Endothelial cells sinusoid

Unlike the liver injury that occurs with toxic chemicals (see above), reperfusion injury affects not only the hepatocytes but also the endothelial cells that line the sinusoids as an important primary target. It is thought that there may be some aspects of preservation-reperfusion injury that are unique to the liver and UW solution is apparently more effective in this tissue than in others (Clavien aal., 1992). The principle characteristic of this injury is that it involves damage to the sinusoidal cells such that leucocytes and platelets are stimulated to adhere on reperfusion. 

Under normal conditions the sinusoidal endothelial cells are flat thin cells lying close against the hepatocyte surface, separated only by the periplasmic space. Cold preservation of the liver causes the endothelial cells to round up and detach, although they are not actually... 

The penis consists of three components, two dorsolateral corpora cavernosa and a ventral corpus spongiosum that surrounds the penile urethra and distally forms the glans penis. The corpora cavernosa consist of blood-filled sinusoidal or lacunar spaces, which are lined with endothelial cells, supported by trabecular smooth muscle, and surrounded by a thick fibrous sheath called the tunica albuginea. The caver-nosal arteries, which are branches of the penile artery, penetrate the tunica albuginea and supply blood flow to the penis. 

CSF-1 is synthesized by many different cell types including fibroblasts, endothelial cells, bone marrow stromal cells, osteoblasts, keratinocytes, astrocytes, myoblasts and, during pregnancy, under the control of estrogen and progesterone, by uterine epithelial cells. Circulating CSF-1 (ti/2 = 10 min) is synthesized by endothelial cells and smooth muscle cells. It is primarily cleared by CSF-lR-mediated internalization and destruction by Kupffer cells. Thus the number of sinusoidally located macrophages actually determines the concentration of the cytokine... 

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.

The viability and function tests described above are used to evaluate the hepatocytes within the slice. Up to now, tests to measure the viability of the non-parenchymal cells have not been reported. The presence of the latter cell types is one of the conceptual advantages of slices as compared to isolated hepatocytes. As some drug targeting devices are designed to target non-parenchymal cells in the liver, the development of tests for the sinusoidal cell types deserves more attention. For example, the uptake of substrates such as succinylated human serum albumin (Suc-HSA,which is specifically endocytosed by endothelial cells [79]), or hyaluronic acid [80], can be used to assess the functionality of endocytotic pathways in the endothelial cells in the liver [81]. Other modified proteins that are specifically taken up by Kupffer cells such as mannosylated HSA, may be used to assess the functionality of the endocytotic pathway in Kupffer cells [79]. Another parameter which can be used to assess the functionality of these non-parenchymal liver cells, is the excretion of cytokines in response to pro-inflammatory stimuli. Non-parench5mal cell function in liver slices will be described in more detail in the Section 12.7. 

Ischemia may also be a component of cytotoxic damage, and consequently interference with liver blood flow by toxic compounds such as phalloidin, which causes swelling of the endothelial cells lining the sinusoids, may cause or contribute toward cytotoxicity. 

Occasionally toxic compounds can directly damage the hepatic sinusoids and capillaries. One such toxic compound is monocrotaline, a naturally occurring pyrrolozidine alkaloid, found in certain plants (Heliotropium, Senecio, and Crotolaria species). Monocrotaline (Fig. 7.7) is metabolized to a reactive metabolite, which is directly cytotoxic to the sinusoidal and endothelial cells, causing damage and occlusion of the lumen. The blood flow in the liver is therefore reduced and ischemic damage to the hepatocytes ensues. Centrilobular necrosis results, and the venous return to the liver is blocked. Hence, this is known as veno-occlusive disease and results in extensive alteration in hepatic vasculature and function. Chronic exposure causes cirrhosis. 

Lewis, J.G. Swenberg, J.A. (1983) The kinetics of DNA alkylation, repair and replication in hepatocytes, Kupffer cells, and sinusoidal endothelial cells in rat liver during continuous exposure to 1,2-dimethylhydrazine. Carcinogenesis, 4, 529-536... 

The central event in the development of liver fibrosis is the enhanced sinusoidal deposition of extracellular matrix proteins that are mainly produced by activated HSC [86, 112, 113] and to a minor extent by endothelial cells [44-46] and hepatocytes [114, 115]. So far, no evidence has been found that KC are directly involved in the production of extracellular matrix proteins [39]. The accumulation of extracellular matrix proteins is caused by a disturbed balance between the synthesis and the degradation of the matrix proteins. This imbalance leads to a 5 to 10-fold increase in the total amount of matrix molecules and to an altered composition of the extracellular matrix. In contrast to normal livers, the sinusoids in fibrotic livers are stuffed with the fibrillar collagens type I and III. This colla-genization of the sinusoids, referred to as sinusoidal capillarization, causes severe disturbances of the blood flow and an impaired exchange of proteins between the liver cells and blood. Furthermore, this capillarization is accompanied by a loss of fenestration of the sinusoidal endothelial lining, which further hampers the diffusion of proteins between plasma and hepatic cells. 

B. Smedsrod, J. Melkko, N. Araki, H. Sano, and S. Horiuchi. Advanced glycation end products are eliminated by scavenger-receptor-mediated endocytosis in hepatic sinusoidal Kupffer and endothelial cells, Biochem. J. 322 567-573 (1997). 

A. W. Lohse, P. A. Knolle, K. Bilo, A. Uhrig, C. Waldmann, M. Ibe, E. Schmitt, G. Gerken, and K. H. Meyer zum Btischenfelde, Antigen-presenting function and B7 expression of murine sinusoidal endothelial cells and Kupffer cells. Gastroenterology 770 1175-1181 (1996). 

J. J. Widmann, R. S. Cotran, and H. D. Fahimi, Mononuclear phagocytes (Kupffer cells) and endothelial cells. Identification of two functional cell types in rat fiver sinusoids by endogenous peroxidase activity, J. Cell Biol. 52 159-170 (1972). 

J. Y. Scoazes and G. Feldman, In situ immunophenotyping study of endothelial cells of the human hepatic sinusoid Results and functional implications, Hepatology 74 789-797 (1991). 

K. Kagawa, and K. Kashima, The change of sinusoidal endothelial cells in experimental liver cirrhosis—in vivo and in vitro study, Cells of Hepatic Sinusoid (D. 

J. J. Maher and R. F. McGuire, Extracellular matrix gene expression increases preferentially in rat lipocytes and sinusoidal endothelial cells during hepatic fibrosis in vivo, J. Clin. Invest. 86 1641-1688 (1990). 

I. Kosugi, H. Muro, H. Shirasawa, and I. Ito, Endocytosis of soluble IgG immune complex and its transport to lysosomes in hepatic sinusoidal endothelial cells, J. Hepatol. 76 106-114 (1992). 

H. Muro, H. Shirasawa, I. Kosugi, and S. Nakamura, Defect of Fc receptors and phenotypical changes in sinusoidal endothelial cells in human liver cirrhosis, Am. J. Pathol. 743 105-120 (1993). 

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