Alterations of Bone Marrow Sinusoidal Endothelium in Rat and Patients with Liver Cirrhosis

Abstract

Whether bone marrow changes occur and potentially contribute to the hematological abnormalities in liver cirrhosis remain unclear. In this study, we established a rat model of liver cirrhosis induced by carbon tetrachloride. Electron microscopy examination showed focal lesions in bone marrow sinusoidal endothelium and hematopoietic cells in animals with cirrhosis. With the persistence of liver cirrhosis, injuries of bone marrow sinusoidal endothelium progressed from mild mitochondrial changes to nuclear pycnosis and cell disruption, and the trilineage hematopoietic cells showed apoptosis and necrosis. Immunohistochemistry revealed increased expression of E-selectin, P-selectin and vWF in bone marrow sinusoidal endothelium of the cirrhotic rats, which was consistent with the data from semiquantitative reverse transcriptase-polymerase chain reaction analysis. Autopsy specimens from patients with liver cirrhosis (in the absence of other disease) showed the same findings as detected by immunohistochemistry in animal models. The results provide evidence of the association between liver cirrhosis and bone marrow alterations by demonstrating the bone marrow sinusoidal endothelium lesions in both a rat model and patients. It also indicates that activation or injury of bone marrow sinusoidal endothelium mediated by E-selectin, P-selectin, and vWF might have a role in pathogenesis of bone marrow changes during liver cirrhosis. The lesions of bone marrow sinusoidal endothelium might contribute to the hematological abnormalities in the end stage of liver disease.

Screening of differentially expressed protein kinases in bone marrow endothelial cells and the protective effects of the p38a inhibitor SB203580 on bone marrow in liver fibrosis

“…In a previous study, the ultrastructure of BMECs in rats with LF was observed to be altered (22). Furthermore, vWF, an endothelial cell injury biomarker, was increased compared with normal controls (22).…”

“…Furthermore, vWF, an endothelial cell injury biomarker, was increased compared with normal controls (22). In the process of vascular endothelial damage, vWF mediates leukocyte and platelet adhesion (23).…”

“…Therefore, TNFα may serve an important role in p38a-mediated BMEC apoptosis during LC. In addition, endotoxins may exacerbate bone marrow damage during LC (22). Portal hypertension during LC leads to reduced intestinal blood perfusion and damage to intestinal mucosa barrier function, which results in bacterial translocation (25,36).…”

Portal hypertension-related inflammatory phenotypes: From a vitelline and amniotic point of view

“…If so, the excessive splanchnic angiogenic response induced by portal hypertension could be related to the embrionary colonization process by cells bearing a dual hemato-endothelial phenotype. In addition, there is evidence of the association between liver cirrhosis and bone marrow alterations in both rats and patients [79]. Inflammatory mediators may be responsible for increased expression of adhesion molecules in the bone marrow sinusoidal endothelium.…”

“…Inflammatory mediators may be responsible for increased expression of adhesion molecules in the bone marrow sinusoidal endothelium. However, more investigation is needed to clarify the precise mechanism of how sinusoidal endothelium changes affect the hematopoietic cells [79]. Greater understanding is required pertaining to the relationship of portal hypertension with both processes, i.e., angiogenic and hematopoietic.…”