Mecanismes involucrats en la regulació del to vascular hepàtic en la cirrosi: Paper dels prostanoids vasoconstrictors i de l'estrès oxidatiu

[spa] La hipertensión portal es la principal complicación de la cirrosis. El factor primario en el desarrollo de hipertensión portal es el incremento de la resistencia vascular intrahepática (RVI) del hígado cirrótico. El denominado componente dinámico de la RVI es derivado de una exagerada presencia de agentes vasoconstrictores intrahepáticos, junto a una hiperrespuesta a éstos, además de una disminución en la disponibilidad de vasodilatadores y una hiporespuesta a los mismos. La presente tesis doctoral se dirigió a explorar nuevos mecanismos de regulación del tono vascular intrahepático en la cirrosis así como profundizar en el conocimiento de cuales son los mediadores vasoactivos implicados.Los resultados obtenidos nos muestran que: 1- Las células endoteliales sinusoidales (CES) de hígados cirróticos son capaces de generar prostanoides vasoconstrictores (TXA2) tanto a partir de la administración de ácido araquidónico así como al estimularlas con el agonista alfa-adrenérgico metoxamina. Además, los hígados cirróticos presentan un marcado aumento de la presión portal al administrarles AA, la cual sería derivada de un incremento en la síntesis de TXA2 y PGH2. Por último, se demuestra que los hígados cirróticos presentan un incremento en la actividad de la enzima productora de AA, la fosfolipasa A2.2- El complejo enzimático NADPH oxidasa no sería responsable del elevado estrés oxidativo hepático, la disfunción endotelial ni del aumentado tono vascular intrahepático del hígado cirrótico.3- Los hígados cirróticos presentan elevados niveles de estrés oxidativo (derivado de una elevada síntesis por parte de ciclooxigenasa y xantina oxidasa, además de una reducida eliminación por superóxido dismutasa) que se acompañan de una baja disponibilidad del vasodilatador óxido nítrico y de elevados niveles de nitrotirosinación proteica (marcador de la reacción entre radical superóxido y óxido nítrico). Por último, en células endoteliales sinusoidales se demuestra por primera vez que un aumento intracelular del estrés oxidativo conlleva una marcada reducción de la disponibilidad de óxido nítrico y que el uso de terapias antioxidantes previene la reducción de la disponibilidad de este vasodilatador.En conclusión, los estudios incluidos en esta tesis doctoral muestran que las CES juegan un importante papel en la modulación del tono vascular intrahepático en la cirrosis. No solo por una reducida producción de óxido nítrico sino también por un incremento en la síntesis de prostanoides vasoconstrictores. Asimismo, que el uso de antioxidantes, al eliminar el exceso de radicales libres de oxígeno, sería una nueva estrategia terapéutica para incrementar la biodisponibilidad de óxido nítrico intrahepático y reducir el tono vascular hepático en la cirrosis

Terutroban, A TP-receptor antagonist, reduces portal pressure in cirrhotic rats

Increased production of vasoconstrictive prostanoids, such as thromboxane A2 (TXA2 ), contributes to endothelial dysfunction and increased hepatic vascular tone in cirrhosis. TXA2 induces vasoconstriction by way of activation of the thromboxane-A2 /prostaglandin-endoperoxide (TP) receptor. This study investigated whether terutroban, a specific TP receptor blocker, decreases hepatic vascular tone and portal pressure in rats with cirrhosis due to carbon tetrachloride (CCl4 ) or bile duct ligation (BDL). Hepatic and systemic hemodynamics, endothelial dysfunction, liver fibrosis, hepatic Rho-kinase activity (a marker of hepatic stellate cell contraction), and the endothelial nitric oxide synthase (eNOS) signaling pathway were measured in CCl4 and BDL cirrhotic rats treated with terutroban (30 mg/kg/day) or its vehicle for 2 weeks. Terutroban reduced portal pressure in both models without producing significant changes in portal blood flow, suggesting a reduction in hepatic vascular resistance. Terutroban did not significantly change arterial pressure in CCl4 -cirrhotic rats but decreased it significantly in BDL-cirrhotic rats. In livers from CCl4 and BDL-cirrhotic terutroban-treated rats, endothelial dysfunction was improved and Rho-kinase activity was significantly reduced. In CCl4 -cirrhotic rats, terutroban reduced liver fibrosis and decreased alpha smooth muscle actin (α-SMA), collagen-I, and transforming growth factor beta messenger RNA (mRNA) expression without significant changes in the eNOS pathway. In contrast, no change in liver fibrosis was observed in BDL-cirrhotic rats but an increase in the eNOS pathway. CONCLUSION: Our data indicate that TP-receptor blockade with terutroban decreases portal pressure in cirrhosis. This effect is due to decreased hepatic resistance, which in CCl4 -cirrhotic rats was linked to decreased hepatic fibrosis, but not in BDL rats, in which the main mediator appeared to be an enhanced eNOS-dependent vasodilatation, which was not liver-selective, as it was associated with decreased arterial pressure. The potential use of terutroban for portal hypertension requires further investigation

Extracellular vesicles in hepatology: Physiological role, involvement in pathogenesis, and therapeutic opportunities.

Since the first descriptions of hepatocyte-released exosome-like vesicles in 2008, the number of publications describing Extracellular Vesicles (EVs) released by liver cells in the context of hepatic physiology and pathology has grown exponentially. This growing interest highlights both the importance that cell-to-cell communication has in the organization of multicellular organisms from a physiological point of view, as well as the opportunity that these circulating organelles offer in diagnostics and therapeutics. In the present review, we summarize systematically and comprehensively the myriad of works that appeared in the last decade and lighted the discussion about the best opportunities for using EVs in liver disease therapeutics

Effects of warm ischemia and reperfusion on the liver microcirculatory phenotype of rats: underlying mechanisms and pharmacological therapy

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

Biomechanical forces promote embryonic haematopoiesis

Biomechanical forces are emerging as critical regulators of embryogenesis, particularly in the developing cardiovascular system. After initiation of the heartbeat in vertebrates, cells lining the ventral aspect of the dorsal aorta, the placental vessels, and the umbilical and vitelline arteries initiate expression of the transcription factor Runx1 (refs 3-5), a master regulator of haematopoiesis, and give rise to haematopoietic cells. It remains unknown whether the biomechanical forces imposed on the vascular wall at this developmental stage act as a determinant of haematopoietic potential. Here, using mouse embryonic stem cells differentiated in vitro, we show that fluid shear stress increases the expression of Runx1 in CD41(+)c-Kit(+) haematopoietic progenitor cells, concomitantly augmenting their haematopoietic colony-forming potential. Moreover, we find that shear stress increases haematopoietic colony-forming potential and expression of haematopoietic markers in the para-aortic splanchnopleura/aorta-gonads-mesonephros of mouse embryos and that abrogation of nitric oxide, a mediator of shear-stress-induced signalling, compromises haematopoietic potential in vitro and in vivo. Collectively, these data reveal a critical role for biomechanical forces in haematopoietic development

Papel actual del acetato de ulipristal en el tratamiento de los síntomas asociados a los miomas uterinos. [Current role of ulipristal acetate in the management of uterine fibroids.]

post-print221 K

Liraglutide improves liver microvascular dysfunction in cirrhosis: Evidence from translational studies

Hepatic stellate cells (HSC) play a key role in the development of chronic liver disease (CLD). Liraglutide, well-established in type 2 diabetes, showed anti-inflammatory and anti-oxidant properties. We evaluated the effects of liraglutide on HSC phenotype and hepatic microvascular function using diverse pre-clinical models of CLD. Human and rat HSC were in vitro treated with liraglutide, or vehicle, and their phenotype, viability and proliferation were evaluated. In addition, liraglutide or vehicle was administered to rats with CLD. Liver microvascular function, fibrosis, HSC phenotype and sinusoidal endothelial phenotype were determined. Additionally, the effects of liraglutide on HSC phenotype were analysed in human precision-cut liver slices. Liraglutide markedly improved HSC phenotype and diminished cell proliferation. Cirrhotic rats receiving liraglutide exhibited significantly improved liver microvascular function, as evidenced by lower portal pressure, improved intrahepatic vascular resistance, and marked ameliorations in fibrosis, HSC phenotype and endothelial function. The anti-fibrotic effects of liraglutide were confirmed in human liver tissue and, although requiring further investigation, its underlying molecular mechanisms suggested a GLP1-R-independent and NF-κB-Sox9-dependent one. This study demonstrates for the first time that liraglutide improves the liver sinusoidal milieu in pre-clinical models of cirrhosis, encouraging its clinical evaluation in the treatment of chronic liver disease

Al margen. Reflexiones en torno a la imagen

Colección de textos de investigación en torno a la imagen fija y la imagen en movimiento

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

Clustering COVID-19 ARDS patients through the first days of ICU admission. An analysis of the CIBERESUCICOVID Cohort

Background Acute respiratory distress syndrome (ARDS) can be classified into sub-phenotypes according to different inflammatory/clinical status. Prognostic enrichment was achieved by grouping patients into hypoinflammatory or hyperinflammatory sub-phenotypes, even though the time of analysis may change the classification according to treatment response or disease evolution. We aimed to evaluate when patients can be clustered in more than 1 group, and how they may change the clustering of patients using data of baseline or day 3, and the prognosis of patients according to their evolution by changing or not the cluster.Methods Multicenter, observational prospective, and retrospective study of patients admitted due to ARDS related to COVID-19 infection in Spain. Patients were grouped according to a clustering mixed-type data algorithm (k-prototypes) using continuous and categorical readily available variables at baseline and day 3.Results Of 6205 patients, 3743 (60%) were included in the study. According to silhouette analysis, patients were grouped in two clusters. At baseline, 1402 (37%) patients were included in cluster 1 and 2341(63%) in cluster 2. On day 3, 1557(42%) patients were included in cluster 1 and 2086 (57%) in cluster 2. The patients included in cluster 2 were older and more frequently hypertensive and had a higher prevalence of shock, organ dysfunction, inflammatory biomarkers, and worst respiratory indexes at both time points. The 90-day mortality was higher in cluster 2 at both clustering processes (43.8% [n = 1025] versus 27.3% [n = 383] at baseline, and 49% [n = 1023] versus 20.6% [n = 321] on day 3). Four hundred and fifty-eight (33%) patients clustered in the first group were clustered in the second group on day 3. In contrast, 638 (27%) patients clustered in the second group were clustered in the first group on day 3.Conclusions During the first days, patients can be clustered into two groups and the process of clustering patients may change as they continue to evolve. This means that despite a vast majority of patients remaining in the same cluster, a minority reaching 33% of patients analyzed may be re-categorized into different clusters based on their progress. Such changes can significantly impact their prognosis