Damage To Liver Sinusoidal Endothelial Cells Research Articles

Role of liver sinusoidal endothelial cell damage in the developmental process of hepatic sinusoidal obstruction syndrome: a focus on the research progress of immune inflammatory mechanisms

Hepatic sinusoidal obstruction syndrome (HSOS) is a type of secondary vascular disease of the liver that is mainly associated with the ingestion of pyrrole alkaloids (PAs) and hematopoietic stem cell transplantation (HSCT) treatment, resulting in severe liver dysfunction, multiple organ failure, and even death. Hepatic sinusoidal dilatation and obstruction, hepatocyte coagulative necrosis, and hepatic lobular inflammation are the main pathological manifestations of HSOS. The key initiating process for the pathogenesis of HSOS is damage to liver sinusoidal endothelial cells (LSECs). Currently, it is believed that LSECs are damaged by the involvement of multiple etiologies and mechanisms, and secondary coagulation and fibrinolysis disorders, oxidative stress, and inflammatory responses are the occurrence contributors to HSOS; however, the mechanism has not been fully elucidated. Therefore, the role of immune-inflammatory mechanisms has received increasing attention in LSEC damage. This article provides an overview of the epidemiology, etiology, and pathological changes of HSOS and reviews the physiological functions, common etiological damage mechanisms, and the key role of LSEC damage in the pathogenesis of HSOS, with a special focus on the role and research progress of immune-inflammatory mechanisms for LSEC damage in recent years. Furthermore, we believe that in-depth study and elucidation of the role of immune-inflammatory mechanisms in LSEC damage and the pathogenesis of HSOS and diagnosis will provide feasible research and development ideas for the screening and identification of new markers and drug treatment targets for HSOS.

Thromboxane A2 receptor signaling in endothelial cells attenuates monocrotaline-induced liver injury

Sinusoidal obstruction syndrome (SOS) is a major complication of chemotherapy and hematopoietic stem cell transplantation. The early stage of SOS is characterized by liver sinusoidal endothelial cell (LSEC) injury accompanied by platelet aggregation. Thromboxane A2 (TxA2) induces platelet aggregation through the thromboxane prostanoid (TP) receptor. In this study, we explored the role of TP signaling in a monocrotaline (MCT)-induced mouse model of SOS. Relative to wild-type (WT) mice, TP-deficient (TP−/−) mice exhibited more severe MCT-liver injury, as indicated by elevated levels of alanine aminotransferase (ALT) and coagulative necrosis. Extensive accumulation of platelets in the liver was observed in both WT and TP−/− mice. TP expression co-localized with CD31-positive LSECs. MCT treatment caused LSEC destruction, concomitant with elevated expression of matrix metalloproteinases (MMPs) and adhesion molecules in WT mice, and LSEC damage was further exacerbated in TP−/− mice. Viability of isolated LSECs was lower in cells from TP−/− mice, whereas mRNA levels of MMPs and adhesion molecules were higher; U46619, a TxA2 agonist, reduced these levels in WT mice. These data suggest that TP signaling has no effect on platelet accumulation during MCT-induced liver injury, but instead prevents injury by suppressing LSEC damage.

The liver sinusoidal endothelial cell damage in rats caused by heatstroke

This study was designed to explore whether liver sinusoidal endothelial cells (SECs) play a pathological role in liver injury of heatstroke (HS) in rats. An HS rat model was prepared in a pre-warmed incubator. Rats were randomized into four groups: HS-sham group (SHAM group), the 39°C group, the 42°C group, and the HS group. The serum concentrations of SEC injury biomarkers including hyaluronic acid (HA), von Willebrand factor (vWF), thrombomodulin (TM), were measured. Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and endothelium-derived vasoactive substances including endothelin-1 (ET-1) and nitric oxide (NO) were determined using a commercially available kit. Hepatic tissues were obtained for histopathological examination, electron microscopy examination, immunohistochemistry, and reverse transcription polymerase chain reaction (PCR) analysis. Our study team found increased levels of plasma ALT/AST during the course of HS. We were also able to detect microcirculation changes and inflammatory injury of the liver (especially in the sinusoidal areas). In addition, markers of SEC injury were significantly elevated. Thrombosis-related markers including vWF and TF expression levels were significantly upregulated and TM levels downregulated. Furthermore, imbalance between ET-1 and NO levels were detected. In conclusion, damage of SECs could result in microcirculation disturbances and pro-inflammatory injury in the liver during HS, which could prove to be a potential pathogenic mechanism of liver injury in HS.

The Correlation Between Platelet Activation and Liver Injury by Conditioning and Bone Marrow Transplantation

Hepatic veno-occlusive disease (HVOD) is a common severe complication after transplantation which is closely related to liver sinusoidal endothelial cell (LSEC) injury. Although platelet activation might play a key role in the progress of HVOD, the relationship between the P-selectin and HVOD is still unclear. In this study, the P-selectin, liver functions, and observed damage of LSEC after transplantation were detected. The P-selectin, alanine aminotransferase (ALT) and bilirubin were first detected in the patients. The ALT of patients reached the first peak of 144 ± 45.04 U/L, on day 7 after busulfan + cyclophosphamide (BU/CY) pretreatment, and reached the second peak of 220.5 ± 40.58 U/L on day 7 after transplantation. Similarly, the concentration of bilirubin increased BU/CY pretreatment and reached peak on day 15 after transplantation at 38.8 ± 5.99 μmol/L. However, the level of P-selectin was significantly higher than normal levels for a long time and peaked on day 3 after BU/CY pretreatment and on day 12 after transplantation (P < .05). Then the P-selectin, liver function, liver index, hepatocytes, and LSEC were observed using a transplantation model of C57BL/6 (H-2b) donor to BALB/c (H-2d) recipient. The P-selectin, liver index, and liver function of total body irradiation (TBI) mice and bone marrow transplantation (BMT) mice were significantly increased, but the increase of TBI mice were more significant. On day 5, the ratio of TBI mice peripheral blood platelets which expressed P-selectin was higher and reached an earlier peak at 15.6 ± 2.63%, whereas that of BMT mice was 6.59 ± 1.17%, and peaked on day 15 at 8.36 ± 1.55% (P < .05). Moreover, the ALT and bilirubin levels of TBI mice were higher and reached earlier peaks on day 5 at 58.65 ± 1.43 U/L and 27.14 ± 1.32 μmol/L, respectively, whereas those of BMT mice peaked on day 5 at 50.22 ± 2.02 U/L and day 30 at 39.57 ± 1.55 μmol/L, respectively (P < .05). The LSEC damage and hepatocyte edema in BMT mice were most serious at day 15, and at day 30 injuries did not allow recovery. The liver score of TBI mice peaked on day 5, whereas that of BMT mice peaked on day 15. Moreover, the degree of damage and platelet activation positively correlated. This study implied that P-selectin could be used as a predictor of HVOD.

Lactoferrin Protects Against Acetaminophen‐Induced Liver Injury in Mice

Acetaminophen‐induced liver injury (AILI) is a significant health problem and represents the most frequent cause of drug‐induced liver failure in the United States. The development and implementation of successful therapeutic intervention strategies have been demanding, due to significant limitations associated with the current treatment for AILI. Lactoferrin (Lac), a glycoprotein present in milk, has been demonstrated to possess a multitude of biological functions. Our study demonstrated a profound protective effect of Lac in a murine model of AILI, which was not dependent on its iron binding ability, inhibition of acetaminophen (APAP) metabolism, or a direct cytoprotective effect on hepatocytes. Instead, Lac treatment significantly attenuated APAP‐induced liver sinusoidal endothelial cell dysfunction and ameliorated hepatic microcirculation disorder. This protective effect of Lac appeared to be dependent on hepatic resident macrophages (Kupffer cells, KC). Collectively, our data indicated that Lac, through activation of KC, inhibited APAP‐induced liver sinusoidal endothelial cell damage and improved hepatic congestion, thereby protecting against AILI. These findings reveal the significant therapeutic potential of Lac during AILI and other types of liver diseases.

Lactoferrin protects against acetaminophen-induced liver injury in mice

Acetaminophen-induced liver injury (AILI) is a significant health problem and represents the most frequent cause of drug-induced liver failure in the United States. The development and implementation of successful therapeutic intervention strategies have been demanding, due to significant limitations associated with the current treatment for AILI. Lactoferrin (Lac), a glycoprotein present in milk, has been demonstrated to possess a multitude of biological functions. Our study demonstrated a profound protective effect of Lac in a murine model of AILI, which was not dependent on its iron-binding ability, inhibition of acetaminophen (APAP) metabolism, or a direct cytoprotective effect on hepatocytes. Instead, Lac treatment significantly attenuated APAP-induced liver sinusoidal endothelial cell dysfunction and ameliorated hepatic microcirculation disorder. This protective effect of Lac appeared to be dependent on hepatic resident macrophages (Kupffer cells [KCs]). Collectively, our data indicate that Lac, through activation of KCs, inhibited APAP-induced liver sinusoidal endothelial cell damage and improved hepatic congestion, thereby protecting against AILI. These findings reveal the significant therapeutic potential of Lac during AILI and other types of liver diseases.

Vascular endothelial growth factor in improving liver function of rats following partial liver transplantation

Objective To determine the impact of exogenous vascular endothelial growth factor (VEGF) on rat liver function after partial liver transplantation. Methods Male SD rats which had undergone 30% partial liver transplantation were divided into VEGF treatment group (n=60) and control group (n=60). Animals in each group were injected with solution of VEGF or saline, respectively. Serum ALT, AST, and hyaluronic acid (HA) levels were assessed at 0, 12, 24, 72, 168 hours after operation. Results Serum ALT, AST and HA levels were significantly decreased at 72 hours after transplantation in VEGF treatment group compared with controls (t =4.681, 4.252, 2.853, P<0.05). In accordance with liver function, treatment with VEGF minimized the damage to the liver sinusoidal endothelial cells and decreased the infiltration of inflamatory cells. Conclusion Administration of VEGF may improve the liver function of rats after partial liver transplantation by maintaining the integrality of the sinusoidal structure and reducing the inflamation reaction. Key words: Liver transplantation; Vascular endothelial growth factor; Rat