РОЛЬ ЭНДОТЕЛИЯ В ФОРМИРОВАНИИ ФИБРОЗА ПЕЧЕНИ

Abstract

Chronic liver disease is a worldwide health problem. A significant proportion of the manifestations and complications of chronic liver diseases is due to liver fibrosis and its subsequent transition to liver cirrhosis. The initial and the key link in the formation of fibrotic changes in the liver are liver sinusoidal endothelial cells (LSEC). In view of the unique structure and central position of the liver endothelial tissue in the pathogenesis of fibrosis, it seems relevant to present current data in the form of this review. LSECs are the only endothelial cells in the body that lack a basement membrane and contain transcellular pores called fenestrae. At the initial stages of the fibrogenesis process, LSECs change their phenotype: they lose fenestrae and develop a basement membrane, turning into a continuous endothelium. LSECs are involved in fibrosis through the secretion of angiocrine signals that act as paracrine factors that balance the liver’s response to injury towards fibrosis or regeneration. LSEC cells are very sensitive to the slightest changes in the microenvironment, with prolonged exposure they quickly change their phenotype, their numerous functions are disrupted, including vasodilator, anti-inflammatory, antithrombotic and antifibrotic, as well as the regulation of angiogenesis and regeneration, and prevention of HSC activation. Such changes in the phenotype are called endothelial dysfunction. Loss of fenestres (capillaryization) by LSEC cells is the initial event in liver fibrosis. It precedes HSC activation and promotes fibrosis and progression to cirrhosis. Fenestra maintains liver homeostasis, promotes efficient transport of lipoproteins, regulates liver regeneration and immune tolerance. LSEC fenestra are approximately 50-200 nm in diameter, and most of them are clustered into several dozen ultrastructures called sieve plates. Chronic liver injury leads to deep dedifferentiation of LSECs, which lose their vasoprotective properties and become vasoconstrictive, proinflammatory, and prothrombotic. Major molecular dysregulations seen in LSEC in chronic liver disease include fenestra loss and basement membrane development that interfere with the exchange of molecules such as lipoproteins and oxygen with hepatocytes, promoting steatosis and parenchymal apoptosis; reduction of NO by suppression of KLF2 and endothelial NO synthase (eNOS) activity, together with an increase in ROS-mediated NO uptake, leading to activation of hepatic stellate cells and deposition of extracellular matrix; increased production of vasoconstrictors (such as endothelin 1 or thromboxane A2) and pro-inflammatory cytokines, further exacerbating sinusoidal constriction. These pathological changes lead to sinusoidal vasoconstriction, microvascular dysfunction, fibrosis, and ultimately portal hypertension. Thus, LSECs play complex interrelated roles in maintaining liver homeostasis and are involved as factors in inflammation and fibrogenesis in liver diseases. Their unique position, phenotype, and function make them attractive candidates for organ-specific therapies, and it is likely that more therapies targeting these cells will be tested in the future as novel therapies to reduce liver damage and inflammation, and to prevent or reversal of fibrogenesis.