Artykuły w czasopismach na temat „Liver sinusoidal endothelial cell”
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Couvelard, A., JY Scoazec, MC Dauge, AF Bringuier, F. Potet i G. Feldmann. "Structural and functional differentiation of sinusoidal endothelial cells during liver organogenesis in humans". Blood 87, nr 11 (1.06.1996): 4568–80. http://dx.doi.org/10.1182/blood.v87.11.4568.bloodjournal87114568.
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During fetal life, human liver sinusoids, which differentiate between 4 and 12 weeks of gestation from capillaries of the septum transversum, must support an important hematopoietic function and acquire the structural and functional characteristics of adult sinusoids. To gain insight into their differentiation process, we studied the expression of (1) markers of continuous endothelia, absent from adult sinusoidal endothelial cells (PECAM-1, CD34, and 1F10); (2) functional markers of adult sinusoidal endothelial calls (CD4, 1CAM-1, CD32, and CD14); and (3) extracellular matrix components (laminin, tenascin, fibronectin, and thrombospondin) in 37 fetuses of different gestational ages. We identified two successive differentiation events. (1) An early structural differentiation, occurring from 5 to 12 weeks of gestation, was characterized by the loss of continuous endothelial cell markers and a reduction in the perisinusoidal amount of laminin and in the deposition of tenascin, fibronectin, and thrombospondin; at the end of this process, fetal liver sinusoids present structural characteristics comparable to those of the sinuses in adult hematopoietic bone marrow. (2) A later functional differentiation was characterized by the acquisition of the markers of adult sinusoidal endothelial cells, initiating at 10 weeks of gestation and completed by 20 weeks of gestation; this process likely contributes to adapt liver sinusoids to the specific functions of the adult hepatic tissue.
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Maretti-Mira, Ana, i Laurie DeLeve. "Liver Sinusoidal Endothelial Cell: An Update". Seminars in Liver Disease 37, nr 04 (listopad 2017): 377–87. http://dx.doi.org/10.1055/s-0037-1617455.
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AbstractThis update focuses on two main topics. First, recent developments in our understanding of liver sinusoidal endothelial cell (LSEC) function will be reviewed, specifically elimination of blood-borne waste, immunological function of LSECs, interaction of LSECs with liver metastases, LSECs and liver regeneration, and LSECs and hepatic fibrosis. Second, given the current emphasis on rigor and transparency in biomedical research, the update discusses the need for standardization of methods to demonstrate identity and purity of isolated LSECs, pitfalls in methods that might lead to a selection bias in the types of LSECs isolated, and questions about long-term culture of LSECs. Various surface markers used for immunomagnetic selection are reviewed.
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Tee, Jie, Li Ng, Hannah Koh, David Leong i Han Ho. "Titanium Dioxide Nanoparticles Enhance Leakiness and Drug Permeability in Primary Human Hepatic Sinusoidal Endothelial Cells". International Journal of Molecular Sciences 20, nr 1 (21.12.2018): 35. http://dx.doi.org/10.3390/ijms20010035.
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Liver sinusoidal endothelial cells (LSECs) represent the permeable interface that segregates the blood compartment from the hepatic cells, regulating hepatic vascular tone and portal pressure amidst changes in the blood flow. In the presence of pathological conditions, phenotypic changes in LSECs contribute to the progression of chronic liver diseases, including the loss of endothelial permeability. Therefore, modulating LSECs offers a possible way to restore sinusoidal permeability and thereby improve hepatic recovery. Herein, we showed that titanium dioxide nanoparticles (TiO2 NPs) could induce transient leakiness in primary human hepatic sinusoidal endothelial cells (HHSECs). Interestingly, HHSECs exposed to these NPs exhibited reduced protein kinase B (Akt) phosphorylation, an important protein kinase which regulates cell attachment. Using a 3D co-culture system, we demonstrated that TiO2 NPs diminished the attachment of HHSECs onto normal human hepatic cell LO2. To further illustrate the significance of leakiness in liver sinusoids, we showed that NP-induced leakiness promoted Sunitinib transport across the HHSEC layer, resulting in increased drug uptake and efficacy. Hence, TiO2 NPs have the potential to modulate endothelial permeability within the specialized sinusoidal endothelium, especially during events of fibrosis and occlusion. This study highlighted the possible use of inorganic NPs as a novel strategy to promote drug delivery targeting the diseased liver.
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Cogger, Victoria Carroll, Mashani Mohamad, Samantha Marie Solon-Biet, Alistair M. Senior, Alessandra Warren, Jennifer Nicole O'Reilly, Bui Thanh Tung i in. "Dietary macronutrients and the aging liver sinusoidal endothelial cell". American Journal of Physiology-Heart and Circulatory Physiology 310, nr 9 (1.05.2016): H1064—H1070. http://dx.doi.org/10.1152/ajpheart.00949.2015.
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Fenestrations are pores within the liver sinusoidal endothelial cells (LSECs) that line the sinusoids of the highly vascularized liver. Fenestrations facilitate the transfer of substrates between blood and hepatocytes. With pseudocapillarization of the hepatic sinusoid in old age, there is a loss of fenestrations. LSECs are uniquely exposed to gut-derived dietary and microbial substrates delivered by the portal circulation to the liver. Here we studied the effect of 25 diets varying in content of macronutrients and energy on LSEC fenestrations using the Geometric Framework method in a large cohort of mice aged 15 mo. Macronutrient distribution rather than total food or energy intake was associated with changes in fenestrations. Porosity and frequency were inversely associated with dietary fat intake, while fenestration diameter was inversely associated with protein or carbohydrate intake. Fenestrations were also linked to diet-induced changes in gut microbiome, with increased fenestrations associated with higher abundance of Firmicutes and reduced abundance of Bacteroidetes. Diet-induced changes in levels of several fatty acids (C16:0, C19:0, and C20:4) were also significantly inversely associated with fenestrations, suggesting a link between dietary fat and modulation of lipid rafts in the LSECs. Diet influences fenestrations and these data reflect both the key role of the LSECs in clearing gut-derived molecules from the vascular circulation and the impact these molecules have on LSEC morphology.
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Enomoto, Katsuhiko, Yuji Nishikawa, Yasufumi Omori, Takuo Tokairin, Masayuki Yoshida, Naoto Ohi, Takuya Nishimura, Youhei Yamamoto i Qinchang Li. "Cell biology and pathology of liver sinusoidal endothelial cells". Medical Electron Microscopy 37, nr 4 (grudzień 2004): 208–15. http://dx.doi.org/10.1007/s00795-004-0261-4.
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Wang, Lin, Xiangdong Wang, Guanhua Xie, Lei Wang, Colin K. Hill i Laurie D. DeLeve. "Liver sinusoidal endothelial cell progenitor cells promote liver regeneration in rats". Journal of Clinical Investigation 122, nr 4 (2.04.2012): 1567–73. http://dx.doi.org/10.1172/jci58789.
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Pitas, R. E., J. Boyles, R. W. Mahley i D. M. Bissell. "Uptake of chemically modified low density lipoproteins in vivo is mediated by specific endothelial cells." Journal of Cell Biology 100, nr 1 (1.01.1985): 103–17. http://dx.doi.org/10.1083/jcb.100.1.103.
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Acetoacetylated (AcAc) and acetylated (Ac) low density lipoproteins (LDL) are rapidly cleared from the plasma (t1/2 approximately equal to 1 min). Because macrophages, Kupffer cells, and to a lesser extent, endothelial cells metabolize these modified lipoproteins in vitro, it was of interest to determine whether endothelial cells or macrophages could be responsible for the in vivo uptake of these lipoproteins. As previously reported, the liver is the predominant site of the uptake of AcAc LDL; however, we have found that the spleen, bone marrow, adrenal, and ovary also participate in this rapid clearance. A histological examination of tissue sections, undertaken after the administration of AcAc LDL or Ac LDL (labeled with either 125I or a fluorescent probe) to rats, dogs, or guinea pigs, was used to identify the specific cells binding and internalizing these lipoproteins in vivo. With both techniques, the sinusoidal endothelial cells of the liver, spleen, bone marrow, and adrenal were labeled. Less labeling was noted in the ovarian endothelia. Uptake of AcAc LDL by endothelial cells of the liver, spleen, and bone marrow was confirmed by transmission electron microscopy. These data suggest uptake through coated pits. Uptake of AcAc LDL was not observed in the endothelia of arteries (including the coronaries and aorta), veins, or capillaries of the heart, testes, kidney, brain, adipose tissue, and duodenum. Kupffer cells accounted for a maximum of 14% of the 125I-labeled AcAc LDL taken up by the liver. Isolated sinusoidal endothelial cells from the rat liver displayed saturable, high affinity binding of AcAc LDL (Kd = 2.5 X 10(-9) M at 4 degrees C), and were shown to degrade AcAc LDL 10 times more effectively than aortic endothelial cells. These data indicate that specific sinusoidal endothelial cells, not the macrophages of the reticuloendothelial system, are primarily responsible for the removal of these modified lipoproteins from the circulation in vivo.
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Koch, Philipp-Sebastian, Ki Hong Lee, Sergij Goerdt i Hellmut G. Augustin. "Angiodiversity and organotypic functions of sinusoidal endothelial cells". Angiogenesis 24, nr 2 (21.03.2021): 289–310. http://dx.doi.org/10.1007/s10456-021-09780-y.
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Abstract‘Angiodiversity’ refers to the structural and functional heterogeneity of endothelial cells (EC) along the segments of the vascular tree and especially within the microvascular beds of different organs. Organotypically differentiated EC ranging from continuous, barrier-forming endothelium to discontinuous, fenestrated endothelium perform organ-specific functions such as the maintenance of the tightly sealed blood–brain barrier or the clearance of macromolecular waste products from the peripheral blood by liver EC-expressed scavenger receptors. The microvascular bed of the liver, composed of discontinuous, fenestrated liver sinusoidal endothelial cells (LSEC), is a prime example of organ-specific angiodiversity. Anatomy and development of LSEC have been extensively studied by electron microscopy as well as linage-tracing experiments. Recent advances in cell isolation and bulk transcriptomics or single-cell RNA sequencing techniques allowed the identification of distinct LSEC molecular programs and have led to the identification of LSEC subpopulations. LSEC execute homeostatic functions such as fine tuning the vascular tone, clearing noxious substances from the circulation, and modulating immunoregulatory mechanisms. In recent years, the identification and functional analysis of LSEC-derived angiocrine signals, which control liver homeostasis and disease pathogenesis in an instructive manner, marks a major change of paradigm in the understanding of liver function in health and disease. This review summarizes recent advances in the understanding of liver vascular angiodiversity and the functional consequences resulting thereof.
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Gibert-Ramos, Albert, David Sanfeliu-Redondo, Peio Aristu-Zabalza, Ana Martínez-Alcocer, Jordi Gracia-Sancho, Sergi Guixé-Muntet i Anabel Fernández-Iglesias. "The Hepatic Sinusoid in Chronic Liver Disease: The Optimal Milieu for Cancer". Cancers 13, nr 22 (15.11.2021): 5719. http://dx.doi.org/10.3390/cancers13225719.
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The liver sinusoids are a unique type of microvascular beds. The specialized phenotype of sinusoidal cells is essential for their communication, and for the function of all hepatic cell types, including hepatocytes. Liver sinusoidal endothelial cells (LSECs) conform the inner layer of the sinusoids, which is permeable due to the fenestrae across the cytoplasm; hepatic stellate cells (HSCs) surround LSECs, regulate the vascular tone, and synthetize the extracellular matrix, and Kupffer cells (KCs) are the liver-resident macrophages. Upon injury, the harmonic equilibrium in sinusoidal communication is disrupted, leading to phenotypic alterations that may affect the function of the whole liver if the damage persists. Understanding how the specialized sinusoidal cells work in coordination with each other in healthy livers and chronic liver disease is of the utmost importance for the discovery of new therapeutic targets and the design of novel pharmacological strategies. In this manuscript, we summarize the current knowledge on the role of sinusoidal cells and their communication both in health and chronic liver diseases, and their potential pharmacologic modulation. Finally, we discuss how alterations occurring during chronic injury may contribute to the development of hepatocellular carcinoma, which is usually developed in the background of chronic liver disease.
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Zhang, Xingqin, Yi Chen, Liqun Tang, Yunhai Zhang, Pengkai Duan, Lei Su i Huasheng Tong. "The liver sinusoidal endothelial cell damage in rats caused by heatstroke". European Journal of Inflammation 16 (styczeń 2018): 205873921879432. http://dx.doi.org/10.1177/2058739218794328.
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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.
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DeLeve, Laurie D. "Liver sinusoidal endothelial cells and liver regeneration". Journal of Clinical Investigation 123, nr 5 (1.05.2013): 1861–66. http://dx.doi.org/10.1172/jci66025.
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Xie, Guanhua, Steve S. Choi, Wing-Kin Syn, Gregory A. Michelotti, Marzena Swiderska, Gamze Karaca, Isaac S. Chan, Yuping Chen i Anna Mae Diehl. "Hedgehog signalling regulates liver sinusoidal endothelial cell capillarisation". Gut 62, nr 2 (23.02.2012): 299–309. http://dx.doi.org/10.1136/gutjnl-2011-301494.
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Tong, Chun-Fang, Yan Zhang, Shou-Qin Lü, Ning Li, Yi-Xin Gong, Hao Yang, Shi-Liang Feng, Yu Du, Dan-Dan Huang i Mian Long. "Binding of intercellular adhesion molecule 1 to β2-integrin regulates distinct cell adhesion processes on hepatic and cerebral endothelium". American Journal of Physiology-Cell Physiology 315, nr 3 (1.09.2018): C409—C421. http://dx.doi.org/10.1152/ajpcell.00083.2017.
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Flowing polymorphonuclear neutrophils (PMNs) are forced to recruit toward inflamed tissue and adhere to vascular endothelial cells, which is primarily mediated by the binding of β2-integrins to ICAM-1. This process is distinct among different organs such as liver and brain; however, the underlying kinetic and mechanical mechanisms regulating tissue-specific recruitment of PMNs remain unclear. Here, binding kinetics measurement showed that ICAM-1 on murine hepatic sinusoidal endothelial cells (LSECs) bound to lymphocyte function-associated antigen-1 (LFA-1) with higher on- and off-rates but lower effective affinity compared with macrophage-1 antigen (Mac-1), whereas ICAM-1 on cerebral endothelial cells (BMECs or bEnd.3 cells) bound to LFA-1 with higher on-rates, similar off-rates, and higher effective affinity compared with Mac-1. Physiologically, free crawling tests of PMN onto LSEC, BMEC, or bEnd.3 monolayers were consistent with those kinetics differences between two β2-integrins interacting with hepatic sinusoid or cerebral endothelium. Numerical calculations and Monte Carlo simulations validated tissue-specific contributions of β2-integrin-ICAM-1 kinetics to PMN crawling on hepatic sinusoid or cerebral endothelium. Thus, this work first quantified the biophysical regulation of PMN adhesion in hepatic sinusoids compared with cerebral endothelium.
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Natarajan, Vaishaali, Edward N. Harris i Srivatsan Kidambi. "SECs (Sinusoidal Endothelial Cells), Liver Microenvironment, and Fibrosis". BioMed Research International 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/4097205.
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Liver fibrosis is a wound-healing response to chronic liver injury such as alcoholic/nonalcoholic fatty liver disease and viral hepatitis with no FDA-approved treatments. Liver fibrosis results in a continual accumulation of extracellular matrix (ECM) proteins and paves the way for replacement of parenchyma with nonfunctional scar tissue. The fibrotic condition results in drastic changes in the local mechanical, chemical, and biological microenvironment of the tissue. Liver parenchyma is supported by an efficient network of vasculature lined by liver sinusoidal endothelial cells (LSECs). These nonparenchymal cells are highly specialized resident endothelial cell type with characteristic morphological and functional features. Alterations in LSECs phenotype including lack of LSEC fenestration, capillarization, and formation of an organized basement membrane have been shown to precede fibrosis and promote hepatic stellate cell activation. Here, we review the interplay of LSECs with the dynamic changes in the fibrotic liver microenvironment such as matrix rigidity, altered ECM protein profile, and cell-cell interactions to provide insight into the pivotal changes in LSEC physiology and the extent to which it mediates the progression of liver fibrosis. Establishing the molecular aspects of LSECs in the light of fibrotic microenvironment is valuable towards development of novel therapeutic and diagnostic targets of liver fibrosis.
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Zhang, Chunqing, Juren Zu, Hengmei Shi, Jiyong Liu i Chengyong Qin. "The Effect of Ginkgo biloba Extract (EGb 761) on Hepatic Sinusoidal Endothelial Cells and Hepatic Microcirculation in CCl4 Rats". American Journal of Chinese Medicine 32, nr 01 (styczeń 2004): 21–31. http://dx.doi.org/10.1142/s0192415x04001692.
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It has been shown that Ginkgo biloba Extract (EGb 761) increases peripheral and cerebral blood flow and microcirculation and improves myocardial ischemia reperfusion injury. This study was designed to investigate the effect of EGb 761 on hepatic endothelial cells and hepatic microcirculation. Sixty male Wister rats were divided into normal, carbon tetrachloride ( CCl 4) and EGb groups, and were given normal saline, CCl 4 and CCl 4 plus EGb 761, respectively, for 10 weeks. Samples were taken from the medial lobe of the rat livers ten weeks later. Hepatic sinusoidal endothelial cells and other parameters of hepatic microcirculation were observed under transmission electron microscopy (TEM). The amount of malondialdehyde (MDA), endothelin (ET-1), platelet-activating factor (PAF) and nitric oxide (NO) in liver tissue was determined by spectrophotometry and radioimmunoassay, respectively. Compared with the CCl 4 group, aggregation of blood cell or micro thrombosis in hepatic sinusoids, deposition of collagen in hepatic sinusoids and space of Disse, injury of endothelial cells and capillization of hepatic sinusoid was significantly reduced in the EGb group. The amount of MDA, ET-1 and PAF was markedly reduced in the EGb group than in the CCl 4 group, while no significant difference in the amount of NO was observed between the two groups. The results demonstrate that EGb 761 has protective effect on hepatic endothelial cells and hepatic microcirculation in rats with chronic liver injury induced by CCl 4. The mechanisms may involve its inhibition on ET-1, PAF and lipid peroxidation.
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Serra, Monica, Michela Marongiu, Antonella Contini, Toshio Miki, Erika Cadoni, Ezio Laconi i Fabio Marongiu. "Evidence of Amniotic Epithelial Cell Differentiation toward Hepatic Sinusoidal Endothelial Cells". Cell Transplantation 27, nr 1 (styczeń 2018): 23–30. http://dx.doi.org/10.1177/0963689717727541.
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Amniotic epithelial cells (AECs) represent a useful and noncontroversial source for liver-based regenerative medicine, as they can differentiate into hepatocytes upon transplantation into the liver. However, the possibility that AECs can differentiate into other liver cell types, such as hepatic sinusoidal endothelial cells (HSECs), has never been assessed. In order to test this hypothesis, rat- and human-derived AECs (rAECs and hAECs, respectively) were subjected to endothelial cell tube formation assay in vitro. Moreover, to evaluate differentiation in vivo, the retrorsine (RS) model of liver repopulation was used. Pyrrolizidine alkaloids (including RS) are known to target both hepatocytes and endothelial cells, inducing cell enlargement and inhibition of cell cycle progression. rAECs and hAECs were able to form capillary-like structures when cultured under proangiogenic conditions. For in vivo experiments, rAECs were obtained from dipeptidyl peptidase type IV (DPP-IV, CD26) donors and were transplanted into the liver of recipient CD26 negative animals pretreated with RS. rAEC-derived cells were engrafted in between hepatocytes and resembled HSECs as assessed by morphological analysis and the pattern of expression of CD26. Donor-derived CD26+ cells coexpressed HSEC markers RECA-1 and SE-1, while they lacked expression of typical hepatocyte markers (i.e., cytochrome P450, hepatocyte nuclear factor 4α). As such, these results provide the first evidence that AECs can respond to proangiogenic signals in vitro and differentiate into HSECs in vivo. Furthermore, they support the conclusion that AECs possesses great plasticity and represents a promising tool in the field of regenerative medicine both in the liver and in other organs.
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Kabarriti, R., H. Zhou, J. V. Vainshtein, S. Saha, R. Hannan, N. Thawani, A. Alfieri, S. Kalnicki i C. Guha. "Transplantation of Liver Sinusoidal Endothelial Cells Repairs HIR Induced Hepatic Endothelial Cell Damage". International Journal of Radiation Oncology*Biology*Physics 78, nr 3 (listopad 2010): S41. http://dx.doi.org/10.1016/j.ijrobp.2010.07.131.
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Speilberg, L., Ø. Evensen i B. H. Dannevig. "A Sequential Study of the Light and Electron Microscopic Liver Lesions of Infectious Anemia in Atlantic Salmon (Salmo salar L.)". Veterinary Pathology 32, nr 5 (wrzesień 1995): 466–78. http://dx.doi.org/10.1177/030098589503200503.
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The present study describes light and electron microscopic changes in the liver of Atlantic salmon during the development of infectious salmon anemia (ISA). Atlantic salmon postsmolts weighing 80-100 g were infected by intraperitoneal injections, and liver samples were collected sequentially between day 0 and day 25 post infection (p.i.), with time intervals of 3-4 days. At each collection time, livers from five infected fish and two control fish were examined. Changes involving the perisinusoidal macrophages were observed by transmission electron microscopy, from day 4 p.i. Large vacuoles, containing a fine-granular material with low electron density, accumulated in the cytoplasm. These changes persisted and became more severe throughout the investigation, leading to a considerable increase in the size of the cells. At day 14 p.i., degenerative features of the sinusoidal endothelium were observed. By day 18 p.i., areas of the liver were devoid of a sinusoidal endothelial lining, bringing hepatocytes in direct contact with blood cells. At this stage, the sinusoids were moderately congested. From day 21 p.i., heavy sinusoidal congestion, peliosis hepatis, and degeneration of the hepatocytes were observed. No virus was observed in any of the inhabitant cell types of the liver. Gross and light microscopic changes were first recorded at day 18 p.i., as was a significant decrease in the hematocrit values. By day 25 p.i., characteristic multifocal, confluent, hemorrhagic necroses were present. Results of the present investigation suggest that the liver lesions observed with ISA are not the result of the development of an anemia alone or caused by direct viral damage to hepatocytes. Hepatocellular degeneration succeeded changes in the perisinusoidal macrophages and degeneration of the sinusoidal endothelium. These changes may have impeded the sinusoidal blood flow and hence caused an ischemic hepatocellular necrosis.
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Kermani, Pouneh, Anita Ramnarain, Raul Catena, Zu-Lin Chen, Barbara Hempstead, Sidney Strickland i Karen-Sue B. Carlson. "Laminin Expression Is Necessary for Maintenance of the Vascular Hematopoietic Niche". Blood 118, nr 21 (18.11.2011): 217. http://dx.doi.org/10.1182/blood.v118.21.217.217.
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Abstract Abstract 217 Laminins are heterotrimeric proteins that are the backbone for all basal laminas. They provide structural support, points for focal adhesion, and biochemical feedback for nearby cells. Laminins are found in many tissues, including bone marrow and lymphoid organs, and are detected in the discontinuous basal lamina of sinusoidal blood vessels. Laminin g1 is the predominant gamma subunit found in the bone marrow and lymphoid tissues. Here we show that the continuous expression of laminin in adulthood is necessary for viability of the vascular hematopoietic niche (sinusoidal endothelial cells). In the absence of laminin, this niche fails and hematopoiesis is impaired. To determine if sinusoidal laminin expression correlates with bone marrow failure and recovery, we used a well-established model of bone marrow failure. Wild type mice were treated with a sublethal dose of 5-fluoruracil (5-FU), and bone marrow was analyzed for disruption of sinusoid architecture and endothelial cell receptor and laminin expression. As described in other studies, shortly after treatment with 5-FU, bone marrow sinusoids became disorganized and hemorrhagic, and endothelial cells lost expression of VEGFR2. In addition, sinusoids lost their laminin-containing basal lamina. These changes correlated with bone marrow failure and onset of peripheral blood pancytopenia. As the sinusoids regained normal cytoarchitecture and VEGFR2 expression was normalized, sinusoid expression of laminin also returned to basal levels. With 5-FU-induced bone marrow failure and recovery, hematopoiesis correlated with laminin expression in the vascular hematopoietic stem cell niche. To test whether laminin expression directly affects the quality of the niche and hematopoiesis, a mutant mouse line was generated in which laminin g1 expression could be deleted by brief exposure to tamoxifen (TM). Control mice were littermates that lacked the TM-responsive Cre transgene. Prior to TM treatment, adult mutant and control mice had normal peripheral blood cell counts, and there was no evidence of gene recombination in genomic DNA samples. Adult mutant and control mice were then injected with either TM or vehicle, and the peripheral blood, bone marrow, spleen, and liver were collected after three weeks. Laminin g1 genes were deleted and laminin expression was lost in bone marrow, spleen, and liver sinusoids of only the TM-treated mutant mice. These mice also became thrombocytopenic and leukopenic. Flow cytometry showed early arrest of B-lymphocyte development within the bone marrow, bone marrow sinusoids became hemorrhagic, and the normal cytoarchitecture of the sinusoids and endothelial expression of VEGFR2 were lost. All other mouse groups were unaffected. These results suggest that continuous laminin expression is necessary for support of sinusoidal endothelial cells and the vascular hematopoietic niche. Disruption of the hematopoietic microenvironment is sufficient to alter blood cell development and release into peripheral circulation. These studies support the critical role of the microenvironment and stroma in supporting hematopoiesis. Disclosures: No relevant conflicts of interest to declare.
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Liu, Songling, i Don C. Rockey. "Cicletanine stimulates eNOS phosphorylation and NO production via Akt and MAP kinase/Erk signaling in sinusoidal endothelial cells". American Journal of Physiology-Gastrointestinal and Liver Physiology 305, nr 2 (15.07.2013): G163—G171. http://dx.doi.org/10.1152/ajpgi.00003.2013.
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The function of the endothelial isoform of nitric oxide synthase (eNOS) and production of nitric oxide (NO) is altered in a number of disease states. Pharmacological approaches to enhancing NO synthesis and thus perhaps endothelial function could have substantial benefits in patients. We analyzed the effect of cicletanine, a synthetic pyridine with potent vasodilatory characteristics, on eNOS function and NO production in normal (liver) and injured rat sinusoidal endothelial cells, and we studied the effect of cicletanine-induced NO on stellate cell contraction and portal pressure in an in vivo model of liver injury. Sinusoidal endothelial cells were isolated from normal and injured rat livers. After exposure to cicletanine, eNOS phosphorylation, NO synthesis, and the signaling pathway regulating eNOS activation were measured. Cicletanine led to an increase in eNOS (Ser1177) phosphorylation, cytochrome c reductase activity, l-arginine conversion to l-citrulline, as well as NO production. The mechanism of the effect of cicletanine appeared to be via the protein kinase B (Akt) and MAP kinase/Erk signaling pathways. Additionally, cicletanine improved NO synthesis in injured sinusoidal endothelial cells. NO production induced by cicletanine in sinusoidal endothelial cells increased protein kinase G (PKG) activity as well as relaxation of stellate cells. Finally, administration of cicletanine to mice with portal hypertension induced by bile duct ligation led to reduction of portal pressure. The data indicate that cicletanine might improve eNOS activity in injured sinusoidal endothelial cells and likely activates hepatic stellate cell NO/PKG signaling. It raises the possibility that cicletanine could improve intrahepatic vascular function in portal hypertensive patients.
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McDonald, Braedon, Lisheng Zhuo, Koji Kimata i Paul Kubes. "Activation of TLR4 on endothelium alone initiates neutrophil adhesion within the liver microcirulation during endotoxemia (102.22)". Journal of Immunology 186, nr 1_Supplement (1.04.2011): 102.22. http://dx.doi.org/10.4049/jimmunol.186.supp.102.22.
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Abstract During sepsis and endotoxemia, neutrophils are recruited to the liver where they cause tissue damage and vascular dysfunction. We have previously reported that neutrophils adhere within sinusoids of the endotoxemic liver via interactions between neutrophil CD44 and endothelial hyaluronan. In this study, we aimed to characterize the cellular sentinels that detect circulating LPS via TLR4 and the pathways leading to initiation of neutrophil adhesion via CD44-hyaluronan interactions. Intravital microscopy of bone marrow chimeric mice revealed that TLR4 expression by non-bone marrow derived cells was required for neutrophil recruitment into the liver during endotoxemia (1 mg/kg LPS, i.v.). Furthermore, LPS-induced neutrophil adhesion in sinusoids was equivalent between wild-type mice and transgenic mice that express TLR4 only on endothelium (tlr4-/-Tie2tlr4, named endoTLR4), but surprisingly, sinusoidal occlusion (vascular damage) was attenuated in endoTLR4 mice. Intravital immunofluorescence imaging demonstrated that stimulation of endothelial TLR4 induced the deposition of serum-derived hyaluronan associated protein (SHAP) within liver sinsusoids, which was required for activation of endothelial hyaluronan to bind neutrophil CD44. These data reveal that endothelial cells are the key sentinels that recognize circulating LPS and initiate neutrophil adhesion in the liver during endotoxemia, but the development of liver pathology requires TLR4 activation on additional cell types.
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Brougham-Cook, Aidan, Hannah R. C. Kimmel, Chase P. Monckton, Daniel Owen, Salman R. Khetani i Gregory H. Underhill. "Engineered matrix microenvironments reveal the heterogeneity of liver sinusoidal endothelial cell phenotypic responses". APL Bioengineering 6, nr 4 (1.12.2022): 046102. http://dx.doi.org/10.1063/5.0097602.
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Fibrosis is one of the hallmarks of chronic liver disease and is associated with aberrant wound healing. Changes in the composition of the liver microenvironment during fibrosis result in a complex crosstalk of extracellular cues that promote altered behaviors in the cell types that comprise the liver sinusoid, particularly liver sinusoidal endothelial cells (LSECs). Recently, it has been observed that LSECs may sustain injury before other fibrogenesis-associated cells of the sinusoid, implicating LSECs as key actors in the fibrotic cascade. A high-throughput cellular microarray platform was used to deconstruct the collective influences of defined combinations of extracellular matrix (ECM) proteins, substrate stiffness, and soluble factors on primary human LSEC phenotype in vitro. We observed remarkable heterogeneity in LSEC phenotype as a function of stiffness, ECM, and soluble factor context. LYVE-1 and CD-31 expressions were highest on 1 kPa substrates, and the VE-cadherin junction localization was highest on 25 kPa substrates. Also, LSECs formed distinct spatial patterns of LYVE-1 expression, with LYVE-1+ cells observed in the center of multicellular domains, and pattern size regulated by microenvironmental context. ECM composition also influenced a substantial dynamic range of expression levels for all markers, and the collagen type IV was observed to promote elevated expressions of LYVE-1, VE-cadherin, and CD-31. These studies highlight key microenvironmental regulators of LSEC phenotype and reveal unique spatial patterning of the sinusoidal marker LYVE-1. Furthermore, these data provide insight into understanding more precisely how LSECs respond to fibrotic microenvironments, which will aid drug development and identification of targets to treat liver fibrosis.
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Zhang, J. X., M. Bauer i M. G. Clemens. "Vessel- and target cell-specific actions of endothelin-1 and endothelin-3 in rat liver". American Journal of Physiology-Gastrointestinal and Liver Physiology 269, nr 2 (1.08.1995): G269—G277. http://dx.doi.org/10.1152/ajpgi.1995.269.2.g269.
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We studied the sinusoidal and extrasinusoidal constrictor response of hepatic microcirculation to endothelin-1 (ET-1) and endothelin-3 (ET-3) and the possible role of Ito cells vs. Kupffer cells or endothelial cells in mediating this response, using isolated rat livers under high-power intravital microscopy. Rats were pretreated by injection of 2.6 x 10(8) fluorescent latex beads (1 micron) intravenously to label Kupffer cells. Three hours later livers were isolated and perfused before and during the infusion of 1 nM ET-1 or ET-3 with or without the endothelin type A (ETA) receptor antagonist BQ-123 or ETB antagonist IRL-1038. Alternatively, the perfused livers were infused with the ETB agonist sarafotoxin 6c (S6c, 1 or 5 nM). Sinusoid diameters were quantitated at the sites of Ito cells (identified by vitamin A fluorescence) or Kupffer cells (phagocytosed fluorescent latex beads) or where neither cell type was found (endothelial cells). ET-1 was found to induce significant sinusoid constriction at the sites of Ito cells (13.21 +/- 0.58 microns control vs. 10.47 +/- 0.48 microns during ET-1 infusion) but not at the sites of Kupffer cells or endothelial cells (13.26 +/- 0.79 vs. 12.92 +/- 0.61 microns and 12.20 +/- 0.71 vs. 11.98 +/- 0.40 microns, respectively), whereas neither ET-3 nor S6c had any effect on sinusoid narrowing, despite a 1.8-fold (ET-3) or 5.6-fold (5 nM S6c) greater increase in total portal resistance compared with ET-1.(ABSTRACT TRUNCATED AT 250 WORDS)
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FRENOY, J., S. MAGNUSSON, E. TURPIN i T. BERG. "Interaction of ricin with sinusoidal endothelial rat liver cells". Cell Biology International Reports 14 (wrzesień 1990): 248. http://dx.doi.org/10.1016/0309-1651(90)91091-h.
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de Haan, Willeke, Cristina Øie, Mohammed Benkheil, Wouter Dheedene, Stefan Vinckier, Giulia Coppiello, Xabier López Aranguren i in. "Unraveling the transcriptional determinants of liver sinusoidal endothelial cell specialization". American Journal of Physiology-Gastrointestinal and Liver Physiology 318, nr 4 (1.04.2020): G803—G815. http://dx.doi.org/10.1152/ajpgi.00215.2019.
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Liver sinusoidal endothelial cells (LSECs) are the first liver cells to encounter waste macromolecules, pathogens, and toxins in blood. LSECs are highly specialized to mediate the clearance of these substances via endocytic scavenger receptors and are equipped with fenestrae that mediate the passage of macromolecules toward hepatocytes. Although some transcription factors (TFs) are known to play a role in LSEC specialization, information about the specialized LSEC signature and its transcriptional determinants remains incomplete. Based on a comparison of liver, heart, and brain endothelial cells (ECs), we established a 30-gene LSEC signature comprising both established and newly identified markers, including 7 genes encoding TFs. To evaluate the LSEC TF regulatory network, we artificially increased the expression of the 7 LSEC-specific TFs in human umbilical vein ECs. Although Zinc finger E-box-binding protein 2, homeobox B5, Cut-like homolog 2, and transcription factor EC (TCFEC) had limited contributions, musculoaponeurotic fibrosarcoma (C-MAF), GATA binding protein 4 (GATA4), and MEIS homeobox 2 (MEIS2) emerged as stronger inducers of LSEC marker expression. Furthermore, a combination of C-MAF, GATA4, and MEIS2 showed a synergistic effect on the increase of LSEC signature genes, including liver/lymph node-specific ICAM-3 grabbing non-integrin ( L-SIGN) (or C-type lectin domain family member M ( CLEC4M)), mannose receptor C-Type 1 ( MRC1), legumain ( LGMN), G protein-coupled receptor 182 ( GPR182), Plexin C1 ( PLXNC1), and solute carrier organic anion transporter family member 2A1 ( SLCO2A1). Accordingly, L-SIGN, MRC1, pro-LGMN, GPR182, PLXNC1, and SLCO2A1 protein levels were elevated by this combined overexpression. Although receptor-mediated endocytosis was not significantly induced by the triple TF combination, it enhanced binding to E2, the hepatitis C virus host-binding protein. We conclude that C-MAF, GATA4, and MEIS2 are important transcriptional regulators of the unique LSEC fingerprint and LSEC interaction with viruses. Additional factors are however required to fully recapitulate the molecular, morphological, and functional LSEC fingerprint. NEW & NOTEWORTHY Liver sinusoidal endothelial cells (LSECs) are the first liver cells to encounter waste macromolecules, pathogens, and toxins in the blood and are highly specialized. Although some transcription factors are known to play a role in LSEC specialization, information about the specialized LSEC signature and its transcriptional determinants remains incomplete. Here, we show that Musculoaponeurotic Fibrosarcoma (C-MAF), GATA binding protein 4 (GATA4), and Meis homeobox 2 (MEIS2) are important transcriptional regulators of the unique LSEC signature and that they affect the interaction of LSECs with viruses.
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Werner, Melanie, Stefan Schefczyk, Martin Trippler, Juergen W. Treckmann, Hideo A. Baba, Guido Gerken, Joerg F. Schlaak i Ruth Broering. "Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3". Viruses 14, nr 2 (24.01.2022): 218. http://dx.doi.org/10.3390/v14020218.
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The role of non-parenchymal liver cells as part of the hepatic, innate immune system in the defense against hepatotropic viruses is not well understood. Here, primary human Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells were isolated from liver tissue obtained after tumor resections or liver transplantations. Cells were stimulated with Toll-like receptor 1–9 ligands for 6–24 h. Non-parenchymal liver cells expressed and secreted inflammatory cytokines (IL6, TNF and IL10). Toll-like receptor- and cell type-specific downstream signals included the phosphorylation of NF-κB, AKT, JNK, p38 and ERK1/2. However, only supernatants of TLR3-activated Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells contained type I and type III interferons and mediated an antiviral activity in the interferon-sensitive subgenomic hepatitis C virus replicon system. The antiviral effect could not be neutralized by antibodies against IFNA, IFNB nor IFNL, but could be abrogated using an interferon alpha receptor 2-specific neutralization. Interestingly, TLR3 responsiveness was enhanced in liver sinusoidal endothelial cells isolated from hepatitis C virus-positive donors, compared to uninfected controls. In conclusion, non-parenchymal liver cells are potent activators of the hepatic immune system by mediating inflammatory responses. Furthermore, liver sinusoidal endothelial cells were identified to be hyperresponsive to viral stimuli in chronic hepatitis C virus infection.
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Knolle, Percy A., i Dirk Wohlleber. "Immunological functions of liver sinusoidal endothelial cells". Cellular & Molecular Immunology 13, nr 3 (4.04.2016): 347–53. http://dx.doi.org/10.1038/cmi.2016.5.
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Rieder, H., K.-H. Meyer zum Büschenfelde i G. Ramadori. "Functional spectrum of sinusoidal endothelial liver cells". Journal of Hepatology 15, nr 1-2 (maj 1992): 237–50. http://dx.doi.org/10.1016/0168-8278(92)90042-n.
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Parrow, Nermi L., i Robert E. Fleming. "Liver sinusoidal endothelial cells as iron sensors". Blood 129, nr 4 (26.01.2017): 397–98. http://dx.doi.org/10.1182/blood-2016-12-754499.
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Klenerman, Paul, i Narayan Ramamurthy. "Liver Sinusoidal Endothelial Cells: An Antiviral “Defendothelium”". Gastroenterology 148, nr 2 (luty 2015): 288–91. http://dx.doi.org/10.1053/j.gastro.2014.12.010.
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DeLeve, Laurie D. "Liver sinusoidal endothelial cells in hepatic fibrosis". Hepatology 61, nr 5 (23.03.2015): 1740–46. http://dx.doi.org/10.1002/hep.27376.
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Jarnagin, W. R., D. C. Rockey, V. E. Koteliansky, S. S. Wang i D. M. Bissell. "Expression of variant fibronectins in wound healing: cellular source and biological activity of the EIIIA segment in rat hepatic fibrogenesis." Journal of Cell Biology 127, nr 6 (15.12.1994): 2037–48. http://dx.doi.org/10.1083/jcb.127.6.2037.
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We have examined the cell-specific expression of two fibronectin isoforms, EIIIA and EIIIB, during experimental hepatic fibrosis induced by ligation of the biliary duct. AT the mRNA level, EIIIA and EIIIB were undetectable in normal liver but expressed early injury, preceding fibrosis. The cellular sources of these changes were determined by fractionating the liver at various time points after bile duct ligation into its constituent cell populations and extracting RNA from the fresh isolates. EIIIA-containing fibronectin mRNA was undetectable in normal sinusoidal endothelial cells but increased rapidly within 12 h of injury. By contrast, the EIIIB form was restricted to hepatic lipocytes (Ito or fat-storing cells) and appeared only after a lag of 12-24 h: it was minimal in sinusoidal endothelial cells. Both forms were minimal in hepatocytes. At the protein level, EIIIA-containing fibronectin was markedly increased within two days of injury and exhibited a sinusoidal distribution. Secretion of this form by endothelial cells was confirmed in primary culture. Matrices deposited in situ by endothelial cells from injured liver accelerated the conversion ("activation") of normal lipocytes to myofibroblast-like cells, and pretreatment of matrices with monoclonal antibody to the EIIIA segment blocked this response. Finally, recombinant fibronectin peptide containing the EIIIA segment was stimulatory to lipocytes in culture. We conclude that expression of EIIIA fibronectin by sinusoidal endothelial cells is a critical early event in the liver's response to injury and that the EIIIA segment is biologically active, mediating the conversion of lipocytes to myofibroblasts.
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Balaphas, Alexandre, Jeremy Meyer, Remo Perozzo, Magali Zeisser-Labouebe, Sarah Berndt, Antoine Turzi, Pierre Fontana, Leonardo Scapozza, Carmen Gonelle-Gispert i Leo Bühler. "Platelet Transforming Growth Factor-β1 Induces Liver Sinusoidal Endothelial Cells to Secrete Interleukin-6". Cells 9, nr 5 (25.05.2020): 1311. http://dx.doi.org/10.3390/cells9051311.
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The roles and interactions of platelets and liver sinusoidal endothelial cells in liver regeneration are unclear, and the trigger that initiates hepatocyte proliferation is unknown. We aimed to identify the key factors released by activated platelets that induce liver sinusoidal endothelial cells to produce interleukin-6 (IL-6), a cytokine implicated in the early phase of liver regeneration. We characterized the releasate of activated platelets inducing the in vitro production of IL-6 by mouse liver sinusoidal endothelial cells and observed that the stimulating factor was a thermolabile protein. Following gel filtration, a single fraction of activated platelet releasate induced a maximal IL-6 secretion by liver sinusoidal endothelial cells (90.2 ± 13.9 versus control with buffer, 9.0 ± 0.8 pg/mL, p < 0.05). Mass spectroscopy analysis of this fraction, followed by in silico processing, resulted in a reduced list of 18 candidates. Several proteins from the list were tested, and only recombinant transforming growth factor β1 (TGF-β1) resulted in an increased IL-6 production up to 242.7 ± 30.5 pg/mL, which was comparable to non-fractionated platelet releasate effect. Using neutralizing anti-TGF-β1 antibody or a TGF-β1 receptor inhibitor, IL-6 production by liver sinusoidal endothelial cells was dramatically reduced. These results support a role of platelet TGF-β1 β1 in the priming phase of liver regeneration.
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Colucci, Silvia, Sandro Altamura, Matthias Hentze i Martina U. Muckenthaler. "Sensing of Liver Iron Content Requires Cell-Cell Communication between Hepatocytes and Liver Sinusoidal Endothelial Cells". Blood 134, Supplement_1 (13.11.2019): 432. http://dx.doi.org/10.1182/blood-2019-125586.
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The liver stores iron and senses systemic and tissue iron availability. Hepatocytes control iron homeostasis by producing the peptide hormone hepcidin that controls dietary iron absorption and iron release from intracellular stores. Recent data challenged the exclusive role of hepatocytes in controlling iron levels. Indeed, liver sinusoidal endothelial cells (LSECs) increase BMP2 and BMP6 levels in response to iron, which control hepcidin expression in a paracrine manner. However the molecular mechanism(s) of how BMPs respond to iron levels remain unknown. We established primary murine LSEC cultures and exposed these to iron sources. Unexpectedly, BMP2 mRNA expression is strongly reduced by iron treatment, while BMP6 levels are only mildly increased. This finding suggests that intracellular iron content cannot directly activate BMP2 transcription and only slightly contribute to BMP6 upregulation in LSEC cultures. However, if LSECs are co-cultured with iron-loaded primary hepatocytes the expression of BMP2 and BMP6 is increased and the fold induction of BMP6 is greater compared to LSECs cultured alone, suggesting that the iron status of hepatocytes instructs the LSEC BMP response. These data are supported by findings in a genetic mouse model of iron overload (Slc40a1C326S/C326S). Hepatocytes isolated from Slc40a1C326S/C326S mice display an iron-loaded molecular signature and the expected low mRNA expression of Transferrin Receptor 1 (Tfr1). By contrast, LSECs show high expression of Tfr1, indicating intracellular iron deficiency. Despite this, hepatic BMP levels are increased, suggesting that BMP2 and BMP6 expression are directly related to the intracellular iron content of hepatocytes but not LSECs. RNA-sequencing of isolated hepatic cell populations is ongoing to identify putative hepatocyte regulators involved in the iron-mediated BMP2 and BMP6 regulation. Disclosures Muckenthaler: Silence Therapeutics: Consultancy; Novartis: Research Funding.
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Vats, Ravi, Ziming Li, Eun-Mi Ju, Rikesh K. Dubey, Tomasz W. Kaminski, Simon Watkins i Tirthadipa Pradhan-Sundd. "Intravital imaging reveals inflammation as a dominant pathophysiology of age-related hepatovascular changes". American Journal of Physiology-Cell Physiology 322, nr 3 (1.03.2022): C508—C520. http://dx.doi.org/10.1152/ajpcell.00408.2021.
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Aging is the most significant risk factor for the majority of chronic diseases, including liver disease. The cellular, molecular, and pathophysiological mechanisms that promote age-induced hepatovascular changes are unknown due to our inability to visualize changes in liver pathophysiology in live mice over time. We performed quantitative liver intravital microscopy (qLIM) in live C57BL/6J mice to investigate the impact of aging on the hepatovascular system over a 24-mo period. qLIM revealed that age-related hepatic alterations include reduced liver sinusoidal blood flow, increased sinusoidal vessel diameter, and loss of small hepatic vessels. The ductular cell structure deteriorates with age, along with altered expression of hepatic junctional proteins. Furthermore, qLIM imaging revealed increased inflammation in the aged liver, which was linked to increased expression of proinflammatory macrophages, hepatic neutrophils, liver sinusoidal endothelial cells, senescent cells, and procoagulants. Finally, we detected elevated NF-κB pathway activity in aged livers. Overall, these findings emphasize the importance of inflammation in age-related hepatic vasculo-epithelial alterations and highlight the utility of qLIM in studying age-related effects in organ pathophysiology.
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Ezhilarasan, Devaraj. "Endothelin-1 in portal hypertension: The intricate role of hepatic stellate cells". Experimental Biology and Medicine 245, nr 16 (13.08.2020): 1504–12. http://dx.doi.org/10.1177/1535370220949148.
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Portal hypertension is one of the most important cirrhosis-associated complications of chronic liver disease, leading to significant morbidity and mortality. After chronic liver injury, hepatic stellate cells reside in the perisinusoidal space activted and acquire a myofibroblast-like phenotype. The activated hepatic stellate cells act as both sources as well as the target for a potent vasoconstrictor endothelin-1. Activation of hepatic stellate cells plays a vital role in the onset of cirrhosis by way of increased extracellular matrix production and the enhanced contractile response to vasoactive mediators such as endothelin-1. In fibrotic/cirrhotic liver, activated hepatic stellate cells produce endothelin-1 leading to an imbalance between pro and antifibrotic factors responsible for enormous extracellular matrix synthesis. Thus, extracellular matrix deposition in the perisinusoidal space further augments liver stiffness and elevates the vascular tone and portal hypertension. Portal hypertension is a complex process modulated by several cell types like hepatic stellate cells, liver sinusoidal endothelial cells, Kupffer cells, injured hepatocytes, immune cells, and biliary epithelial cells. Therefore, targeting a single cell type may not be useful for regression of cirrhosis and portal hypertension. Nevertheless, numerous findings indicate that functionally liver sinusoidal endothelial cells and hepatic stellate cells closely regulate the sinusoidal blood flow via synthesis of several vasoactive molecules including endothelin-1, and hence targeting these cells with novel pharmacological agents may offer promising results. Impact statement Portal hypertension is pathologically defined as increase of portal venous pressure, mainly due to chronic liver diseases such as fibrosis and cirrhosis. In fibrotic liver, activated hepatic stellate cells increase their contraction in response to endothelin-1 (ET-1) via autocrine and paracrine stimulation from liver sinusoidal endothelial cells and injured hepatocytes. Clinical studies are limited with ET receptor antagonists in cirrhotic patients with portal hypertension. Hence, studies are needed to find molecules that block ET-1 synthesis. Accumulation of extracellular matrix proteins in the perisinusoidal space, tissue contraction, and alteration in blood flow are prominent during portal hypertension. Therefore, novel matrix modulators should be tested experimentally as well as in clinical studies. Specifically, tumor necrosis factor-α, transforming growth factor-β1, Wnt, Notch, rho-associated protein kinase 1 signaling antagonists, and peroxisome proliferator-activated receptor α and γ, interferon-γ and sirtuin 1 agonists should be tested elaborately against cirrhosis patients with portal hypertension.
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Ribera, Jordi, Montse Pauta, Pedro Melgar-Lesmes, Bernat Córdoba, Anna Bosch, Maria Calvo, Daniel Rodrigo-Torres i in. "A small population of liver endothelial cells undergoes endothelial-to-mesenchymal transition in response to chronic liver injury". American Journal of Physiology-Gastrointestinal and Liver Physiology 313, nr 5 (1.11.2017): G492—G504. http://dx.doi.org/10.1152/ajpgi.00428.2016.
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Rising evidence points to endothelial-to-mesenchymal transition (EndMT) as a significant source of the mesenchymal cell population in fibrotic diseases. In this context, we hypothesized that liver endothelial cells undergo EndMT during fibrosis progression. Cirrhosis in mice was induced by CCl4. A transgenic mouse expressing a red fluorescent protein reporter under the control of Tie2 promoter (Tie2-tdTomato) was used to trace the acquisition of EndMT. Sinusoidal vascular connectivity was evaluated by intravital microscopy and high-resolution three-dimensional confocal microscopy. A modest but significant fraction of liver endothelial cells from both cirrhotic patients and CCl4-treated Tie2-tdTomato mice acquired an EndMT phenotype characterized by the coexpression of CD31 and α-smooth muscle actin, compared with noncirrhotic livers. Bone morphogenetic protein-7 (BMP-7) inhibited the acquisition of EndMT induced by transforming growth factor-β1 (TGF-β1) treatment in cultured primary mouse liver endothelial cells from control mice. EndMT was also reduced significantly in vivo in cirrhotic Tie2-tdTomato mice treated intraperitoneally with BMP-7 compared with untreated mice (1.9 ± 0.2 vs. 3.8 ± 0.3%, respectively; P < 0.05). The decrease of EndMT in cirrhotic livers correlated with a significant decrease in liver fibrosis ( P < 0.05) and an improvement in the vascular disorganization rate ( P < 0.05). We demonstrated the acquisition of the EndMT phenotype by a subpopulation of endothelial cells from cirrhotic livers in both animal models and patients. BMP-7 treatment decreases the occurrence of the EndMT phenotype and has a positive impact on the severity of disease by reducing fibrosis and sinusoidal vascular disorganization. NEW & NOTEWORTHY A subpopulation of liver endothelial cells from cirrhotic patients and mice with liver fibrosis undergoes endothelial-to-mesenchymal transition. Liver endothelial cells from healthy mice could transition into a mesenchymal phenotype in culture in response to TGF-β1 treatment. Fibrotic livers treated chronically with BMP-7 showed lower EndMT acquisition, reduced fibrosis, and improved vascular organization.
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Yokomori, Hiroaki. "New insights into the dynamics of sinusoidal endothelial fenestrae in liver sinusoidal endothelial cells". Medical Molecular Morphology 41, nr 1 (marzec 2008): 1–4. http://dx.doi.org/10.1007/s00795-007-0390-7.
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Meyer, Jeremy, Stéphanie Lacotte, Philippe Morel, Carmen Gonelle-Gispert i Léo Bühler. "An optimized method for mouse liver sinusoidal endothelial cell isolation". Experimental Cell Research 349, nr 2 (grudzień 2016): 291–301. http://dx.doi.org/10.1016/j.yexcr.2016.10.024.
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Romayor, Irene, Joana Márquez, Aitor Benedicto, Alba Herrero, Beatriz Arteta i Elvira Olaso. "Tumor DDR1 deficiency reduces liver metastasis by colon carcinoma and impairs stromal reaction". American Journal of Physiology-Gastrointestinal and Liver Physiology 320, nr 6 (1.06.2021): G1002—G1013. http://dx.doi.org/10.1152/ajpgi.00078.2021.
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Tumor DDR1 acts as a key factor during the desmoplastic response surrounding hepatic colorectal metastasis. Hepatic sinusoidal cell-derived soluble factors stimulate tumor DDR1 activation. DDR1 modulates matrix remodeling to promote metastasis in the liver through the interaction with hepatic stromal cells, specifically liver sinusoidal endothelial cells and hepatic stellate cells.
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Kostallari, Enis, i Vijay H. Shah. "Angiocrine signaling in the hepatic sinusoids in health and disease". American Journal of Physiology-Gastrointestinal and Liver Physiology 311, nr 2 (1.08.2016): G246—G251. http://dx.doi.org/10.1152/ajpgi.00118.2016.
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The capillary network irrigating the liver is important not only for nutrient and oxygen delivery, but also for the signals distributed to other hepatic cell types necessary to maintain liver homeostasis. During development, endothelial cells are a key component in liver zonation. In adulthood, they maintain hepatic stellate cells and hepatocytes in quiescence. Their importance in pathobiology is highlighted in liver regeneration and chronic liver diseases, where they coordinate paracrine cell behavior. During regeneration, liver sinusoidal endothelial cells induce hepatocyte proliferation and angiogenesis. During fibrogenesis, they undergo morphological and functional changes, which are reflected by their role in hepatic stellate cell activation, inflammation, and distorted sinusoidal structure. Therapeutic strategies to target angiocrine signaling are in progress but are in the early stages. Here, we offer a short synthesis of recent studies on angiocrine signaling in liver homeostasis, regeneration, and fibrogenesis.
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Sun, Xinghui, i Edward N. Harris. "New aspects of hepatic endothelial cells in physiology and nonalcoholic fatty liver disease". American Journal of Physiology-Cell Physiology 318, nr 6 (1.06.2020): C1200—C1213. http://dx.doi.org/10.1152/ajpcell.00062.2020.
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The liver is the central metabolic hub for carbohydrate, lipid, and protein metabolism. It is composed of four major types of cells, including hepatocytes, endothelial cells (ECs), Kupffer cells, and stellate cells. Hepatic ECs are highly heterogeneous in both mice and humans, representing the second largest population of cells in liver. The majority of them line hepatic sinusoids known as liver sinusoidal ECs (LSECs). The structure and biology of LSECs and their roles in physiology and liver disease were reviewed recently. Here, we do not give a comprehensive review of LSEC structure, function, or pathophysiology. Instead, we focus on the recent progress in LSEC research and other hepatic ECs in physiology and nonalcoholic fatty liver disease and other hepatic fibrosis-related conditions. We discuss several current areas of interest, including capillarization, scavenger function, autophagy, cellular senescence, paracrine effects, and mechanotransduction. In addition, we summarize the strengths and weaknesses of evidence for the potential role of endothelial-to-mesenchymal transition in liver fibrosis.
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Wang, Lin, Xiangdong Wang, Lei Wang, Jenny D. Chiu, Gijs van de Ven, William A. Gaarde i Laurie D. DeLeve. "Hepatic Vascular Endothelial Growth Factor Regulates Recruitment of Rat Liver Sinusoidal Endothelial Cell Progenitor Cells". Gastroenterology 143, nr 6 (grudzień 2012): 1555–63. http://dx.doi.org/10.1053/j.gastro.2012.08.008.
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Neubauer, Katrin, Thomas Wilfling, Andreas Ritzel i Giuliano Ramadori. "Platelet-endothelial cell adhesion molecule-1 gene expression in liver sinusoidal endothelial cells during liver injury and repair". Journal of Hepatology 32, nr 6 (czerwiec 2000): 921–32. http://dx.doi.org/10.1016/s0168-8278(00)80096-3.
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Dini, L., A. Lentini, G. D. Diez, M. Rocha, L. Falasca, L. Serafino i F. Vidal-Vanaclocha. "Phagocytosis of apoptotic bodies by liver endothelial cells". Journal of Cell Science 108, nr 3 (1.03.1995): 967–73. http://dx.doi.org/10.1242/jcs.108.3.967.
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Using electron microscopy and cytofluorimetry we studied the role of carbohydrate-specific recognition systems in the interaction of apoptotic bodies with normal and interleukin 1-activated sinusoidal endothelial cells. Microfluorimetric observation of liver tissue sections revealed octadecylrhodamine B-labelled apoptotic body binding to the sinusoidal wall of mouse liver, when they were injected intraportally. Plate-scanning cytofluorimetry demonstrated that about 20–25% of Acridine Orange-labelled apoptotic bodies could adhere specifically to cultured endothelial cells after 15 minutes of incubation. Adhesion increased to 30% when the cells were incubated for 60 minutes. Using a mixture of galactose/N-acetylglucosamine/mannose as competition solution apoptotic body adhesion was significantly reduced especially after longer times of incubation, when the percentage of inhibition reached 50%. Following 4 hours exposure of liver endothelial cells to 1 ng/ml human recombinant interleukin-1 beta adhesion markedly increased after 60 minutes of incubation, whereas the co-incubation of interleukin-1 beta with the inhibitors brings down the adhesion to basal values obtained in controls. Electron microscopic observation of the adhesion process showed that the number of endothelial cells binding apoptotic bodies gradually increased from low to high values with time. After 60 minutes of incubation, the majority of apoptotic bodies were seen inside phagosomes and only a few remained at the cell surface. Liver endothelial cells bound and endocytosed apoptotic bodies through carbohydrate-specific receptors. Moreover, this scavenger action was interleukin-1 enhanced, thus suggesting its possible activation during inflammatory and immune processes.
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Hutchins, Noelle, Joshua Borgerding, Chun-Shiang Chung i Alfred Ayala. "Liver sinusoidal endothelial cells undergo apoptosis during sepsis, leading to organ dysfunction. (54.13)". Journal of Immunology 186, nr 1_Supplement (1.04.2011): 54.13. http://dx.doi.org/10.4049/jimmunol.186.supp.54.13.
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Abstract Sepsis is the leading cause of death in critically ill patients, and treatment options are limited. Our laboratory studies polymicrobial sepsis in murine models, and uses the liver as a model organ to investigate the disease’s pathophysiology. The liver, characterized as an immune tolerant organ, is susceptible to septic induced inflammation. We have previously reported that there is a twofold increase in the number of liver CD8+ T cells, 24 hours following cecal ligation and puncture (CLP—a surgical procedure that generates sepsis in mice). Since activated T lymphocytes must transverse the endothelium to reach the site of infection, it is possible that they directly interact with LSECs, and mediate liver injury through Fas-mediated apoptosis. This led us to hypothesize that as CD8+ T cells directly interact with LSECs, endothelial cell dysfunction occurs. Our preliminary results indicate that septic liver CD8+ T cells have cytotoxic effects on endothelial monolayer integrity, and release pro-inflammatory cytokines when directly co-cultured with CRL-2167, a murine endothelial cell line. We have also observed through flow cytometry that LSECs (CD146+/CD45- and CD31+/CD45- populations) have an increased expression of CD54 (ICAM-1), Fas, and Annexin V staining in vivo. These data suggest that CD8+ T cells directly interact with LSECs, alter the tolerance capacity of LSECs, and potentially kill LSECs through the Fas-FasL system, ultimately leading to liver organ injury in sepsis.
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Feng, Ya-xing, Wei Li, Xu-dong Wen, Ning Zhang, Wei-hui Liu i Zhan-yu Yang. "Sinusoidal Endothelial Cell Progenitor Cells Promote Tumour Progression in Patients with Hepatocellular Carcinoma". Stem Cells International 2020 (28.11.2020): 1–12. http://dx.doi.org/10.1155/2020/8819523.
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Objective. As sinusoidal endothelial cell progenitor cells (SEPCs) play a significant role in liver regeneration, it is necessary to elucidate whether SEPCs participate in tumour progression of hepatocellular carcinoma (HCC). Methods. A total of 45 patients with primary HCC who underwent liver resection were included in this study. The liver tumours were removed from the patients, and partial tissues were prepared to identify SEPCs through double staining of CD133/CD45 and CD133/CD31 at the same location. Blood samples were collected to examine liver function parameters and tumour markers. The demographics and clinicopathological characteristics of the patients were collected for correlation analysis with SEPCs. Results. SEPCs were observed in several blood vessels within the HCC nodules of all 45 patients, but no SEPCs were detected in the tumour-adjacent tissues. The number of SEPCs was correlated with the expression levels of HCC tumour markers α-fetoprotein (AFP) and CA199. There was a positive correlation between the expression of SEPC markers and diameter of HCC tumours in differently differentiated specimens ( P < 0.01 ). The expression levels of SEPC markers were significantly higher in patients with poorly differentiated HCC than in patients with moderately and highly differentiated HCC ( P < 0.05 ). Conclusions. SEPCs are closely associated with HCC progression; therefore, SEPCs may be considered potential prognostic and metastatic biomarkers and therapeutic candidates for HCC.
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Gudapati, Shweta, Tomasz W. Kaminski, Ravi Vats, Prithu Sundd i Tirthadipa Pradhan-Sundd. "A Dedifferentiated Sinusoidal Endothelium Impacts Liver-Directed Gene Transfer in Hemophilia-a Mice". Blood 138, Supplement 1 (5.11.2021): 3981. http://dx.doi.org/10.1182/blood-2021-152905.
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Abstract Hemophilia A is an X-linked recessive bleeding disorder that affects 1 in 5000 males and is caused by procoagulant factor VIII deficiency. Affected people are at danger of spontaneous bleeding into organs, which can be fatal and lead to persistent damage. Current therapy includes intravenous infusion of FVIII protein concentrate which carries the danger of transmitting blood-borne diseases. As a result of recent advancements in liver-directed gene transfer, gene therapy based innovative strategy for treating hemophilia has emerged. In patients with severe hemophilia B, intravenous infusion of an adeno-associated viral (AAV) vector encoding factor IX (FIX) under the control of a liver-directed promoter resulted in expression of FIX for a considerable period of time. In hemophilia-A patients, gene treatment utilizing AAV vectors has demonstrated to be less effective than Hemophilia B due to the size of the F8 coding sequence and the decreased release of FVIII protein. Among other concerns high immunogenicity of FVIII with 25-30% of hemophilia A patients forming inhibitors and overexpression of FVIII in hepatocytes triggering a cellular stress response are significantly challenging. A phase 1 clinical trial is now being conducted to examine the AAV8 induced liver directed gene expression strategy to circumvent these challenges. The Factor VIII null mouse has been effective in understanding the disease pathogenesis as well as the development of liver directed novel gene therapy techniques to treat hemophilia. FVIII is predominantly produced in the liver. Thus, liver directed adenoviral and retroviral vectors have been studied by several groups to understand the gene delivery method in hemophilia. A few of these studies have shown limited effectiveness in hemophilia animal models. Although the coagulation anomaly seen in hemophilia murine model was completely repaired immediately after liver directed adenovirus-mediated treatment, the effect was transient. Additionally, adeno associated virus (AAV8)-FVIII overexpression has been associated with increased cellular stress. In this study we evaluated the stability and efficacy of liver driven gene transfer mechanism in FVIII null mouse using recombinant AAV8 vector. Recombinant AAV8 vector delivered through the systemic circulation successfully transduces to target tissues via passing through the permeable barrier of sinusoidal endothelial cell. The bidirectional passage through sinusoidal endothelial cell is mainly supported by the presence of discontinuous fenestrated endothelium. Remarkably, we found that liver directed gene transfer was significantly delayed in FVIII null mice. Using quantitative liver intravital imaging we found that upon AAV8-GFP administration liver sinusoidal endothelial cells shows increased apoptosis. Moreover, structural analysis of the liver sinusoidal endothelial cells using intravital and electron micrograph imaging showed significant structural functional difference in liver sinusoidal endothelial cells of FVIII KO mouse. Work is currently underway to understand how absence of FVIII can affect the LSECs. In conclusion, detailed molecular characterization of LSEC-mediated liver directed gene transfer in a hemophilia mouse model is critical for understanding the efficacy and stability of gene-based hemophilia treatment. Disclosures Sundd: Bayer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring Inc: Research Funding.
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Frenzel, C., J. Wasielica, J. Herkel i A. W. Lohse. "637 Murine liver sinusoidal endothelial cells suppress T cell activation by dendritic cells". Journal of Hepatology 44 (kwiecień 2006): S236. http://dx.doi.org/10.1016/s0168-8278(06)80637-9.
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Konkle, BA, SJ Schuster, MD Kelly, K. Harjes, DE Hassett, M. Bohrer i M. Tavassoli. "Plasminogen activator inhibitor-1 messenger RNA expression is induced in rat hepatocytes in vivo by dexamethasone". Blood 79, nr 10 (15.05.1992): 2636–42. http://dx.doi.org/10.1182/blood.v79.10.2636.2636.
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Abstract Plasminogen activator inhibitor-1 (PAI-1), the major physiologic inhibitor of tissue plasminogen activator (tPA), plays a crucial role in the regulation of fibrinolysis. Both hepatocytes and endothelial cells have been implicated as major sources of plasma PAI-1. To study the relative contribution of these cell types to hepatic PAI-1 production, we have separated hepatocytes and hepatic sinusoidal endothelial cells by fractionation of freshly isolated rat livers using metrizamide density gradients and centrifugal elutriation. In untreated animals, PAI-1 messenger RNA (mRNA) was detected only in the purified endothelial cell fraction, and not in the hepatocyte fraction or in unfractionated liver. However, when the animals were treated with dexamethasone, PAI-1 mRNA expression was transiently induced in the liver. This induction paralleled the appearance of PAI-1 mRNA in purified hepatocytes, while PAI-1 expression in sinusoidal endothelial cells was unchanged. Four hours after dexamethasone treatment, plasma PAI-1 levels were increased approximately twofold over levels measured in animals treated with the diluent alone. These data suggest that PAI- 1 production by hepatocytes may contribute to elevated plasma PAI-1 levels in the setting of acute injury and stress.