Identification of the suprachiasmatic nucleus venous portal system in the mammalian brain.

There is only one known portal system in the mammalian brain - that of the pituitary gland, first identified in 1933 by Popa and Fielding. Here we describe a second portal pathway in the mouse linking the capillary vessels of the brain's clock suprachiasmatic nucleus (SCN) to those of the organum vasculosum of the lamina terminalis (OVLT), a circumventricular organ. The localized blood vessels of portal pathways enable small amounts of important secretions to reach their specialized targets in high concentrations without dilution in the general circulatory system. These brain clock portal vessels point to an entirely new route and targets for secreted SCN signals, and potentially restructures our understanding of brain communication pathways.

Application of CT-based radiomics in predicting portal pressure and patient outcome in portal hypertension.

PURPOSE: Portal venous pressure (PVP) measurement is of clinical significance, especially in patients with portal hypertension. However, the invasive nature and associated complications limits its application. The aim of the study is to propose a noninvasive predictive model of PVP values based on CT-extracted radiomic features. METHODS: Radiomics PVP (rPVP) models based on liver, spleen and combined features were established on an experimental cohort of 169 subjects. Radiomics features were extracted from each ROI and reduced via the LASSO regression to achieve an optimal predictive formula. A validation cohort of 62 patients treated for gastroesophageal varices (GOV) was used to confirm the utility of rPVP in predicting variceal recurrence. The association between rPVP and response to treatment was observed. RESULTS: Three separate predictive formula for PVP were derived from radiomics features. rPVP was significantly correlated to patient response to endoscopic treatment for GOV. Among which, the model containing both liver and spleen features has the highest predictability of variceal recurrence, with an optimal cut-off value at 29.102 mmHg (AUC 0.866). A Kaplan Meier analysis further confirmed the difference between patients with varying rPVP values. CONCLUSION: PVP values can be accurately predicted by a non-invasive, CT derived radiomics model. rPVP serves as a non-invasive and precise reference for predicting treatment outcome for GOV secondary to portal hypertension.

Blood flow of the venous system during resuscitative endovascular balloon occlusion of the aorta: Noninvasive evaluation using phase contrast magnetic resonance imaging.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a viable resuscitation approach for a subdiaphragmatic injury that can regulate arterial blood flow. On the other hand, the evaluation of venous or portal venous blood flow during REBOA remains insufficient because invasive cannulation or exposure of the vessel may affect the blood flow, and Doppler echography is highly operator-dependent. However, phase contrast magnetic resonance imaging has enabled accurate evaluation and noninvasive measurement. This study aimed to investigate the change of venous and portal venous blood flow during REBOA in a porcine model. METHODS: Seven pigs were anesthetized, and a REBOA catheter was placed. The blood flows of the inferior vena cava (IVC), hepatic vein (HV), portal vein (PV), and superior vena cava (SVC) were measured using phase contrast magnetic resonance imaging, in both the balloon deflated (no-REBOA) and fully balloon inflated (REBOA) states. Mean arterial pressure (MAP), central venous pressure, cardiac index, and systemic vascular resistance index were measured. RESULTS: The blood flows of the suprahepatic, infrahepatic, and distal IVC, HV, and PV in the no-REBOA state were 1.40 ± 0.36 L·min, 0.94 ± 0.16 L·min, 0.50 ± 0.19 L·min, 0.060 ± 0.018 L·min, and 0.32 ± 0.091 L·min, respectively. The blood flow of each section in the REBOA condition was significantly decreased at 0.41 ± 0.078 (33% of baseline), 0.15 ± 0.13 (15%), 0.043 ± 0.034 (9%), 0.029 ± 0.017 (37%), and 0.070 ± 0.034 L·min (21%), respectively. The blood flow of the SVC increased significantly in the REBOA condition (1.4 ± 0.63 L·min vs. 0.53 ± 0.14 L·min [257%]). Mean arterial pressure, central venous pressure, cardiac index, and systemic vascular resistance index were significantly increased after REBOA inflation. CONCLUSION: Resuscitative endovascular balloon occlusion of the aorta decreased blood flows of the IVC, HV, and PV and increased blood flow of the SVC. This result could be explained by the collateral flow from the lower body to the SVC. A better understanding of the effect of REBOA on the venous and portal venous systems may help control liver injury.

Roles of the Hepatic Endocannabinoid and Apelin Systems in the Pathogenesis of Liver Fibrosis.

Hepatic fibrosis is the consequence of an unresolved wound healing process in response to chronic liver injury and involves multiple cell types and molecular mechanisms. The hepatic endocannabinoid and apelin systems are two signalling pathways with a substantial role in the liver fibrosis pathophysiology-both are upregulated in patients with advanced liver disease. Endogenous cannabinoids are lipid-signalling molecules derived from arachidonic acid involved in the pathogenesis of cardiovascular dysfunction, portal hypertension, liver fibrosis, and other processes associated with hepatic disease through their interactions with the CB1 and CB2 receptors. Apelin is a peptide that participates in cardiovascular and renal functions, inflammation, angiogenesis, and hepatic fibrosis through its interaction with the APJ receptor. The endocannabinoid and apelin systems are two of the multiple cell-signalling pathways involved in the transformation of quiescent hepatic stellate cells into myofibroblast like cells, the main matrix-producing cells in liver fibrosis. The mechanisms underlying the control of hepatic stellate cell activity are coincident despite the marked dissimilarities between the endocannabinoid and apelin signalling pathways. This review discusses the current understanding of the molecular and cellular mechanisms by which the hepatic endocannabinoid and apelin systems play a significant role in the pathophysiology of liver fibrosis.

Portal milieu and the interplay of multiple antidiabetic effects after gastric bypass surgery.

Diabetes is a worldwide health problem. Roux-en-Y gastric bypass (RYGB) leads to rapid resolution of type 2 diabetes (T2D). Decreased hepatic insulin resistance is key, but underlying mechanisms are poorly understood. We hypothesized that changes in intestinal function and subsequent changes in portal venous milieu drive some of these postoperative benefits. We therefore aimed to evaluate postoperative changes in portal milieu. Two rat strains, healthy [Sprague-Dawley (SD)] and obese diabetic [Zucker diabetic fatty (ZDF)] rats, underwent RYGB or control surgery. After 4 wk, portal and systemic blood was sampled before and during an intestinal glucose bolus to investigate changes in intestinal glucose absorption (Gabsorp) and utilization (Gutil), and intestinal secretion of incretins and glucagon-like peptide-2 (GLP-2). Hepatic activity of dipeptidyl peptidase-4 (DPP4), which degrades incretins, was also measured. RYGB decreased Gabsorp in both rat strains. Gutil increased in SD rats and decreased in ZDF rats. In both strains, there was increased expression of intestinal hexokinase and gluconeogenesis enzymes. Systemic incretin and GLP-2 levels also increased after RYGB. This occurred without an increase in secretion. Hepatic DPP4 activity and expression were unchanged. RYGB perturbs multiple intestinal pathways, leading to decreased intestinal glucose absorption and increased incretin levels in both healthy and diabetic animals. In diabetic rats, intestinal glucose balance shifts toward glucose release. The portal vein as the gut-liver axis may integrate these intestinal changes to contribute to rapid changes in hepatic glucose and hormone handling. This fresh insight into the surgical physiology of RYGB raises the hope of less invasive alternatives. NEW & NOTEWORTHY Portal milieu after gastric bypass surgery is an underinvestigated area. Roux-en-Y gastric bypass perturbs multiple intestinal pathways, reducing intestinal glucose absorption and increasing incretin levels. In diabetic rats, the intestine becomes a net releaser of glucose, increasing portal glucose levels. The portal vein as the gut-liver axis may integrate these intestinal changes to contribute to changes in hepatic glucose handling. This fresh insight raises the hope of less invasive alternatives.

ß-Blockers Improve Presinusoidal Portal Hypertension.

BACKGROUND: Presinusoidal portal hypertension is a clinically important cause of gastric and gastroesophageal varices. Whereas ß-blockers have an established prophylactic role against bleeding from esophageal and gastric varices in portal hypertension due to cirrhosis, the effect on presinusoidal portal hypertension is unknown. AIMS: To evaluate the hemodynamic effect of ß-blockers in non-cirrhotic patients with presinusoidal portal hypertension. METHODS: We measured the blood pressure gradient from spleen pulp to free hepatic vein in 12 patients with presinusoidal portal hypertension by combined hepatic vein catheterization and spleen pulp puncture while on and off ß-blocker treatment (random sequence). RESULTS: The ß-blockers reduced the gradient from a mean off-treatment value of 32 mm Hg to a on-treatment value of 26 mm Hg (P < 0.05) with a reduction of at least 20% in five patients (42%). CONCLUSIONS: ß-blocker treatment caused a clinically significant reduction in the pressure gradient from spleen pulp to the free hepatic vein. This finding supports the recommendation for prophylactic ß-blockage in patients with presinusoidal portal hypertension.

Effect of mono- and diglycerides on the digestion and absorption of lutein in lymph fistula rats.

Breast milk lutein is better absorbed by infants than lutein delivered in infant formula. Therefore, we wanted to better understand the possible absorption differences of lutein in breast milk vs. that in infant formula by determining its bioavailability after gastric administration and whether the intestinal absorption of lutein can be improved by using new delivery vehicles. Study 1 compared the intestinal uptake,and the lymphatic and portal transport of lutein in conscious lymph fistula rats. Four groups of lymph- and portal vein-cannulated rats ( n = 8-10/group) were randomized to receive via gastric tube increasing doses (10, 20, 40, or 80 mg/kg) of 20% lutein in safflower oil (SO) suspension to assess whether there was a saturable level of lutein that could be absorbed and transported in lymph. Aliquots of hourly portal blood and lymph were taken for lutein and zeaxanthin analyses. The dose-response study showed that 20 mg/kg lutein was the saturable level of lymphatic lutein absorption with no lutein detected in portal circulation at any dosage level tested. Study 2 randomized five groups of lymph fistula rats ( n = 4-9/group) to receive 20 mg/kg lutein from either lutein in SO or lutein in four different mono- and diglyceride oils (MDGs). Gastric infusion of lutein suspended in MDG (20 mg/kg) significantly improved (71-211%, P < 0.05) lymphatic lutein output 2-6 h after lipid feeding vs. lutein in SO. Lymphatic zeaxanthin (10% of the lutein fed mixture) transport in both Study 1 and Study 2 followed that of lutein. We conclude that a mixture of MDGs helps solubilize lutein and facilitate gastrointestinal micelle formation, thus improving lymphatic lutein absorption compared with triglyceride oils. NEW & NOTEWORTHY This paper describes how lutein is digested and absorbed by the gastrointestinal tract by using the conscious lymph fistula rat model. Our dose-response study showed that absorption and lymphatic transport of lutein is a saturable process with no lutein detected in portal circulation at any dosage level tested. Our paper also provides insight into how this process can be improved by modifying the typical lipid mixtures carrying the lutein.

Portal-drained viscera heat production in Iberian pigs fed betaine- and conjugated linoleic acid-supplemented diets.

BACKGROUND: Betaine and conjugated linoleic acid (CLA) may alter growth and body composition in pigs, although their mode of action is not well understood. Portal-drained viscera (PDV) have a disproportionate influence with respect to their masses, and this may affect the productivity of more profitable tissues. The objective of this study was to determine if the use of betaine and/or CLA in the diet affects PDV heat production. RESULTS: Postprandial portal blood flow (PBF) was greater (19.0%, P = 0.004) for control compared with the other three diets. The lowest (P < 0.001) value for postprandial PDV O2 consumption corresponded to betaine + CLA followed by betaine and CLA diets (32.7, 25.4 and 17.7% respectively with respect to control diet). Postprandial PDV heat production was greater (26.4%, P < 0.001) for control with respect to the other three diets, with the minimum value corresponding to betaine + CLA (34.1% lower than control). CONCLUSION: Supplementation with betaine and/or CLA reduced the PBF, O2 consumption and therefore PDV heat production with respect to control diet. This effect was more pronounced when betaine and CLA were supplemented together, potentially increasing the energy availability for other body tissues. © 2016 Society of Chemical Industry.

Validação das diretrizes gerais de comunicação do enfermeiro com o cego / Validation of the general guidelines of communication between the nurse and the blind / Validación de las directrices generales de la comunicación entre la enfermera y el ciego

Objetivou-se validar as diretrizes gerais da comunicação do enfermeiro com o cego. Estudo quantitativo, realizado entre abril de 2008 e março de 2009 em Fortaleza-CE. Participaram 30 enfermeiros e 30 cegos divididos em grupo controle e experimental. Realizaram-se 30 consultas de enfermagem filmadas e analisadas por especialistas. O grupo experimental apresentou desempenho bom e excelente em todas as diretrizes para a comunicação verbal e não verbal com o cego, contrariamente ao grupo controle. Os resultados do estudo apontam para a urgência da adoção do ensino destas diretrizes gerais de comunicação com cegos nos cursos de enfermagem, além de capacitar enfermeiros no cuidado a pessoas cegas.

This quantitative study, conducted between 2008 April and 2009 March in Fortaleza-CE, Brazil, aimed to validate the general guidelines of the communication of the nurse with the blind. Thirty nurses and 30 blinds, divided into control and experimental groups, participated in the study. Thirty nursing consultations were videotaped and analyzed by experts. In contrast to the control group, the experimental group showed good and excellent performance in all guidelines for verbal and non-verbal communication with the blinds. The study results point to the urgency of adopting the teaching of these general guidelines for communicating with the blind in nursing courses, in addition to training nurses in caring for the blind people.

Estudio cuantitativo, realizado entre abril de 2008 y marzo de 2009, en Fortaleza-CE, Brasil, que tuvo como objetivo validar los lineamientos generales de la comunicación del enfermero con los ciegos. Los participantes fueron 30 enfermeros y 30 ciegos, divididos en grupos control y experimental. Fueran realizadas 30 consultas de enfermería, registradas y analizadas por expertos. El grupo experimental mostró un buen y excelente rendimiento en todas las directrices para comunicación verbal y no verbal con los ciegos, en contraste con el grupo de control. Los resultados del estudio apuntan a la urgencia de la adopción de la enseñanza de estas directrices generales para la comunicación con los ciegos en los cursos de enfermería, además de la formación de enfermeras en el cuidado de las personas ciegas.

The portal fibroblast: not just a poor man's stellate cell.

Portal fibroblasts, the resident fibroblasts of the portal tract, are found in the mesenchyme surrounding the bile ducts. Their roles in liver homeostasis and response to injury are undefined and controversial. Although portal fibroblasts almost certainly give rise to myofibroblasts during the development of biliary fibrosis, recent lineage tracing studies suggest that their contribution to fibrogenesis is limited compared with that of hepatic stellate cells. Other functions of portal fibroblasts include participation in the peribiliary stem cell niche, regulation of cholangiocyte proliferation, and deposition of specific matrix proteins. Portal fibroblasts synthesize elastin and other components of microfibrils; these may serve structural roles, providing stability to ducts and the vasculature under conditions of increased ductal pressure, or could regulate the bioavailability of the fibrogenic transforming growth factor ß in response to injury. Viewing portal fibroblasts in the context of fibroblast populations throughout the body and studying their niche-specific roles in matrix deposition and epithelial regulation could yield new insights into their contributions in the normal and injured liver. Understanding the functions of portal fibroblasts will require us to view them as more than just an alternative to hepatic stellate cells in fibrosis.

Are intact peptides absorbed from the healthy gut in the adult human?

For over 100 years it was believed that dietary protein must be completely hydrolysed before its constituent amino acids could be absorbed via specific amino acid transport systems. It is now known that the uptake of di- and tripeptides into the enterocyte is considerable, being transported across the intestinal endothelium by the PepT1 H+/peptide co-transporter. There is also evidence that some di- and tripeptides may survive cytosolic hydrolysis and be transported intact across the basolateral membrane. However, other than antigen sampling, the transport of larger intact macromolecules across the intestinal endothelium of the healthy adult human remains a controversial issue as there is little unequivocal in vivo evidence to support this postulation. The aim of the present review was to critically evaluate the scientific evidence that peptides/proteins are absorbed by healthy intestinal epithelia and pass intact into the hepatic portal system. The question of the absorption of oliogopeptides is paramount to the emerging science of food-derived bioactive peptides, their mode of action and physiological effects. Overall, we conclude that there is little unequivocal evidence that dietary bioactive peptides, other than di- and tripeptides, can cross the gut wall intact and enter the hepatic portal system in physiologically relevant concentrations.

Portal glucose influences the sensory, cortical and reward systems in rats.

The detection of glucose in the hepatoportal area is a simple but crucial peripheral cue initiating a nervous signal that ultimately leads to a wide array of metabolic and behavioural responses, such as decreased food intake, tighter control of glucose homeostasis, or appearance of food preference. This signal has been suggested to mediate the effects of high-protein diets, as opposed to high-fat/high-sucrose diets. Nevertheless, the central targets of the signal originating from the hepatoportal area remain largely undocumented. Using immunohistochemistry on the brain of male rats, we show here that portal glucose increases c-Fos expression in the brainstem, in the hypothalamus (in particular in neurons expressing pro-opiomelanocortin) and also in olfactory and other limbic and cortical areas, including those functionally implicated in reward (Experiment 1). In similar postabsorptive conditions, a high-protein diet induced similar effects in the hypothalamus and the granular cells of the main olfactory bulb, whereas the high-fat/high-sucrose diet actually reduced the basal expression of c-Fos in cortical layers. Both diets also decreased the number of neurons expressing c-Fos in the amygdala and gustatory areas (Experiment 2). Altogether, these findings suggest that the peripheral signal primed by portal glucose sensing may influence behavioural adaptation such as food preference via a network including the olfactory pathway, central amygdala, nucleus accumbens and orbitofrontal cortex, in addition to satiety and metabolic effects primarily implicating the hypothalamic response.

[The mechanisms of adaptation of the vascular bed to hemodynamic changes in portal hypertension].

The data of the literature on the mechanisms of restructuring of vascular bed in response to hemodynamic changes due to portal hypertension. Despite the fact that these changes are compensatory-adaptive reaction to the deteriorating conditions of blood circulation, they contribute to its progression, promoting the development of serious complications, one of which was bleeding from esophageal varices.

Laser captured hepatocytes show association of butyrylcholinesterase gene loss and fibrosis progression in hepatitis C-infected drug users.

UNLABELLED: Chronic hepatitis C virus (HCV) infection is complicated by hepatic fibrosis. Hypothesizing that early fibrogenic signals may originate in cells susceptible to HCV infection, hepatocyte gene expression was analyzed from persons with chronic HCV at different stages of liver fibrosis. Four HCV-infected subjects with precirrhosis liver fibrosis (Ishak fibrosis 3-5) were matched for age, race, and gender to five HCV-infected subjects with no evidence of fibrosis (Ishak fibrosis 0). Hepatocytes from each subject were isolated from liver biopsies using laser capture microdissection. Transcriptome profiling was performed on hepatocyte RNA using hybridization arrays. We found that hepatocytes in precirrhosis fibrosis were depleted for genes involved in small molecule and drug metabolism, especially butyrylcholinesterase (BCHE), a gene involved in the metabolism of drugs of abuse. Differential expression of BCHE was validated in the same tissues and cross-sectionally in an expanded cohort of 143 HCV-infected individuals. In a longitudinal study, serum BCHE activity was already decreased at study inception in 19 fibrosis progressors compared with 20 fibrosis nonprogressors (P < 0.05). Nonprogressors also had decreased BCHE activity over time compared with initial values, but these evolved a median (range) 8.6 (7.8-11.4) years after the study period inception (P < 0.05). Laser captured portal tracts were enriched for immune related genes when compared with hepatocytes but precirrhosis livers lost this enrichment. CONCLUSION: Chronic HCV is associated with hepatocyte BCHE loss years before hepatic synthetic function is impaired. These results indicate that BCHE may be involved in the pathogenesis of HCV-related fibrosis among injection drug users.

Simulation of differential drug pharmacokinetics under heat and exercise stress using a physiologically based pharmacokinetic modeling approach.

Under extreme conditions of heat exposure and exercise stress, the human body undergoes major physiological changes. Perturbations in organ blood flows, gastrointestinal properties, and vascular physiology may impact the body's ability to absorb, distribute, and eliminate drugs. Clinical studies on the effect of these stressors on drug pharmacokinetics demonstrate that the likelihood of pharmacokinetic alteration is dependent on drug properties and the intensity of the stressor. The objectives of this study were to use literature data to quantify the correlation between exercise and heat exposure intensity to changing physiological parameters and further, to use this information for the parameterization of a whole-body, physiologically based pharmacokinetic model for the purposes of determining those drug properties most likely to demonstrate altered drug pharmacokinetics under stress. Cardiac output and most organ blood flows were correlated with heart rate using regression analysis. Other altered parameters included hematocrit and intravascular albumin concentration. Pharmacokinetic simulations of intravenous and oral administration of hypothetical drugs with either a low or high value of lipophilicity, unbound fraction in plasma, and unbound intrinsic hepatic clearance demonstrated that the area under the curve of those drugs with a high unbound intrinsic clearance was most affected (up to a 130% increase) following intravenous administration, whereas following oral administration, pharmacokinetic changes were smaller (<40% increase in area under the curve) for all hypothetical compounds. A midazolam physiologically based pharmacokinetic model was also used to demonstrate that simulated changes in pharmacokinetic parameters under exercise and heat stress were generally consistent with those reported in the literature.

Toll-like receptors in acute liver injury and regeneration.

Liver is the lymphoid organ with an overwhelming innate immune system, which functions as a filter organ at the first line between the digestive tract and the rest of the body, with receiving 80% of the blood supply through portal vein. TLRs are widely expressed on parenchymal and non-parenchymal cells in the liver, which play critical roles for the liver health. Recent studies indicate that TLR-medicated signals have been involved in almost all liver diseases such as acute and chronic hepatitis, liver fibrosis and cirrhosis, alcoholic and non-alcoholic liver disease, ischemia/reperfusion liver injury, liver regeneration and hepatocellular carcinoma. In this review, the expressions of TLRs in hepatic cell populations including hepatocytes, LSECs, Kupffer cells, lymphocytes, DCs, biliary epithelial cells and HSCs, and TLR ligands and signaling in the liver are summarized. Further, recent advances in the roles of TLRs in acute liver injury and regeneration as mediator and regulator, and their potential therapeutic targets are discussed.

Portal hypertension: pathophysiology, diagnosis, and treatment.

Portal hypertension (PH) is the result of increased vascular resistance in the portal circulation, increased portal venous blood flow, or both. In veterinary medicine, where portal pressure is seldom measured directly, the diagnosis of PH often is inferred from identification of associated complications including multiple acquired portosystemic shunts, ascites, and hepatic encephalopathy. Likewise, treatment of PH primarily is aimed at controlling these complications. The goal of this review is to provide an update on the pathophysiology, diagnosis, and treatment of PH. The review draws from information in the veterinary hepatology literature, reviews, and consensus statements in human hepatology and the literature on experimental models of PH.

Cellular changes in hepatocytes and intestinal endothelium after hepatoduodenal ligament occlusion and protective effects of caspase inhibition.

INTRODUCTION: Hepatic vascular control is used by many surgeons to prevent massive hemorrhage during hepatectomy. However, this may carry a risk of ischemic damage to the hepatocytes. Another major drawback of intraoperative occlusion of the hepatoduodenal ligament is portal stasis with resultant intestinal congestion which may cause adverse effects on the intestinal functions. CD44 is a transmembrane glycoprotein present in many types of epithelial cells. By mediating the attachment of dividing crypt cells to the basal lamina via hyaluronan, CD44 is considered to play a role in maintaining the intestinal villus integrity. Apoptosis is a pathway of cell death orchestrated by a family of proteases called caspases. ZVAD-fmk is a cell-permeable irreversible inhibitor of caspase and might block the processing of many caspases. This study is designed with the purpose to evaluate the impact of intraoperative occlusion of the hepatoduodenal ligament on hepatocyte and intestine functions and also to evaluate the potential influence of ZVAD-fmk on the hepatocyte and intestine functions. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomized to 5 groups. Group 1(C) underwent sham operation. Group 2 (HDL30) underwent occluding the hepatoduodenal ligament by for 30 minutes. Group 3 (HDL 15) underwent occluding the hepatoduodenal ligament by for 15 minutes, releasing for 5 minutes, underwent occlusion for another 15 minutes. Group 4 (ZHDL30) first received ZVAD-fmk, then underwent occluding the hepatoduodenal ligament by for 30 minutes. Group 5 (ZHDL15) first received ZVAD-fmk, then underwent occluding the hepatoduodenal ligament for 15 minutes, releasing for 5 minutes, underwent occlusion for another 15 minutes. After removing the temporary occlusion, liver tissue and proximal jejunum were harvested. Hepatocyte and intestine apoptosis were quantitated using the TUNEL method. CD 44 status of jejunum were determined by immunohistochemical staining. RESULTS: Hepatocyte apoptosis was significantly increased in group (HDL30) and group (HDL15) when compared with group (C). ZVAD-fmk effectively attenuated this phenomenon in both groups. There was no significant difference between group (HDL30) and group (HDL15). Jejunal apoptosis was significantly increased in group (HDL30) and group (HDL15) when compared with group (C). ZVAD-fmk effectively attenuated this phenomenon in both groups. There was no significant difference between group (HDL30) and group (HDL15). CD44 expression on jejunum was significantly increased in group (HDL30) and group (HDL15) when compared with group (C). ZVAD-fmk failed to effectively diminish this phenomenon. CONCLUSION: Occlusion of the hepatoduodenal ligament significantly increased both hepatocyte and jejunal apoptosis and pretreatment with ZVAD-fmk could effectively diminish such phenomenon. CD44 expression on jejunum was also significantly increased by intraoperative occlusion of the hepatoduodenal ligament, yet pretreatment with ZVAD-fmk failed to show significant effect on such phenomenon.

Immediate neuroendocrine signaling after partial hepatectomy through acute portal hyperpressure and cholestasis.

BACKGROUND & AIMS: Early neuroendocrine pathways contribute to liver regeneration after partial hepatectomy (PH). We investigated one of these pathways involving acute cholestasis, immediate portal hyperpressure, and arginine vasopressin (AVP) secretion. METHODS: Surgical procedure (PH, Portal vein stenosis (PVS), bile duct ligation (BDL), spinal cord lesion (SCL)) and treatments (capsaicin, bile acids (BA), oleanolic acid (OA)) were performed on rats and/or wild type or TGR5 (GPBAR1) knock-out mice. In these models, the activation of AVP-secreting supraoptic nuclei (SON) was analyzed, as well as plasma BA, AVP, and portal vein pressure (PVP). Plasma BA, AVP, and PVP were also determined in human living donors for liver transplantation. RESULTS: Acute cholestasis (mimicked by BDL or BA injection) as well as portal hyperpressure (mimicked by PVS) independently activated SON and AVP secretion. BA accumulated in the brain after PH or BDL, and TGR5 was expressed in SON. SON activation was mimicked by the TGR5 agonist OA and inhibited in TGR5 KO mice after BDL. An afferent nerve pathway also contributed to post-PH AVP secretion, as capsaicin treatment or SCL resulted in a weaker SON activation after PH. CONCLUSIONS: After PH in rodents, acute cholestasis and portal hypertension, via the nervous and endocrine routes, stimulate the secretion of AVP that may protect the liver against shear stress and bile acids overload. Data in living donors suggest that this pathway may also operate in humans.