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Physiological Reviews Oct 2009The complex functions of the liver in biosynthesis, metabolism, clearance, and host defense are tightly dependent on an adequate microcirculation. To guarantee hepatic... (Review)
Review
The complex functions of the liver in biosynthesis, metabolism, clearance, and host defense are tightly dependent on an adequate microcirculation. To guarantee hepatic homeostasis, this requires not only a sufficient nutritive perfusion and oxygen supply, but also a balanced vasomotor control and an appropriate cell-cell communication. Deteriorations of the hepatic homeostasis, as observed in ischemia/reperfusion, cold preservation and transplantation, septic organ failure, and hepatic resection-induced hyperperfusion, are associated with a high morbidity and mortality. During the last two decades, experimental studies have demonstrated that microcirculatory disorders are determinants for organ failure in these disease states. Disorders include 1) a dysregulation of the vasomotor control with a deterioration of the endothelin-nitric oxide balance, an arterial and sinusoidal constriction, and a shutdown of the microcirculation as well as 2) an overwhelming inflammatory response with microvascular leukocyte accumulation, platelet adherence, and Kupffer cell activation. Within the sequelae of events, proinflammatory mediators, such as reactive oxygen species and tumor necrosis factor-alpha, are the key players, causing the microvascular dysfunction and perfusion failure. This review covers the morphological and functional characterization of the hepatic microcirculation, the mechanistic contributions in surgical disease states, and the therapeutic targets to attenuate tissue injury and organ dysfunction. It also indicates future directions to translate the knowledge achieved from experimental studies into clinical practice. By this, the use of the recently introduced techniques to monitor the hepatic microcirculation in humans, such as near-infrared spectroscopy or orthogonal polarized spectral imaging, may allow an early initiation of treatment, which should benefit the final outcome of these critically ill patients.
Topics: Animals; Cell Death; Hepatitis; Humans; Liver Circulation; Liver Diseases; Microcirculation
PubMed: 19789382
DOI: 10.1152/physrev.00027.2008 -
Physiological Reviews Jan 1963
Topics: Blood Circulation; Hepatic Artery; Hepatic Veins; Humans; Liver; Liver Circulation; Portal Vein
PubMed: 14015033
DOI: 10.1152/physrev.1963.43.1.115 -
Best Practice & Research. Clinical... Aug 2013The liver may be injured during the course of many systemic diseases. The mechanisms of injury can be broadly divided into four pathways: vascular, toxic, immune, and... (Review)
Review
The liver may be injured during the course of many systemic diseases. The mechanisms of injury can be broadly divided into four pathways: vascular, toxic, immune, and hormonal. Vascular obstruction may be an early event but is also the late common pathway from all mechanisms. Despite the large number of possible initiating factors, the end results are few, including death of hepatocytes or cholangiocytes, leading to the stereotyped syndromes of acute liver failure, non-cirrhotic portal hypertension, or cirrhosis. This small number of outcomes is a reflection of the few anatomic patterns that can be generated by microvascular obstruction. Vascular obstruction may occur by thrombosis, inflammation, or congestive injury. The innate immunity pathway is activated by endotoxin and other agents, leading to inflammatory infiltration, release of cytokines and reactive oxygen species, and necrosis. The adaptive immune pathway involves the generation of antibodies and antigen-specific cell-mediated attack on hepatic cells. Hormonal effects are principally involved when overnutrition leads to hyperinsulinemia followed by hepatocellular necrosis.
Topics: Animals; Cell Communication; Cytokines; Hepatocytes; Humans; Hypertension, Portal; Immunity, Innate; Liver Circulation; Liver Cirrhosis; Liver Failure, Acute; Venous Thrombosis
PubMed: 24090936
DOI: 10.1016/j.bpg.2013.08.002 -
Anesthesiology Dec 1984Hepatic arterial blood flow (HABF) and portal blood flow (PBF) were measured in 18 dogs while awake and during isoflurane and halothane anesthesia. Surgical preparation... (Comparative Study)
Comparative Study
Hepatic arterial blood flow (HABF) and portal blood flow (PBF) were measured in 18 dogs while awake and during isoflurane and halothane anesthesia. Surgical preparation 1 week before the measurements consisted of a left thoracotomy, placement of a left atrial catheter, and insertion of another catheter into the distal aorta via the left femoral artery. Cardiac output and liver blood flow were determined using microspheres at three stages: stage 1-awake state; stage 2-after 45 min of 1 MAC of isoflurane (eight dogs) or halothane (10 dogs) anesthesia; and stage 3-after 45 min of 2 MAC of inhalation anesthesia. Half-life and fractional clearance for indocyanine green (ICG) were determined 1 day before the experiment (awake state), and at the end of stages 2 and 3. Mean arterial pressure (MAP) and cardiac index (CI), as well as PBF, decreased during isoflurane and halothane anesthesia. HABF increased significantly during isoflurane anesthesia, remained unchanged during 1 MAC of halothane anesthesia, and significantly decreased during 2 MAC of halothane anesthesia. Apparently, hepatic oxygen supply was maintained much better during isoflurane than during halothane anesthesia. PBF correlated with CI during halothane (r = 0.97) and, to a certain extent, with MAP during isoflurane (r = 0.66). HABF correlated with CI and MAP during halothane (r = 0.74 and 0.71, respectively) but did not correlate with systemic hemodynamic variables during isoflurane. ICG half-life significantly increased during 1 and 2 MAC of halothane anesthesia. The degree of increase did not correlate with the level of anesthesia or the decrease in total hepatic blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Blood Pressure; Cardiac Output; Dogs; Half-Life; Halothane; Hepatic Artery; Indocyanine Green; Isoflurane; Liver; Liver Circulation; Methyl Ethers; Microspheres; Portal System
PubMed: 6507927
DOI: 10.1097/00000542-198412000-00017 -
Anatomical Record (Hoboken, N.J. : 2007) Jun 2008Morphological changes in the hepatic sinusoid with old age are increasingly recognized. These include thickening and defenestration of the liver sinusoidal endothelial... (Review)
Review
Morphological changes in the hepatic sinusoid with old age are increasingly recognized. These include thickening and defenestration of the liver sinusoidal endothelial cell, sporadic deposition of collagen and basal lamina in the extracellular space of Disse, and increased numbers of fat engorged, nonactivated stellate cells. In addition, there is endothelial up-regulation of von Willebrand factor and ICAM-1 with reduced expression of caveolin-1. These changes have been termed age-related pseudocapillarization. The effects of old age on Kupffer cells are inconsistent, but impaired responsiveness is likely. There are functional implications of these aging changes in the hepatic sinusoid. There is reduced sinusoidal perfusion, which will impair the hepatic clearance of highly extracted substrates. Blood clearance of a variety of waste macromolecules takes place in liver sinusoidal endothelial cells (LSECs). Previous studies indicated either that aging had no effect, or reduced the endocytic capacity of LSECs. However, a recent study in mice showed reduced endocytosis in pericentral regions of the liver lobules. Reduced endocytosis may increase systemic exposure to potential harmful waste macromolecules such as advanced glycation end products Loss of fenestrations leads to impaired transfer of lipoproteins from blood to hepatocytes. This provides a mechanism for impaired chylomicron remnant clearance and postprandial hyperlipidemia associated with old age. Given the extensive range of substrates metabolized by the liver, age-related changes in the hepatic sinusoid and microcirculation have important systemic implications for aging and age-related diseases.
Topics: Aging; Animals; Corrosion Casting; Endocytosis; Endothelial Cells; Humans; Kupffer Cells; Liver; Liver Circulation; Microcirculation; Microscopy, Electron
PubMed: 18484614
DOI: 10.1002/ar.20661 -
The Anatomical Record. Part A,... Sep 2004The role of neural elements in regulating blood flow through the hepatic sinusoids, solute exchange, and parenchymal function is incompletely understood. This is due in... (Comparative Study)
Comparative Study Review
The role of neural elements in regulating blood flow through the hepatic sinusoids, solute exchange, and parenchymal function is incompletely understood. This is due in part to limited investigation in only a few species whose hepatic innervation may differ significantly from humans. For example, most experimental studies have used rats and mice having livers with little or no intralobular innervation. In contrast, most other mammals, including humans, have aminergic and peptidergic nerves extending from perivascular plexus in the portal space into the lobule, where they course in Disse's space in close relationship to stellate cells (fat storing cells of Ito) and hepatic parenchymal cells. While these fibers extend throughout the lobule, they predominate in the periportal region. Cholinergic innervation, however, appears to be restricted to structures in the portal space and immediately adjacent hepatic parenchymal cells. Neuropeptides have been colocalized with neurotransmitters in both adrenergic and cholinergic nerves. Neuropeptide Y (NPY) has been colocalized in aminergic nerves supplying all segments of the hepatic-portal venous and the hepatic arterial and biliary systems. Nerve fibers immunoreactive for substance P and somatostatin follow a similar distribution. Intralobular distribution of all of these nerve fibers is species-dependent and similar to that reported for aminergic fibers. Vasoactive intestinal peptide and calcitonin gene-related peptide (CGRP) are reported to coexist in cholinergic and sensory afferent nerves innervating portal veins and hepatic arteries and their branches, but not the other vascular segments or the bile ducts. Nitrergic nerves immunoreactive for neuronal nitric oxide (nNOS) are located in the portal tract where nNOS colocalizes with both NPY- and CGRP-containing fibers. In summary, the liver is innervated by aminergic, cholinergic, peptidergic, and nitrergic nerves. While innervation of structures in the portal tract is relatively similar between species, the extent and distribution of intralobular innervation are highly variable as well as species-dependent and may be inversely related to the density of gap junctions between contiguous hepatic parenchymal cells.
Topics: Animals; Cholinergic Agents; Humans; Liver; Liver Circulation; Neurons, Efferent; Neuropeptides; Neurosecretory Systems; Nitric Oxide; Species Specificity
PubMed: 15382019
DOI: 10.1002/ar.a.20087 -
European Surgical Research. Europaische... 2011METHODS/AIMS: Despite improved preoperative evaluation, surgical techniques and perioperative intensive care, some patients still experience postoperative liver failure... (Review)
Review
UNLABELLED
METHODS/AIMS: Despite improved preoperative evaluation, surgical techniques and perioperative intensive care, some patients still experience postoperative liver failure in part due to insufficient regeneration. The aim of this review is to give the reader a historical synopsis of the major trends in animal research on liver regeneration from the early experiments in 1877 up to modern investigation. A major focus is placed on the translational value of experimental surgery.
METHODS
A systematic review of the English literature published in Medline was undertaken with the search words 'pig, porcine, dog, canine, liver regeneration, experimental'.
RESULTS
The evolution of the various models tentatively explaining the process of liver regeneration is described.
CONCLUSIONS
We conclude by emphasizing the importance of large-animal surgical research on liver regeneration as it offers a more integrated, systemic biological understanding of this complex process. Furthermore, in our opinion, a closer collaboration between the hepatologist, liver surgeon/transplant surgeon and the laboratory scientist may advance clinically relevant research in liver regeneration.
Topics: Animals; Energy Metabolism; Hemodynamics; Humans; Intercellular Signaling Peptides and Proteins; Liver; Liver Circulation; Liver Regeneration; Models, Animal; Oxygen
PubMed: 21135558
DOI: 10.1159/000321361 -
American Journal of Physiology.... Oct 2022Impaired oxygen utilization has been proposed to play a significant role in sepsis-induced liver dysfunction, but its magnitude and temporal course during prolonged...
Impaired oxygen utilization has been proposed to play a significant role in sepsis-induced liver dysfunction, but its magnitude and temporal course during prolonged resuscitation is controversial. The aim of this study is to evaluate the capability of the liver to increase oxygen extraction in sepsis during repeated acute portal vein blood flow reduction. Twenty anesthetized and mechanically ventilated pigs with hepatic hemodynamic monitoring were randomized to fecal peritonitis or controls ( = 10, each). After 8-h untreated sepsis, the animals were resuscitated for three days. The ability to increase hepatic O extraction was evaluated by repeated, acute decreases in hepatic oxygen delivery (Do) via reduction of portal flow. Blood samples for liver function and liver biopsies were obtained repeatedly. Although liver function tests, ATP content, and Do remained unaltered, there were signs of liver injury in blood samples and overt liver cell necrosis in biopsies. With acute portal vein occlusion, hepatic Do decreased more in septic animals compared with controls [max. decrease: 1.66 ± 0.68 mL/min/kg in sepsis vs. 1.19 ± 0.42 mL/min/kg in controls; portal venous flow (Qpv) reduction-sepsis interaction: = 0.028]. Hepatic arterial buffer response (HABR) was impaired but recovered after 3-day resuscitation, whereas hepatic oxygen extraction increased similarly during the procedures in both groups (max. increase: 0.27 ± 0.13 in sepsis vs. 0.18 ± 0.09 in controls; all > 0.05). Our data indicate maintained capacity of the liver to acutely increase O extraction, whereas blood flow regulation is transiently impaired with the potential to contribute to liver injury in sepsis. The capacity to acutely increase hepatic O extraction with portal flow reduction is maintained in sepsis with accompanying liver injury, but hepatic blood flow regulation is impaired.
Topics: Adenosine Triphosphate; Animals; Hemodynamics; Hepatic Artery; Liver Circulation; Oxygen; Sepsis; Swine
PubMed: 36044679
DOI: 10.1152/ajpgi.00109.2022 -
American Journal of Physiology.... Sep 2019Extended liver resection results in loss of a large fraction of the hepatic vascular bed, thereby causing abrupt alterations in perfusion of the remnant liver....
Extended liver resection results in loss of a large fraction of the hepatic vascular bed, thereby causing abrupt alterations in perfusion of the remnant liver. Mechanisms of hemodynamic adaptation and associated changes in oxygen metabolism after liver resection and the effect of mechanical portal blood flow reduction were assessed. A pig model ( = 16) of extended partial hepatectomy was established that included continuous observation for 24 h under general anesthesia. Pigs were randomly separated into two groups, one with a portal flow reduction of 70% compared with preoperative values, and the other as a control ( = 8, each). In controls, portal flow [mean (SD)] increased from 74 (8) mL·min·100 g preoperatively to 240 (48) mL·min·100 g at 6 h after resection ( < 0.001). Hepatic arterial buffer response was abolished after resection. Oxygen uptake per unit liver mass increased from 4.0 (1.1) mL·min·100 g preoperatively to 7.7 (1.7) mL·min·100 g 8 h after resection ( = 0.004). Despite this increase in relative oxygen uptake, total hepatic oxygen consumption (V̇o) was not maintained, and markers of hypoxia and anaerobic metabolism were significantly increased in hepatocytes after resection. Reduced postoperative portal flow was associated with significantly decreased levels of aspartate aminotransferase and bilirubin and increased hepatic clearance of indocyanine green. In conclusion, major liver resection was associated with persistent portal hyperperfusion, loss of the hepatic arterial buffer response, decreased total hepatic V̇o and with increased anaerobic metabolism. Portal flow modulation by partial portal vein occlusion attenuated liver injury after extended liver resection. Because of continuous monitoring, the experiments allow precise observation of the influence of liver resection on systemic and local abdominal hemodynamic alterations and oxygen metabolism. Major liver resection is associated with significant and persistent portal hyperperfusion and loss of hepatic arterial buffer response. The correlation of portal hyperperfusion and parameters of liver injury and dysfunction offers a novel therapeutic option to attenuate liver injury after extended liver resection.
Topics: Animals; Aspartate Aminotransferases; Female; Hemodynamics; Hepatectomy; Liver; Liver Circulation; Liver Regeneration; Male; Microcirculation; Portal Pressure; Portal Vein; Protective Agents; Swine
PubMed: 31216172
DOI: 10.1152/ajpgi.00113.2019 -
Scientific Reports Oct 2020The liver is not only the largest organ in the body but also the one playing one of the most important role in the human metabolism as it is in charge of transforming...
The liver is not only the largest organ in the body but also the one playing one of the most important role in the human metabolism as it is in charge of transforming toxic substances in the body. Understanding the way its blood vasculature works is key. In this work we show that the challenge of predicting the hepatic multi-scale vascular network can be met thanks to the constructal law of design evolution. The work unveils the structure of the liver blood flow architecture as a combination of superimposed tree-shaped networks and porous system. We demonstrate that the dendritic nature of the hepatic artery, portal vein and hepatic vein can be predicted, together with their geometrical features (diameter ratio, duct length ratio) as the entire blood flow architectures follow the principle of equipartition of imperfections. At the smallest scale, the shape of the liver elemental systems-the lobules-is discovered, while their permeability is also predicted. The theory is compared with good agreement to anatomical data from the literature.
Topics: Animals; Dendritic Cells; Hepatic Artery; Hepatic Veins; Humans; Liver; Liver Circulation; Models, Theoretical
PubMed: 33004881
DOI: 10.1038/s41598-020-73208-8