Acute liver failure as well as acute-on-chronic liver failure result in the development of acute hepatic encephalopathy (HE) characterized by the major pathophysiologic event in form of the brain edema formation. Among brain cells, astrocytes are considered to be a central cellular population most sensitive to ammonia exposure in HE being the primarily cellular source of glutamine synthetase for ammonia metabolism. Astrocyte swelling is considered to be a principal sign of acute HE, while the exact molecular mechanisms of this event are still not fully understood. According to current concepts on HE, alteration in AQP4 regulation can play one of the central roles in the brain edema development and progression in hyperammonemia states. Considering high region- and context-specific heterogeneity of astroglial populations in the CNS, AQP4 involvement in the links of HE can also sustain mentioned conventional diversity. The aim of the study: to determine the immunohistochemical level of the brain aquaporin 4 (AQP4) expression in the experimental acute liver failure in rats. Materials and methods. The study was conducted in Wistar rats: 5 sham (control) animals and 10 rats with acetaminophen induced liver failure model (AILF). The immunohistochemical study of AQP4 expression was carried out in the sensorimotor cortex, white matter, hippocampus, thalamus and caudate nucleus/putamen regions between 12 and 24 h after acetaminophen treatment. Results. Starting from the 6th hour after acetaminophen treatment all AILF-animals showed the progressive impairment of clinical signs of acute liver failure, evidenced histologically by spread liver centrilobular necrosis and finished in 6 rats by comatose state up to 24 h (constituted subgroup AILF-B, “non-survived”). 4 animals survived until the 24 h - subgroup AILF-A, “survived”. In the AILF-B group, starting from 16 to 24 hours after acetaminophen treatment, a significant (relative to control) regionally-specific dynamic increase AQP4 levels was observed in the brain: in the cortex – by 405.17 %, hippocampus – by 387.38%, caudate nucleus/putamen – by 314.11%; from 12th hour: in the thalamus – by 342.66% and subcortical white matter – by 297.77%; with the highest elevation of AQP4 expression in the cortex among other studied regions: by 5.05 times. Conclusions. AILF in rats induces dynamic increase in AQP4 levels in the cortex, hippocampus and caudate nucleus/putamen by 12th hours and in the white matter and thalamus – by 16th h after the acetaminophen overdosing with the highest elevation in the cortical region. The heterogeneity in the degree of AQP4 elevation among different brain regions potentially may indicate brain territories more susceptible for systemic toxic exposure and damage in acute liver failure. Furthermore, the earliest reliable increase of AQP4 levels in the cortex, hippocampus and caudate/putamen might propose the faster reactivity of the local astroglial populations in response to the hyperammonemia among other regions. Consequently, the later and lower rates of AQP4 elevation in the white matter might indicate local astroglia as less reactive and/or more protected from the harmful exposure at a certain time period of the experiment. The higher cortical levels of AQP4 in the non-survived animals compared to survived ones reflect the significance of AQP4-involving mechanisms in the aggravation of acute HE, as well as the role of AQP4 alterations in thanatogenesis in the conditions of acute liver failure.
Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis, manifesting as a neuropsychiatric syndrome ranging from cognitive deficits to coma. HE pathophysiology is linked to elevated brain ammonia and neuroinflammation [1]. Astrocytes are central brain cells responsible for ammonia detoxification and during acute HE are characterized by severe swelling [1]. Aquaporin-4 (AQP4) is a central protein of astrocytes, predominant water channel in the brain, which undergo alteration in response to hyperammonemia [2]. Studies have evidenced that AQP4 which is enriched in astrocytic perivascular end-feet and responsible for the brain water homeostasis, can be either upregulated or reduced in acute and chronic liver diseases accompanied by hyperammonemia [2]. Despite the controversial findings, it was supposed that AQP4 alteration may play a principal role in cytotoxic and/or vasogenic edema formation occurring during HE [3]. This statement needs further arguments to uncover the mechanisms that control edematous changes during liver cirrhosis in humans. Thus, the present study aimed to study of AQP4 level in 6 brain regions of cirrhotic patients in the course of liver cirrhosis. For this, we examined postmortem material of 90 cirrhotic patients of classes A, B and C according to Child-Pugh classification. Immunohistochemically, using rabbit polyclonal anti-AQP4 (Thermo Scientific, USA), we studied cortex, subcortical white matter, hippocampus, thalamus, striatum and cerebellum. Additionally, data from case histories were analyzed. It was revealed that AQP4+ labeling in all studied regions in control was related to the membranes of perivascular and parenchymal astrocytic processes of individual astrocytes and AQP4 expression appeared to be the highest in the hippocampus and the lowest in the white matter. In cirrhotic groups, AQP4 expression altered in growing manner and correlated with liver cirrhosis aggravation. Increased AQP4 expression was associated with labeling of cell body’s plasmalemmas and increased numbers of positive cells in all studied regions, which caused moderate-to-weak homogenous staining of neuropil. Class A demonstrated increased AQP4 in all studied regions with the highest values in the striatum – 2.62-fold and the least in the cerebellum – 1.66-fold. In class B, AQP4 elevation gained maximal indications of 3.73-fold increase in thalamus, 3.37-fold in the cortex and the least increase in hippocampus – 2.41-fold. The highest increase of AQP4 was observed in the class C. Cortical and thalamic regions showed the most prominent elevation, respectively: 4.25-fold and 4.34-fold. The least AQP4 elevation was related to cerebellum: 2.92-fold. AQP4 expression differed significantly in all pairs of subsequent cirrhotic classes in the white matter, thalamus, striatum and cerebellum. In the cortex and hippocampus, AQP4 levels differed significantly between A vs. B and A vs. C, but not between B vs. C classes.
Запорожский государственный медицинский университет, УкраинаA -концепция и дизайн исследования; B -сбор данных; C -анализ и интерпретация данных; D -написание статьи; E -редактирование статьи; F -окончательное утверждение статьи Протоковая аденокарцинома поджелудочной железы (ПАПЖ) -один из наиболее агрессивных видов рака, устойчивый к лучевой и химиотерапии, в его развитии большое значение имеют плохо изученные раковые стволовые клетки (РСК) и мезенхимальные стволовые клетки (МСК).Цель работы -анализ данных современной научной литературы о роли стволовых клеток в прогрессии ПАПЖ.Пул стволовых клеток ПАПЖ гетерогенен, состоит из РСК и МСК, которые формируют в опухоли ниши стволовых клеток. В самообновлении и дифференцировке панкреатических РСК важную роль играют три сигнальных молекулярных пути: Wnt, Sonic hedgehog и Notch. РСК обладают способностью к самообновлению, симметричному и асиметричному делению, частичной дифференцировке, а также к существованию, самообновлению и дифференцировке вне первичной опухоли. РСК обеспечивают рост и прогрессию опухоли, инвазивность и метастазирование ПАПЖ, а также поддерживают ее химиорезистентность. МСК костномозгового происхождения в поджелудочной железе не участвуют в эпителиальном канцерогенезе, но при взаимодействии с другими клетками микроокружения оказывают на опухоль как стимулирующее, так и ингибирующее влияние. МСК могут выступать в роли промоторов онкогенеза посредством трансформации в канцер-ассоциированные фибробласты, местной иммуносупрессии, стимуляции опухолевого неоангиогенеза, блокады апоптоза раковых клеток, участия в эпителиально-мезенхимальном переходе и метастазировании. МСК могут выступать в роли супрессоров онкогенеза посредством стимуляции иммуноклеточной инфильтрации опухолевой ткани, подавления функции AKT-и Wnt-сигнальных путей, индукции остановки клеточного цикла и запуска апоптоза раковых клеток, угнетения опухолевого неоангиогенеза.Выводы. РСК играют ключевую роль в реализации агрессивных свойств ПАПЖ; МСК воздействуют как на РСК, так и на собственно раковые клетки ПАПЖ, оказывая на опухоль и стимулирующее, и ингибирующее влияние. Данные о роли МСК в прогрессии ПАПЖ пока неоднородны, что обусловливает актуальность дальнейшего изучения этого вопроса.Ракові стовбурові та мезенхімальні стовбурові клітини у протоковій аденокарциномі підшлункової залози В. О. Туманський, І. С. Коваленко Протокова аденокарцинома підшлункової залози (ПАПЗ) -один із найбільш агресивних видів раку, стійкий до променевої та хіміотерапії, в його розвитку велике значення мають погано вивчені ракові стовбурові клітини (РСК) і мезенхімальні стовбурові клітини (МСК).Мета роботи -аналіз даних сучасної фахової літератури про роль стовбурових клітин у прогресії ПАПЗ.Пул стовбурових клітин ПАПЗ гетерогенний, складається з РСК і МСК, які формують у пухлині ніші стовбурових клітин. У самооновленні та диференціюванні панкреатичних РСК важливу роль відіграють три сигнальні молекулярні шляхи: Wnt, Sonic hedgehog і Notch. РСК мають здатність до самовідновлення, симетричного та асиметрично...
Sepsis and acute liver failure are associated with severe endogenous intoxication. Microglia, which are the resident immune brain cells, play diverse roles in central nervous system development, surveillance, and defense, as well as contributing to neuroinflammatory reactions. In particular, microglia are fundamental to the pathophysiology of reactive toxic encephalopathies. We analyzed microglial ultrastructure, morphotypes, and phagocytosis in the sensorimotor cortex of cecal ligation and puncture (CLP) and acetaminophen-induced liver failure (AILF) Wistar rats. A CLP model induced a gradual shift of ~50% of surveillant microglia to amoeboid hypertrophic-like and gitter cell-like reactive phenotypes with active phagocytosis and frequent contacts with damaged neurons. In contrast, AILF microglia exhibited amoeboid, rod-like, and hypertrophic-like reactive morphotypes with minimal indications for efficient phagocytosis, and were mostly in contact with edematous astrocytes. Close interactions of reactive microglia with neurons, astrocytes, and blood–brain barrier components reflect an active contribution of these cells to the tissue adaptation and cellular remodeling to toxic brain damage. Partial disability of reactive microglia may affect the integrity and metabolism in all tissue compartments, leading to failure of the compensatory mechanisms in acute endogenous toxic encephalopathies.
Sepsis-associated liver injury (SALI) induces secondary hepatotoxic brain damage, complementing the mechanisms of sepsis-associated encephalopathy. In these conditions, astrocytes play one of the central roles as being the main homeostatic glia and key cells to metabolize ammonia in the brain. The aim of the study was to determine the ammonia levels and reactive astroglial changes in the brain of deceased septic patients without liver failure and deceased patients with sepsis-associated liver injury. Materials and methods. Sectional material of 40 patients who died from abdominal sepsis was studied. Case histories were analyzed according to the SOFA scale with accent on the brain and liver disfunction confirmation and excluding kidney insufficiency. Septic cases designed two main comparison groups: 1) sepsis without SALI («non-SALI», n = 20); 2) sepsis with SALI («SALI», n = 20). Control group included autopsy material of 30 deceased patients with cardiovascular pathology with no inflammatory, metabolic or toxic comorbidity. In paraffin sections of the postmortem brain cortex, white matter, hippocampus, thalamus, striatum, and cerebellum, it was determined: i) immunohistochemical expression of GFAP, GS, and AQP4; ii) histochemical expression of tissue ammonia with Nessler's reagent according to V. Gutiérrez-de-Juan et al. (2017); iii) Що це за позначення ?numbers of Alzheimer type 2 astrocytes (AA2). Results. In the «non-SALI» group, it is found increased level of all the studied parameters: i) elevated GFAP in six brain regions with the highest growth in the cortex – by 8.46 times; ii) elevated GS in the thalamus and cerebellum (by 1.96 and 1.29 times, respectively); iii) elevated AQP4 in six brain regions with the highest rise in the cortex – by 3 times; iv) elevated histochemical ammonia expression in the thalamus, striatum, and cerebellum (by 1.29, 1.20, and 1.17 times, respectively); v) increased AA2 numbers in the cortex and thalamus (by 2.32 and 1.53 times, respectively). The «SALI» group is characterized by the decreased GFAP expression in six brain regions, with the lowest values in thalamus, striatum, and cerebellum. Herewith, in six brain regions increased levels are typical for: i) GS expression, with maximal aggravation in the cortex and thalamus (by 3.20 and 3.18 times, respectively); ii) AQP4 expression, with maximal increase in thalamus and white matter (by 4.37 and 4.21 times, respectively); iii) histochemical ammonia expression with maximal enhancement in thalamus and cerebellum (by 4.33 and 4.27 times, respectively); iv) severity of AA2-astrocytosis with maximal rates in the cortex and striatum (increase by 3.58 and 3.23 times, respectively). Conclusions. In the brain of deceased septic patients without liver failure, a heterogeneously increased expression of GFAP, AQP4 and GS is observed which is accompanied by a slight increase in the level of tissue ammonia and weak AA2-astrocytosis. In deceased septic patients with sepsis-associated liver injury, a higher level of ammonia in the brain is associated with a significantly reduced level of GFAP, which is accompanied by an enhanced expression of GS and AQP4, as well as more pronounced AA2-astrocytosis, which indicates significant structural and functional remodeling and aggravation of astroglial dystrophy under action of hepatogenic neurointoxicity, which contributes to the disruption of astroglial homeostatic functionality and exacerbates sepsis-associated brain damage.
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