Sinusoid , hepatic

DeLeve and coworkers (DeLeve et al. 1997) examined the possibility that sinusoidal hepatic endothelial cells may metabolize acetaminophen in vitro and that this may be important in toxicity. Previous data indicated that hepatic endothelial cells contain CYP enzymes (Oesch and Steinberg 1987 Steinberg et al. 1990), and that activation of acetaminophen by CYP enzymes in endothelial cells may produce toxicity. Endothelial cells were isolated from two strains of mice. Acetaminophen was not toxic to cultured endothelial cells from Swiss Webster mice but was toxic to cultured endothelial cells from C3H-HEN mice. Glutathione was depleted in the sensitive endothelial cells before the development of toxicity whereas glutathione was not depleted in endothelial cells from the Swiss Webster mice. Addition of glutathione to the incubation or the CYP inhibitor aminobenzo-triazole inhibited development of toxicity in the C3H-HEN cells. However, the two strains of mice appeared to be equally sensitive to the centrilobular hepatic necrosis produced by acetaminophen in vivo. 

Targeting the liver is of great interest as many hepatic diseases do not have efficient pharmacotherapy available. Considering the variety of hepatic cell receptors, lots of drugs are cleared out from the blood circulation by the liver. The main challenge is to target selectively one type of receptor to deliver specifically the drug to the diseased cell. Represented at 80% in volume, parenchymal cells are the best known and referred as hepatocytes non-parenchymal cells are the other main class of liver cells, such as Kupffer cells and sinusoidal hepatic endothelial cells. 

Figure 25-2. The formation and secretion of (A) chylomicrons by an intestinal cell and (B) very low density lipoproteins by a hepatic cell. (RER, rough endoplasmic reticulum SER, smooth endoplasmic reticulum G, Golgi apparatus N, nucleus C, chylomicrons VLDL, very low density lipoproteins E, endothelium SD, space of Disse, containing blood plasma.) Apolipoprotein B, synthesized in the RER, is incorporated into lipoproteins in the SER, the main site of synthesis of triacylglycerol. After addition of carbohydrate residues in G, they are released from the cell by reverse pinocytosis. Chylomicrons pass into the lymphatic system. VLDL are secreted into the space of Disse and then into the hepatic sinusoids through fenestrae in the endothelial lining.

Portal hypertension is a consequence of increased resistance to blood flow through the portal vein. Increased resistance is usually due to restructuring of intrahepatic tissue (sinusoidal damage) but may also be caused by presinusoidal damage such as portal vein occlusion from trauma, malignancy, or thrombosis. A third (and the least common) mechanism is outflow obstruction of the hepatic vein. This latter damage is posthepatic, and normal liver structure is maintained. This chapter will focus on portal hypertension caused by intrahepatic damage from cirrhosis. 

The pathophysiologic mechanisms of portal hypertension and of cirrhosis itself are entwined with the mechanisms of ascites (Fig. 19-3). Cirrhotic changes and the subsequent decrease in synthetic function lead to a decrease in production of albumin (hypoalbuminemia). Albumin is the major intravascular protein involved in maintaining oncotic pressure in the vascular system low serum albumin levels and increased capillary permeability allow fluid to leak from the vascular space into body tissues. This can result in peripheral edema, ascites, and fluid in the pulmonary system. The obstruction of hepatic sinusoids and... 

The liver plays an important role in determining the oral bioavailability of drags. Drag molecules absorbed into the portal vein are taken up by hepatocytes, and then metabolized and/or excreted into the bile. For hydrophilic drugs, transporters located on the sinusoidal membrane are responsible for the hepatic uptake [1, 2]. Biliary excretion of many drags is also mediated by the primary active transporters, referred to as ATP-binding cassette transmembrane (ABC) transporters, located on the bile canalicular membrane [1, 3-5], Recently, many molecular biological... 

Suzuki, H., Sugiyama, Y., Transport of drugs across the hepatic sinusoidal membrane sinusoidal drug influx and efflux in the liver, Semin. Liver Dis. 2000, 20, 251-263. 

Li L, Lee TK, Meier PJ, Ballatori N. Identification of glutathione as a driving force and leukotriene C4 as a substrate for oatpl, the hepatic sinusoidal organic solute transporter. J Biol Chem 1998 273(26) 16184—16191. 

Cirrhosis results in elevation of portal blood pressure because of fibrotic changes within the hepatic sinusoids, changes in the levels of vasodilatory and vasoconstrictor mediators, and an increase in blood flow to the splanchnic vasculature. The pathophysiologic abnormalities that cause it result in the commonly encountered problems of ascites, portal hypertension and esophageal varices, HE, and coagulation disorders. 

Classically the liver has been divided into hexagonal lobules centred around the terminal hepatic venules. Blood enters the liver through the portal tracts that are situated at the corners of the hexagon. The portal tracts are triads of a portal vein, an hepatic artery, and a common hepatic bile duct. The vast expanse of hepatic tissue, mostly consisting of parenchymal cells (PC) or hepatocytes, is serviced via terminal branches of the portal vein and hepatic artery, which enters the tissue at intervals. The hepatocytes are organized into cords of cells radially disposed about the central hepatic venule. Between these cords are vascular sinusoids that transport the blood to the central hepatic venules. The blood is collected through the hepatic venules into the hepatic vein which exits the liver into the inferior vena cava (Figure 4.1). 

Figure 4.1. Schematic representation of the architecture of the liver. Blood enters the liver through the portal vein (PV) and hepatic arteries (HA), flows through the sinusoids, and leaves the liver again via the central vein (CV). KC, Kupffer cells SEC, sinusoidal endothelial cells HSC, hepatic stellate cells BD, bile duct. Modified from reference 98.

Figure 4.2. Diagram outlining the pathogenesis of liver fibrosis. Injury to parenchymal cells (PC) results in the activation of Kupffer cells (KC) and sinusoidal endothelial cells (SEC) and the recruitment of inflammatory cells (IC). These cells release cytokines, growth factors and reactive oxygen species that induce activation and proliferation of hepatic stellate cells (HSC). HSCs gradually transform into myofibroblasts (MF), the major producers of extracellular matrix (ECM) proteins.

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