmitted within an individual cell (intracellular crosstalk) or between different cells (intercellular crosstalk). Intercellular ...crosstalk within the liver microenvironment is critical for the maintenance of normal hepatic functions and for cells survival. Hepatic cells are closely connected to each other, work in synergy, and produce molecules that modulate their differentiation and activity. This review summarises the current knowledge regarding paracrine communication networks in parenchymal and non-parenchymal cells in liver fibrosis due to chronic injury, and regeneration after partial hepatectomy.
Autophagy plays a crucial role in hepatic homeostasis and its deregulation has been associated with chronic liver disease. However, the effect of autophagy on the release of fibrogenic extracellular ...vesicles (EVs) by platelet-derived growth factor (PDGF)-stimulated hepatic stellate cells (HSCs) remains unknown. Herein, we aimed to elucidate the role of autophagy, specifically relating to fibrogenic EV release, in fibrosis.
In vitro experiments were conducted in primary human and murine HSCs as well as LX2 cells. Small EVs were purified by differential ultracentrifugation. Carbon tetrachloride (CCl4) or bile duct ligation (BDL) were used to induce fibrosis in our mouse model. Liver lysates from patients with cirrhosis or healthy controls were compared by RNA sequencing.
In vitro, PDGF and its downstream molecule SHP2 (Src homology 2-containing protein tyrosine phosphatase 2) inhibited autophagy and increased HSC-derived EV release. We used this PDGF/SHP2 model to further investigate how autophagy affects fibrogenic EV release. RNA sequencing identified an mTOR (mammalian target of rapamycin) signaling molecule that was regulated by SHP2 and PDGF. Disruption of mTOR signaling abolished PDGF-dependent EV release. Activation of mTOR signaling induced the release of multivesicular body-derived exosomes (by inhibiting autophagy) and microvesicles (by activating ROCK1 signaling). These mTOR-dependent EVs promoted in vitro HSC migration. To assess the importance of this mechanism in vivo, SHP2 was selectively deleted in HSCs, which attenuated CCl4- or BDL-induced liver fibrosis. Furthermore, in the CCl4 model, mice receiving circulating EVs derived from mice with HSC-specific Shp2 deletion had less fibrosis than mice receiving EVs from control mice. Correspondingly, SHP2 was upregulated in patients with liver cirrhosis.
These results demonstrate that autophagy in HSCs attenuates liver fibrosis by inhibiting the release of fibrogenic EVs.
During liver fibrosis and cirrhosis, activated hepatic stellate cells (HSCs) are the key cell type responsible for fibrotic tissue deposition. Recently, we demonstrated that activated HSCs release nano-sized vesicles enriched with fibrogenic proteins. In the current study, we unveil the mechanism by which these fibrogenic vesicles are released, moving a step closer to the long-term goal of therapeutically targeting this process.
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•PDGF and SHP2 induce fibrogenic EV release by activating mTOR signaling.•mTOR signaling inhibits autophagy, leading to the release of MVB content as exosomes.•mTOR signaling activates ROCK signaling, leading to the release of microvesicles.•Blocking this mechanism inhibits the circulation of pro-fibrotic exosomes and microvesicles, and thus fibrosis in mice.
Alcoholic liver disease includes a broad clinical-histological spectrum from simple steatosis, cirrhosis, acute alcoholic hepatitis with or without cirrhosis to hepatocellular carcinoma as a ...complication of cirrhosis. The pathogenesis of alcoholic liver disease can be conceptually divided into (1) ethanol-mediated liver injury, (2) inflammatory immune response to injury, (3) intestinal permeability and microbiome changes. Corticosteroids may improve outcomes, but this is controversial and probably only impacts short-term survival. New pathophysiology-based therapies are under study, including antibiotics, caspase inhibition, interleukin-22, anakinra, FXR agonist and others. These studies provide hope for better future outcomes for this difficult disease.
Summary Among the common complication of cirrhosis portal hypertension witnessed a major improvement of prognosis during the past decades. Principally due to the introduction of rational treatments ...based on new pathophysiological paradigms (concepts of thought) developed in the 1980s. The best example being the use of non-selective beta-blockers and of vasopressin analogs, somatostatin, and its analogs. Further refinement in the knowledge of the molecular mechanisms involved in the regulation of both the splanchnic and hepatic circulation has led to the emergence of new treatments, which are based on evidence that show not only structural but also vasoactive components increase the hepatic vascular resistance, as well as of angiogenesis. This knowledge and future improvements will most likely result in more effective treatment of portal hypertension and effective prevention of its complications in early stages.
Modern medical care produces large volumes of multimodal patient data, which many clinicians struggle to process and synthesize into actionable knowledge. In recent years, artificial intelligence ...(AI) has emerged as an effective tool in this regard. The field of hepatology is no exception, with a growing number of studies published that apply AI techniques to the diagnosis and treatment of liver diseases. These have included machine‐learning algorithms (such as regression models, Bayesian networks, and support vector machines) to predict disease progression, the presence of complications, and mortality; deep‐learning algorithms to enable rapid, automated interpretation of radiologic and pathologic images; and natural‐language processing to extract clinically meaningful concepts from vast quantities of unstructured data in electronic health records. This review article will provide a comprehensive overview of hepatology‐focused AI research, discuss some of the barriers to clinical implementation and adoption, and suggest future directions for the field.
ACG Clinical Guideline: Alcoholic Liver Disease Singal, Ashwani K; Bataller, Ramon; Ahn, Joseph ...
The American journal of gastroenterology,
02/2018, Letnik:
113, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Alcoholic liver disease (ALD) comprises a clinical-histologic spectrum including fatty liver, alcoholic hepatitis (AH), and cirrhosis with its complications. Most patients are diagnosed at advanced ...stages and data on the prevalence and profile of patients with early disease are limited. Diagnosis of ALD requires documentation of chronic heavy alcohol use and exclusion of other causes of liver disease. Prolonged abstinence is the most effective strategy to prevent disease progression. AH presents with rapid onset or worsening of jaundice, and in severe cases may transition to acute on chronic liver failure when the risk for mortality, depending on the number of extra-hepatic organ failures, may be as high as 20-50% at 1 month. Corticosteroids provide short-term survival benefit in about half of treated patients with severe AH and long-term mortality is related to severity of underlying liver disease and is dependent on abstinence from alcohol. General measures in patients hospitalized with ALD include inpatient management of liver disease complications, management of alcohol withdrawal syndrome, surveillance for infections and early effective antibiotic therapy, nutritional supplementation, and treatment of the underlying alcohol-use disorder. Liver transplantation, a definitive treatment option in patients with advanced alcoholic cirrhosis, may also be considered in selected patients with AH cases, who do not respond to medical therapy. There is a clinical unmet need to develop more effective and safer therapies for patients with ALD.
Alcohol-Associated Hepatitis Bataller, Ramon; Arab, Juan Pablo; Shah, Vijay H.
The New England journal of medicine,
12/2022, Letnik:
387, Številka:
26
Journal Article
Recenzirano
The authors review the epidemiology, pathophysiology, and treatment of alcohol-associated hepatitis, including the evidence for glucocorticoids and liver transplantation.
Mechanosensing and fibrosis Tschumperlin, Daniel J; Ligresti, Giovanni; Hilscher, Moira B ...
The Journal of clinical investigation,
01/2018, Letnik:
128, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Tissue injury disrupts the mechanical homeostasis that underlies normal tissue architecture and function. The failure to resolve injury and restore homeostasis gives rise to progressive fibrosis that ...is accompanied by persistent alterations in the mechanical environment as a consequence of pathological matrix deposition and stiffening. This Review focuses on our rapidly growing understanding of the molecular mechanisms linking the altered mechanical environment in injury, repair, and fibrosis to cellular activation. In particular, our focus is on the mechanisms by which cells transduce mechanical signals, leading to transcriptional and epigenetic responses that underlie both transient and persistent alterations in cell state that contribute to fibrosis. Translation of these mechanobiological insights may enable new approaches to promote tissue repair and arrest or reverse fibrotic tissue remodeling.
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