Defenestration of the sinusoidal endothelial cell in a rat model of cirrhosis

Abstract

We characterized the structural and immunohistological changes of sinusoidal endothelial cells that occur during cirrhosis in rats made cirrhotic with thioacetamide. Thioacetamide (200 mg/kg body wt) was injected intraperitoneally three times a week into male Wistar rats. Two, 4, 6 and 12 wk later, rat livers were observed under transmission and scanning electron microscopy and regular microscopy and immunostained with laminin and von Willebrand factor (factor VIII-related antigen) antibodies. The diameters and numbers of sinusoidal endothelial fenestrations did not change significantly after 2 wk in the thioacetamide-treated rats; however, they decreased within 4 wk after thioacetamide treatment. A basement membranelike structure in Disse's space was noted 6 wk after thioacetamide treatment. Laminin was detected in Disse's space after 4 wk. In vitro, in cultured sinusoidal endothelial cells, the diameter of sinusoidal endothelial fenestrations was significantly lower at 6 wk in thioacetamide-treated rats. von Willebrand factor was detected in the cytoplasm as granular fluorescence after 6 wk of thioacetamide treatment. These results suggest that as fibrosis develops in cirrhosis, the structural and immunohistochemical characteristics of sinusoidal endothelial cells change.

Sinusoidal ultrastructure evaluated during the revascularization of regenerating rat liver

“…1-3. Others have reported that ECM composition can influence fenestration diameter 18,19 and that presented a valid argument for evaluation of ECM protein deposition in this study. Because porosity increases dramatically in the first 24 hours after PHx, survey of resident ECM proteins within the space of Disse may provide evidence for matrix control of SEC porosity in vivo.…”

“…(See also vitro and in vivo studies have also shown that fenestrae can modulate their diameter in response to soluble agents as well as a variety of environmental conditions, including changes in shear stress and portal pressure, and pathological ECM deposition. [10][11][12][13][14][15][16][17][18][19] We sought to investigate the trends in porosity expression in the SEC within and between lobule zones throughout the revascularization process following PHx. We believed that such changes may play a critical role in the sieving function of the sinusoids and contribute to the progression of the regenerative process.…”

“…40 Stellate cells can become myofibroblastic, contributing to extreme ECM deposition seen in pathological conditions of fibrosis and cirrhosis, resulting in the capillarization of the sinusoids. 19,40 Furthermore, stellate cells are not a homogeneous population of cells and can express varying properties of pericytes, smooth muscle cells, as well as myofibroblastic cells. Few data are available on the activation state and morphology of the stellate cells of regenerating liver.…”

“…Therefore, fenestrations are not passive sieves, but are most probably very dynamic structures whose size and density have been shown to be affected by physical factors such as portal pressure and shear stress 10,11 ; soluble substances such as alcohol, 12 serotonin, 13 endotoxin, 14 and nicotine 15 ; and cytoskeletal disruption agents like cytochalasin B, 16,17 as well as the composition of the ECM. 18,19 Given the fact that SEC fenestrations can modulate their diameters in response to a variety of factors and events, we sought to examine fenestration size and sinusoidal porosity index with respect to ultrastructural changes taking place within the regenerating lobule. Here, we document the changes in fenestration diameters and porosity of SEC in the periportal (zone 1) versus pericentral (zone 3) sinusoids during regeneration, from 5 minutes to 14 days following 70% PHx.…”

Distribution of Zinc‐Binding Metallothionein in Cirrhotic Liver of Rats Administered Zinc

“…However, this difference may be interpreted as follows: one possibility is that the lower biosynthesis of metallothionein was due to a reduction of the Zn supply from the bloodstream to the fibrotic areas. In the cirrhotic liver, microcirculatory abnormalities such as capillarization and intrahepatic shunts are believed to prevent substances from reaching the liver cells (Varin & Huet 1984;Mori et al 1993;Nomura et al 1994). Therefore, it was considered that the lower Zn exposure in fibrotic areas with microcirculatory abnormalities might have been responsible for the absence of Zn-metallothionein in these areas.…”