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"Kupffer cell"

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"Kupffer cell"

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Liver fibrosis, cirrhosis, and portal hypertension

Sinusoidal communication in chronic liver disease
Albert Gibert-Ramos, María Andrés-Rozas, Raül Pastó, Pablo Alfaro-Retamero, Sergi Guixé-Muntet, Jordi Gracia-Sancho
Clin Mol Hepatol 2025;31(1):32-55.
Published online October 2, 2024
DOI: https://doi.org/10.3350/cmh.2024.0734
The liver sinusoid, mainly composed of liver sinusoidal endothelial cells, hepatic macrophages and hepatic stellate cells, shapes the hepatic vasculature and is key to maintaining liver homeostasis and function. During chronic liver disease (CLD), the function of sinusoidal cells is impaired, being directly involved in the progression of liver fibrosis, cirrhosis, and main clinical complications including portal hypertension and hepatocellular carcinoma. In addition to their roles in liver diseases pathobiology, sinusoidal cells’ paracrine communication or cross-talk is being studied as a mechanism of disease but also as a remarkable target for treatment. The aim of this review is to gather current knowledge of intercellular signalling in the hepatic sinusoid during the progression of liver disease. We summarise studies developed in pre-clinical models of CLD, especially emphasizing those pathways characterized in human-based clinically relevant models. Finally, we describe pharmacological treatments targeting sinusoidal communication as promising options to treat CLD and its clinical complications.

Citations

Citations to this article as recorded by  Crossref logo
  • Regression of fibrosis and portal hypertension in chronic liver disease: Endothelial perspectives and clinical implications
    Yuly P Mendoza, Raül Pastó, Sonia E Selicean, Jordi Gracia-Sancho
    Annals of Hepatology.2026; : 102174.     CrossRef
  • LSEC-derived CXCL9 orchestrates immune recruitment and hepatocyte reprogramming in liver fibrosis
    Jing Li, Qiannan Di, Xiujuan Zhou, Mengling Chang, Wei Chen
    Acta Biochimica et Biophysica Sinica.2026;[Epub]     CrossRef
  • Nodular Transformation–driven Circulatory Remodeling in Biliary Atresia–induced Pediatric Biliary Cirrhosis: A Three-dimensional Phase-Contrast CT Rendering
    Bei-Ning Qi, Xin-Yan Zhao, Wen-Juan Lv, Shan Shan, Xian-qin Du, Jian-Bo Jian, Chun-Hong Hu
    Radiology.2026;[Epub]     CrossRef
  • Vasomics of the liver
    Chengyan Wang, Eric Felli, Jonathan Andrew Fallowfield, Christoph Frank Dietrich, Don Rockey, Jürgen Hennig, Gao-Jun Teng, Jordi Gracia-Sancho, Xiaolong Qi
    Gut.2025; 74(6): 1008.     CrossRef
  • Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells
    Enis Kostallari, Robert F. Schwabe, Adrien Guillot
    Cellular & Molecular Immunology.2025; 22(10): 1205.     CrossRef
  • Myeloid cells in chronic liver inflammation
    Dimitrios Patseas, Ahmed El-Masry, Zuobin Liu, Prakash Ramachandran, Evangelos Triantafyllou
    Cellular & Molecular Immunology.2025; 22(10): 1237.     CrossRef
  • Toll-like receptor 4-mediated inflammatory stimulation in Kupffer cell enhances arsenite-induced liver fibrosis by triggering hepatic stellate cell activation
    Qian Song, Meitong Zhou, Rui He, Heng Diao, Lili Fan, Chenglong Tu, Xiong Chen, Dapeng Wang
    Ecotoxicology and Environmental Safety.2025; 303: 118903.     CrossRef
  • The pathophysiological role of portal hypertension in metabolic dysfunction–associated steatotic liver disease
    Søren Møller, Sannia M.S. Sjöstedt, Lise Hobolth, Christian Mortensen, Nina Kimer
    Hepatology Communications.2025;[Epub]     CrossRef
  • Hepatocyte-derived extracellular vesicles promote endothelial dedifferentiation in chronic liver disease through the miR-153-3p-pyroptosis axis
    Laia Abad-Jordà, María Andrés-Rozas, Ana Martínez-Alcocer, Jessica Aspas, Yiliam Fundora, Sonia Fernández-Veledo, Carmen Peralta, Sergi Guixé-Muntet, Anabel Fernández-Iglesias, Jordi Gracia-Sancho
    Hepatology.2025;[Epub]     CrossRef
  • Hepatic Fibrosis and Liver Cancer
    Aina Anton, Scott L. Friedman, Bruno Cogliati
    Seminars in Liver Disease.2025;[Epub]     CrossRef
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Liver fibrosis, cirrhosis, and portal hypertension

Nitric oxide in liver fibrosis: The role of inducible nitric oxide synthase
Yasuko Iwakiri
Clin Mol Hepatol 2015;21(4):319-325.
Published online December 24, 2015
DOI: https://doi.org/10.3350/cmh.2015.21.4.319

The inducible form of nitric oxide synthase (iNOS) is expressed in hepatic cells in pathological conditions. Its induction is involved in the development of liver fibrosis, and thus iNOS could be a therapeutic target for liver fibrosis. This review summarizes the role of iNOS in liver fibrosis, focusing on 1) iNOS biology, 2) iNOS-expressing liver cells, 3) iNOS-related therapeutic strategies, and 4) future directions.

Citations

Citations to this article as recorded by  Crossref logo
  • Illuminating liver fibrosis: recent progress in the design and applications of highly sensitive fluorescent probes
    Yutong Lv, Zhe Ma, Yue Chong, Zhenlong Wang, Li Xue, Fu Wang
    Materials Horizons.2026; 13(1): 67.     CrossRef
  • Spermidine‐Based Carbon Quantum Dots Alleviate Liver Sinusoidal Endothelial Dysfunction by Inducing LSEC‐Derived NO to Ameliorate Hepatic Fibrosis and Portal Hypertension
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  • Toxicity and Hepatoprotective Effects of ZnO Nanoparticles on Normal and High-Fat Diet-Fed Rat Livers: Mechanism of Action
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  • Key role of macrophages in the progression of hepatic fibrosis
    Jinqiu Ran, Shengxia Yin, Rahma Issa, Qianwen Zhao, Guangqi Zhu, Huan Zhang, Qun Zhang, Chao Wu, Jie Li
    Hepatology Communications.2025;[Epub]     CrossRef
  • Exploring Extracellular Vesicles: A Novel Approach in Nonalcoholic Fatty Liver Disease
    Andrea del Pilar Abreo Medina, Mengdie Shi, Yanyan Wang, Zhongyu Wang, Kehe Huang, Yunhuan Liu
    Journal of Agricultural and Food Chemistry.2025; 73(5): 2717.     CrossRef
  • Sinusoidal communication in chronic liver disease
    Albert Gibert-Ramos, María Andrés-Rozas, Raül Pastó, Pablo Alfaro-Retamero, Sergi Guixé-Muntet, Jordi Gracia-Sancho
    Clinical and Molecular Hepatology.2025; 31(1): 32.     CrossRef
  • The role of liver sinusoidal endothelial cells in metabolic dysfunction-associated steatotic liver diseases and liver cancer: mechanisms and potential therapies
    Hanjun Mo, Pengfei Yue, Qiaoqi Li, Yinxi Tan, Xinran Yan, Xinyue Liu, Yuanwei Xu, Yingzhe Luo, Suruiya Palihati, Cheng Yi, Hua Zhang, Minlan Yuan, Biao Yang
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  • Lipid Dysmetabolism in Canine Chronic Liver Disease: Relationship Between Clinical, Histological and Immunohistochemical Features
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    Veterinary Sciences.2025; 12(3): 220.     CrossRef
  • Propolis-loaded/dextrose˗coated bilosomes for enhanced protection against CCl4-induced liver injury: In vitro and in vivo assessments
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    Journal of Drug Delivery Science and Technology.2025; 107: 106756.     CrossRef
  • Recent Progress in Small Molecule Fluorescent Probes for Imaging and Diagnosis of Liver Injury
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    Targets.2025; 3(2): 18.     CrossRef
  • Research Progress on Anti-fibrotic Effects and Mechanisms of Tetrandrine
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    Chinese Journal of Integrative Medicine.2025; 31(9): 837.     CrossRef
  • The natural compounds derived from the plant Moquiniastrum polymorphum subsp. polymorphum prevent and treat liver fibrosis in vivo by reducing inflammation and fibrotic markers
    Matheus Scherer Bastos, Kétlin Fernanda Rodrigues, Maria Claudia Rosa Garcia, Carolina Luft, Giovana Vivan Tonial, Giovanna Mezzomo Pavanato, Leandro Vieira Astarita, Barbara Bettanin Gatti, Fábio Luiz Dal Moro Maito, Eliane Romanato Santarém, J.R. de Oli
    Toxicon.2025; 264: 108436.     CrossRef
  • Levistilide A attenuates carbon tetrachloride (CCl4)-induced liver fibrosis by inhibiting the NF-κB/iNOS/NO signalling pathway in M1 macrophages
    Rui Zeng, Liu Shen, Tingjie Ye, Wei Xu, Kai Huang, Fengjun Qiu, Chenghai Liu, Xudong Hu
    Journal of Ethnopharmacology.2025; 351: 120074.     CrossRef
  • Molecular Imaging Probes for Early Detection and Staging of Liver Fibrosis
    Xiuqi Hu, Mengdan Xu, Xiao Xiao, Ning Wang, Qianqian Zhang, Jianxian Ge, Jianfeng Zeng
    Chemical & Biomedical Imaging.2025; 3(11): 702.     CrossRef
  • Stearidonic Acid-Enriched Buglossoides arvensis Oil Alleviates High-Fat Diet-Induced Hepatic Lipid Accumulation and Inflammation via AMPK/SIRT1 Activation in Rats
    Mak-Soon Lee, Bohyeon Kim, Jumi Lee, Yejie Cho, In-Hwan Kim, Yangha Kim
    The Journal of Nutrition.2025; 155(10): 3401.     CrossRef
  • Lawsone can suppress liver fibrosis by inhibition of YAP signaling and induction of CYGB expression in hepatic stellate cells
    Atsuko Daikoku, Tsutomu Matsubara, Misako Sato-Matsubara, Miku Ando, Chiho Kadono, Sayuri Takada, Naoshi Odagiri, Hideto Yuasa, Hayato Urushima, Katsutoshi Yoshizato, Norifumi Kawada, Kazuo Ikeda
    Biomedicine & Pharmacotherapy.2025; 191: 118520.     CrossRef
  • SIRT1 in Aging and Diseases
    Altaf A. Abdulkhaliq, Glowi Alasiri, Johra Khan, Amir Ajoolabady, Jaakko Tuomilehto, Nils Henninger, Suhad Bahijri, Domenico Pratico, Anwar Borai, Bahauddeen M. Alrfaei, Bonglee Kim, Jun Ren
    Journal of Cellular Biochemistry.2025;[Epub]     CrossRef
  • Intravenous Lidocaine Modulates the Perioperative Hepatic Inflammatory Response: Implications for Personalized Medicine in Thoracic Surgery
    Ana Isabel Galve, Ignacio Garutti, Elena Vara, Guillermo González, Gabriel Cusati, Lisa Rancan, Luis Huerta, Javier Casanova, Carlos Simón
    Journal of Personalized Medicine.2025; 15(12): 620.     CrossRef
  • Organelle stress and alterations in interorganelle crosstalk during liver fibrosis
    Saloni Sinha, Nora Hassan, Robert E. Schwartz
    Hepatology.2024; 79(2): 482.     CrossRef
  • Baccharis anomala DC. extract reduces inflammation and attenuates hepatic fibrosis in vivo by decreasing NF-kB and extracellular matrix compounds
    Bruno de Souza Basso, Matheus Scherer Bastos, Géssica Luana Antunes, Lucas Strassburger Matzenbacher, Kétlin Fernanda Rodrigues, Maria Claudia Rosa Garcia, Arieli Cruz de Sousa, Vitor Giancarlo Levorse, Carolina Luft, Giovana Vivan Tonial, Giovanna Mezzom
    Toxicon.2024; 237: 107560.     CrossRef
  • Not just fibrotic: endothelial-derived TGFβ maintains contractile function and lymphatic muscle phenotype during homeostasis
    Miriam Carrillo Diaz de Leon, Keith Keane, Simon Roizes, Shan Liao, Pierre-Yves von der Weid, Matthew Stephens
    American Journal of Physiology-Cell Physiology.2024; 326(1): C269.     CrossRef
  • Thymoquinone protects thioacetamide‐induced chronic liver injury by inhibiting TGF‐β1/Smad3 axis in rats
    Subramanian Raghunandhakumar, Devaraj Ezhilarasan, Karthik Shree Harini
    Journal of Biochemical and Molecular Toxicology.2024;[Epub]     CrossRef
  • Potential i‐Nos/Arg‐1 Switch with NLRP3 and Parasitic Load Down Regulation in Experimental Schistosoma mansoni Infection via Chloroquine Repurposing
    Marwa A. Hasby Saad, Esraa G. El‐Saadi, Dareen A. Ali, Mona M. Watany, Mohammed M. Eid
    Parasite Immunology.2024;[Epub]     CrossRef
  • Bacteroides and NAFLD: pathophysiology and therapy
    Jun Zhang, Jing Zhou, Zheyun He, Hongshan Li
    Frontiers in Microbiology.2024;[Epub]     CrossRef
  • Regulatory disturbances in the dynamical signaling systems of $$Ca^{2+}$$ and NO in fibroblasts cause fibrotic disorders
    Ankit Kothiya, Neeru Adlakha
    Journal of Biological Physics.2024; 50(2): 229.     CrossRef
  • Nitric oxide donor S‐Nitroso‐N‐acetyl penicillamine for hepatic stellate cells to restore quiescence
    Junbao Du, Yin He, Wen Jia, Xiaohua Liang, Quan Kang, Yun He
    Pediatric Discovery.2024;[Epub]     CrossRef
  • Microarray analysis demonstrates up-regulation of the endothelin-1 gene with compensatory down-regulation of the ETA receptor gene in human portal vein
    Nicola E. Owen, Thomas L. Williams, Janet J. Maguire, Rhoda E. Kuc, Emma E. Davenport, Anthony P. Davenport
    Bioscience Reports.2024;[Epub]     CrossRef
  • Delivery Strategy to Enhance the Therapeutic Efficacy of Liver Fibrosis via Nanoparticle Drug Delivery Systems
    Jie Liu, Jinhu Liu, Weiwei Mu, Qingping Ma, Xiangyu Zhai, Bin Jin, Yongjun Liu, Na Zhang
    ACS Nano.2024; 18(32): 20861.     CrossRef
  • Correspondence to editorial on “Liver sinusoidal endothelial cell: An important yet often overlooked player in the liver fibrosis”
    Jiaorong Qu, Le Wang, Xiaojiaoyang Li
    Clinical and Molecular Hepatology.2024; 30(4): 1002.     CrossRef
  • Lipocalin‐2 activates hepatic stellate cells and promotes nonalcoholic steatohepatitis in high‐fat diet–fed Ob/Ob mice
    Kyung Eun Kim, Jaewoong Lee, Hyun Joo Shin, Eun Ae Jeong, Hye Min Jang, Yu Jeong Ahn, Hyeong Seok An, Jong Youl Lee, Meong Cheol Shin, Soo Kyoung Kim, Won Gi Yoo, Won Ho Kim, Gu Seob Roh
    Hepatology.2023; 77(3): 888.     CrossRef
  • (Poly)phenols and nitrolipids: Relevant participants in nitric oxide metabolism
    César G. Fraga, Andrés Trostchansky, Barbara S. Rocha, João Laranjinha, Homero Rubbo, Monica Galleano
    Molecular Aspects of Medicine.2023; 89: 101158.     CrossRef
  • The evolving role of liver sinusoidal endothelial cells in liver health and disease
    Matthew J. McConnell, Enis Kostallari, Samar H. Ibrahim, Yasuko Iwakiri
    Hepatology.2023; 78(2): 649.     CrossRef
  • Nanodrug Delivery Systems for Metabolic Chronic Liver Diseases: Advances and Perspectives
    Foteini Athanasopoulou, Michail Manolakakis, Santiago Vernia, Nazila Kamaly
    Nanomedicine.2023; 18(1): 67.     CrossRef
  • The Role of Pyrazolo[3,4-d]pyrimidine-Based Kinase Inhibitors in The Attenuation of CCl4-Induced Liver Fibrosis in Rats
    Diana K. Ghobrial, Nefertiti El-Nikhely, Eman Sheta, Hanan M. Ragab, Sherif A. F. Rostom, Hesham Saeed, Ahmed Wahid
    Antioxidants.2023; 12(3): 637.     CrossRef
  • Curcuma aromatica Salisb. Protects from Acetaminophen-Induced Hepatotoxicity by Regulating the Sirt1/HO-1 Signaling Pathway
    Hyunseong Kim, Jinyoung Hong, Junseon Lee, Wanjin Jeon, Changhwan Yeo, Yoonjae Lee, Seungho Baek, Inhyuk Ha
    Nutrients.2023; 15(4): 808.     CrossRef
  • Accurate diagnosis of hepatic fibrosis with dual detection of nitric oxide and viscosity by a ratiometric fluorescent probe
    Shaohui Han, Lei Yang, Miaomiao Liu, Haipu Li, Xiangzhi Song
    Chemical Engineering Journal.2023; 463: 142383.     CrossRef
  • The eNOS isoform exhibits increased expression and activation in the main olfactory bulb of nNOS knock-out mice
    David Pérez-Boyero, Carlos Hernández-Pérez, Jorge Valero, Valeria Lorena Cabedo, José Ramón Alonso, David Díaz, Eduardo Weruaga
    Frontiers in Cellular Neuroscience.2023;[Epub]     CrossRef
  • Congenital diaphragmatic hernia increases the sensitivity of pulmonary arteries to nitric oxide
    Alecsander F. Bressan, Victoria Oliveira Maia, Beatriz de Souza Rodrigues, Giuliana Bertozi, Sabrina S. Batah, Alexandre T. Fabro, Glória Pelizzo, Ugo Maria Pierucci, Rita C. Tostes, Lourenço Sbragia, Fernando S. Carneiro
    Pharmacological Research.2023; 191: 106749.     CrossRef
  • Vessel-on-a-Chip: A Powerful Tool for Investigating Endothelial COVID-19 Fingerprints
    Oksana Shevchuk, Svitlana Palii, Anastasiia Pak, Nuria Chantada, Nuria Seoane, Mykhaylo Korda, Manuel Campos-Toimil, Ezequiel Álvarez
    Cells.2023; 12(9): 1297.     CrossRef
  • Mexican Native Black Bean Anthocyanin-Rich Extracts Modulate Biological Markers Associated with Inflammation
    Jonhatan Contreras, Montserrat Alcázar-Valle, Eugenia Lugo-Cervantes, Diego A. Luna-Vital, Luis Mojica
    Pharmaceuticals.2023; 16(6): 874.     CrossRef
  • S-nitrosylation of EMMPRIN influences the migration of HSCs and MMP activity in liver fibrosis
    Xinyan Zhu, Zihui Tang, Wei Li, Xiaojuan Li, Yasuko Iwakiri, Fei Liu
    Acta Biochimica et Biophysica Sinica.2023; 55(10): 1640.     CrossRef
  • Eucalyptol Protects against Cisplatin-Induced Liver Injury in Rats
    Gokhan Akcakavak, Filiz Kazak, Mehmet Zeki Yilmaz Deveci
    Biology Bulletin.2023; 50(5): 987.     CrossRef
  • EASL-ERN position paper on liver involvement in patients with Fontan-type circulation
    Luis Téllez, Audrey Payancé, Eric Tjwa, María Jesús del Cerro, Lars Idorn, Stanislav Ovroutski, Ruth De Bruyne, Henkjan J. Verkade, Fabrizio De Rita, Charlotte de Lange, Annalisa Angelini, Valérie Paradis, Pierre Emmanuel Rautou, Juan Carlos García-Pagán
    Journal of Hepatology.2023; 79(5): 1270.     CrossRef
  • Schisandrin B Promotes Hepatic Stellate Cell Ferroptosis via Wnt Pathway-Mediated Ly6Clo Macrophages
    Xinmiao Li, Feng Jiang, Yuhang Hu, Zhichao Lang, Yating Zhan, Rongrong Zhang, Qiqi Tao, Chengchu Luo, Jinglu Yu, Jianjian Zheng
    Journal of Agricultural and Food Chemistry.2023;[Epub]     CrossRef
  • Ameliorative role of inducible nitric oxide synthase inhibitors against sodium arsenite-induced renal and hepatic dysfunction in rats
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    Drug and Chemical Toxicology.2022; 45(5): 2255.     CrossRef
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    Frontiers in Immunology.2022;[Epub]     CrossRef
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    Ye.V. Stetsuk, O.Ye. Akimov, K.V. Shepitko, N.V. Boruta, A.N. Goltsev
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  • Syntropic Lesions of the Cardiovascular System in Patients With Liver Cirrhosis: Their Determination; Selected Pathogenetic Mechanisms; Characteristics and Specifics; Clinical Markers, Their Prognostic Value; Justification and Effectiveness of Modified Tr
    M. Farmaha, M. Abrahamovych, O. Abrahamovych
    Lviv clinical bulletin.2020; 3(31): 8.     CrossRef
  • Molecular Mechanisms That Link Oxidative Stress, Inflammation, and Fibrosis in the Liver
    Erika Ramos-Tovar, Pablo Muriel
    Antioxidants.2020; 9(12): 1279.     CrossRef
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    Genta Kakiyama, Dalila Marques, Rebecca Martin, Hajime Takei, Daniel Rodriguez-Agudo, Sandra A. LaSalle, Taishi Hashiguchi, Xiaoying Liu, Richard Green, Sandra Erickson, Gregorio Gil, Michael Fuchs, Mitsuyoshi Suzuki, Tsuyoshi Murai, Hiroshi Nittono, Phil
    Journal of Lipid Research.2020; 61(12): 1629.     CrossRef
  • Antrodia Cinnamomea Attenuates Non-Alcoholic Steatohepatitis by Suppressing NLRP3 Inflammasome Activation In Vitro and In Vivo
    I-Chuan Yen, Jung-Chun Lin, Yu Chen, Qian-Wen Tu, Shih-Yu Lee
    The American Journal of Chinese Medicine.2020; 48(08): 1859.     CrossRef
  • Syntropic Lesions of the Cardiovascular System in Patients with Liver Cirrhosis: their Determination; Selected Pathogenetic Mechanisms; Characteristics and Specifics; Clinical Markers, Their Prognostic Value; Justification and Effectiveness of Modified Tr
    M. Farmaha, M. Abrahamovych, O. Abrahamovych, O. Fayura, V. Chemes
    Lviv clinical bulletin.2020; 4(32): 8.     CrossRef
  • Modulation of inducible nitric oxide synthase pathway by eugenol and telmisartan in carbon tetrachloride-induced liver injury in rats
    Moustafa Fathy, Esraa M.M.A. Khalifa, Michael Atef Fawzy
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Liver fibrosis, cirrhosis, and portal hypertension

The role of gut-liver axis in the pathogenesis of liver cirrhosis and portal hypertension
Yeon Seok Seo, Vijay H. Shah
Korean J Hepatol 2012;18(4):337-346.
Published online December 21, 2012
DOI: https://doi.org/10.3350/cmh.2012.18.4.337

Because of the anatomical position and its unique vascular system, the liver is susceptible to the exposure to the microbial products from the gut. Although large amount of microbes colonize in the gut, translocation of the microbes or microbial products into the liver and systemic circulation is prevented by gut epithelial barrier function and cleansing and detoxifying functions of the liver in healthy subjects. However, when the intestinal barrier function is disrupted, large amount of bacterial products can enter into the liver and systemic circulation and induce inflammation through their receptors. Nowadays, there have been various reports suggesting the role of gut flora and bacterial translocation in the pathogenesis of chronic liver disease and portal hypertension. This review summarizes the current knowledge about bacterial translocation and its contribution to the pathogenesis of chronic liver diseases and portal hypertension.

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