Key astroglial markers in human liver cirrhosis of different degree: immunohistochemical study

Abstract

The aim of the study – determining the immunohistochemical levels of the GFAP, GS and AQP4 in different regions of the human brain in the conditions of liver cirrhosis of different degree. Materials and methods. The study was performed on sectional material of 90 patients who suffered during lifetime from liver non-alcoholic cirrhosis of classes A (n = 30, group “A”), B (n = 30, group “B”) and C (n = 30, group “C”) according to Child–Pugh classification, including 59 (65.55 %) cases with clinical symptoms of I–IV grade hepatic encephalopathy. Cortex, white matter, hippocampus, thalamus, striopallidum, cerebellum, were examined using immunohistochemical method for evaluation of GFAP, GS and AQP4 levels. Results. GFAP expression gradually decreased from classes A to C of cirrhosis. The most expressed GFAP decline was found in class C in the cortex and thalamus (6.74- and 6.23-fold decrease). Contrary to GFAP, GS expression gradually increased along with aggravation of cirrhosis. The most prominent augmentation of GS was related in the cortex and thalamus in “C” group, respectively 4.34- and 4.26-fold increase. AQP4 levels also showed growing mode correlated with cirrhosis aggravation. The highest increase was found in the cortex and thalamus in “C” group (4.25- and 4.34-fold increase, respectively). Starting from class B, altered GFAP, GS, and AQP4 levels showed region-dependent relationships. GS and AQP4 were positively correlated in all 6 studied regions, while the inverse relationships were found between GFAP vs. GS and GFAP vs. AQP4 proteins. Conclusions. As early as in class A of cirrhosis, dynamic molecular alterations are occurred in the brain astrocytes, indicating the progressive development of astroglial remodeling with a violation of its cytoskeleton and redistribution of molecular domains within cells. This phenomenon is region- and time-specific; its signs get stronger with time from class to class, becoming most pronounced in class C. Among studied brain regions, cortex and thalamus are characterized by the most pronounced protein changes. Starting from class B, the remarkable relationship is seen between molecular changes of both direct and inverse type. Simultaneously emerging links might indicate synergistic involvement of these molecules in astroglial remodeling in chronic hepatic encephalopathy. Alterations in the mentioned astroglial molecular complex can serve both as a diagnostic marker of reactive astrogliosis during liver cirrhosis and represent a target for novel therapeutic approaches regarding encephalopathy in cirrhotic patients.

Nestin, CD44, Ki-67, GS and AQP4 expression in the brain neurogenic niches of deceased patients with liver cirrhosis of different degree

“…It should be noted that NECs in the studied SVZs and hypothetical alternative neurogenic niches morphologically correspond to the proliferative NSCs described by other researchers [15,24]. Thus, we assume that revealed growth of Nestin+, CD44+, GS+ expression in astrocyte-like cells of SVZs and hypothetical alternative neurogenic niches during compensated and subcompensated cirrhosis is due to the activation of astrocytogenesis programs in response to widespread dysmetabolic astrodystrophy and astrocyte loss developing in patients with cirrhosis [1].…”

“…We found that with the progression of cirrhosis, astrocytes of SVZs and SGZ DG significantly increases GS expression, and this sharply decrease in elderly patient's SVZ with decompensated cirrhosis, as well as in other brain regions [1]. This most likely indicates an adaptive increase in GS synthesis by periventricular, including fibrous astrocytes in response to high levels of ammonia in the brain tissue, which is accompanied by the activation of neurogenesis programs in niches and an increased Nestin level.…”

“…Cirrhosis decompensation leads to a dysfunctional state of the entire astrocytic population, edematous changes and clasmatodendrosis of astrocytes [1]. In patients with decompensated liver cirrhosis and severe Grade 3-4 hepatic encephalopathy, associated with the maximal ammonia accumulation in the brain and aggravation of astrodystrophy [2], compensatory astrocytogenesis in the neurogenic niches drops, characterized by significant decrease in Nestin and CD44 expression, and the absence of Ki-67 expression in all brain regions studied.…”

“…Hepatotoxic brain damage in liver cirrhosis (LC) is chara cterized by a progressive amplification of astrocyte deficiency with the development of astroasthenia, and subsequently decompensated edema and death of these cells [1]. High concentrations of plasma and intracerebral ammonia, along with other neurotoxins, disrupt the astroglia functionality leading to dysfunction and damage of neurons, that clinically manifest as hepatic encephalopathy [2].…”

Immunohistochemical Expression of Gfap, Gs, Aqp4, Alzheimer-2-Astrocytosis and Brain Ammonia Levels in Deceased Septic Patients Without Liver Failure and Those With Sepsis-Associated Liver Injury

“…Sepsis-associated encephalopathy (SAE), which develops under these conditions, has a complex mechanism, since in addition to the neurotoxic effect of systemic infection, its decay products, pathogenassociated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), it is complicated by a pronounced neurotoxic effect of hyperammonemia, which follows a decrease in the detoxifying capacity of the liver. It is evidenced that during chronic liver failure in liver cirrhosis a morphotypical remodeling astroglia occurs with the appearance of the so-called Alzheimer type 2 astrocytes and changes in the expression of its specific proteins, such as glial fibrillar acidic protein (GFAP), glutamine synthetase (GS) and aquaporin-4 (AQP4) [4,5]. Also, in patients with chronic and acute liver failure, the level of intracerebral ammonia increases, which was confirmed using neuroimaging methods [6].…”