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Ram AK, Vats A, Bhatia A, Kumar Y. Evolving Concepts in Etiology of Biliary Atresia: Insights and Perspectives from India. Fetal Pediatr Pathol 2025; 44:236-258. [PMID: 40181637 DOI: 10.1080/15513815.2025.2477704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 03/01/2025] [Accepted: 03/04/2025] [Indexed: 04/05/2025]
Abstract
Introduction: Biliary atresia (BA) is a potentially fatal newborn cholestatic disease. It is a rapidly advancing fibro-obliterative cholangiopathy that leads to liver failure and death if not treated early. The well-known multihit hypothesis proposes that viral or chemical disruption to the biliary epithelium triggers an immune-mediated inflammatory response, resulting in fibrosis and blockage of the intra and extrahepatic biliary systems. Methods: In recent years, several papers have noticed an upsurge in many aspects of BA, particularly its etiopathogenesis, which has opened a vista of various probable mechanisms currently being examined. This review brings them together with an emphasis on reflecting current scientific views for those interested in this illness. Conclusions: Among the different etiological factors proposed for BA, viruses and immune-mediated injury are the strongest contenders as contributors to the disease onset and pathogenesis.
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Affiliation(s)
- Anil Kumar Ram
- Department of Pathology, University of Kansas Medical Center, Kansas City, USA
| | - Akshit Vats
- Department of Immunopathology, Post Graduate Institute of Medical Education & Research, Chandigarh, India
| | - Alka Bhatia
- Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education & Research, Chandigarh, India
| | - Yashwant Kumar
- Department of Immunopathology, Post Graduate Institute of Medical Education & Research, Chandigarh, India
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Zhan J, Liu S, Meng Y, Yang Q, Wang Z, Zhang S, Ge L, Zhao L, Xu X, Zhao Y, Li X, Wang X. Systematic review of the mechanism and assessment of liver fibrosis in biliary atresia. Pediatr Surg Int 2024; 40:205. [PMID: 39033225 DOI: 10.1007/s00383-024-05778-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/06/2024] [Indexed: 07/23/2024]
Abstract
PURPOSE This study systematically reviewed our team's research on the mechanism and assessment of liver fibrosis in BA, summarized our experience, and discussed the future development direction. METHODS In this study, Pubmed and Wanfang databases were searched to collect the literature published by our team on the mechanisms of liver fibrosis in BA and the assessment of liver fibrosis in BA, and the above research results were systematically reviewed. RESULTS A total of 58 articles were retrieved. Among the included articles, 25 articles related to the mechanism of liver fibrosis in BA, and five articles evaluated liver fibrosis in BA. This article introduces the key pathways and molecules of liver fibrosis in BA and proposes a new grading system for liver fibrosis in BA. CONCLUSIONS The new BA liver fibrosis grading method is expected to assess children's conditions, guide treatment, and improve prognosis more accurately. In addition, we believe that the TGF-β1 signaling pathway is the most important in the study of liver fibrosis in BA, and at the same time, the study of EMT occurrence in BA should also be deepened to resolve the controversy on this issue.
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Affiliation(s)
- Jianghua Zhan
- Tianjin Children's Hospital ("Children's Hospital, Tianjin University"), Tianjin, China.
- Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China.
- Department of General Surgery, Tianjin Children's Hospital, 238 Longyan Road, Beichen District, Tianjin, 300134, China.
| | - Shaowen Liu
- Tianjin Children's Hospital ("Children's Hospital, Tianjin University"), Tianjin, China
- Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China
- Department of General Surgery, Tianjin Children's Hospital, 238 Longyan Road, Beichen District, Tianjin, 300134, China
- Clinical School of Paediatrics, Tianjin Medical University, Tianjin, China
| | - Yu Meng
- Tianjin Children's Hospital ("Children's Hospital, Tianjin University"), Tianjin, China
- Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China
- Department of General Surgery, Tianjin Children's Hospital, 238 Longyan Road, Beichen District, Tianjin, 300134, China
- Clinical School of Paediatrics, Tianjin Medical University, Tianjin, China
| | - Qianhui Yang
- Tianjin Children's Hospital ("Children's Hospital, Tianjin University"), Tianjin, China
- Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China
- Department of General Surgery, Tianjin Children's Hospital, 238 Longyan Road, Beichen District, Tianjin, 300134, China
- Clinical School of Paediatrics, Tianjin Medical University, Tianjin, China
| | - Zhiru Wang
- Tianjin Children's Hospital ("Children's Hospital, Tianjin University"), Tianjin, China
- Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China
- Department of General Surgery, Tianjin Children's Hospital, 238 Longyan Road, Beichen District, Tianjin, 300134, China
- Clinical School of Paediatrics, Tianjin Medical University, Tianjin, China
| | - Shujian Zhang
- Tianjin Children's Hospital ("Children's Hospital, Tianjin University"), Tianjin, China
- Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China
- Department of General Surgery, Tianjin Children's Hospital, 238 Longyan Road, Beichen District, Tianjin, 300134, China
| | - Liang Ge
- Tianjin Children's Hospital ("Children's Hospital, Tianjin University"), Tianjin, China
- Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China
- Department of General Surgery, Tianjin Children's Hospital, 238 Longyan Road, Beichen District, Tianjin, 300134, China
| | - Li Zhao
- Tianjin Children's Hospital ("Children's Hospital, Tianjin University"), Tianjin, China
- Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China
- Department of Pathology, Tianjin Children's Hospital, Tianjin, China
| | - Xiaodan Xu
- Tianjin Children's Hospital ("Children's Hospital, Tianjin University"), Tianjin, China
- Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China
- Department of General Surgery, Tianjin Children's Hospital, 238 Longyan Road, Beichen District, Tianjin, 300134, China
- Clinical School of Paediatrics, Tianjin Medical University, Tianjin, China
| | - Yilin Zhao
- Tianjin Children's Hospital ("Children's Hospital, Tianjin University"), Tianjin, China
- Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China
- Department of General Surgery, Tianjin Children's Hospital, 238 Longyan Road, Beichen District, Tianjin, 300134, China
- Clinical School of Paediatrics, Tianjin Medical University, Tianjin, China
| | - Xin Li
- Tianjin Children's Hospital ("Children's Hospital, Tianjin University"), Tianjin, China
- Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China
- Department of General Surgery, Tianjin Children's Hospital, 238 Longyan Road, Beichen District, Tianjin, 300134, China
- Clinical School of Paediatrics, Tianjin Medical University, Tianjin, China
| | - Xueting Wang
- Tianjin Children's Hospital ("Children's Hospital, Tianjin University"), Tianjin, China
- Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China
- Department of General Surgery, Tianjin Children's Hospital, 238 Longyan Road, Beichen District, Tianjin, 300134, China
- Clinical School of Paediatrics, Tianjin Medical University, Tianjin, China
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Marakovits C, Francis H. Unraveling the complexities of fibrosis and ductular reaction in liver disease: pathogenesis, mechanisms, and therapeutic insights. Am J Physiol Cell Physiol 2024; 326:C698-C706. [PMID: 38105754 PMCID: PMC11193454 DOI: 10.1152/ajpcell.00486.2023] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/11/2023] [Accepted: 12/11/2023] [Indexed: 12/19/2023]
Abstract
Ductular reaction and fibrosis are hallmarks of many liver diseases including primary sclerosing cholangitis, primary biliary cholangitis, biliary atresia, alcoholic liver disease, and metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis. Liver fibrosis is the accumulation of extracellular matrix often caused by excess collagen deposition by myofibroblasts. Ductular reaction is the proliferation of bile ducts (which are composed of cholangiocytes) during liver injury. Many other cells including hepatic stellate cells, hepatocytes, hepatic progenitor cells, mesenchymal stem cells, and immune cells contribute to ductular reaction and fibrosis by either directly or indirectly interacting with myofibroblasts and cholangiocytes. This review summarizes the recent findings in cellular links between ductular reaction and fibrosis in numerous liver diseases.
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Affiliation(s)
- Corinn Marakovits
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, United States
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Yang M, Rong L, Zhang X, Li G, Wang Q, Li C, Xiao Y, Wei L, Bi H. Hirsutella sinensis mycelium polysaccharides attenuate the TGF-β1-induced epithelial-mesenchymal transition in human intrahepatic bile duct epithelial cells. Int J Biol Macromol 2024; 254:127834. [PMID: 37926312 DOI: 10.1016/j.ijbiomac.2023.127834] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 10/15/2023] [Accepted: 10/30/2023] [Indexed: 11/07/2023]
Abstract
Hirsutella sinensis is the anamorph of Ophiocordyceps sinensis, and its mycelia has been used to effectively treat a variety of hepatobiliary diseases in clinical practice. In the present study, we performed a systematic study on the composition and structure of its polysaccharides, and then employed a TGF-β1-induced human intrahepatic bile duct epithelial cell-epithelial-mesenchymal transition (HIBEC-EMT) model to investigate their effects on treating primary biliary cholangitis (PBC) based on hepatic bile duct fibrosis. Four polysaccharide fractions were obtained from H. sinensis mycelia by hot-water extraction, DEAE-cellulose column and gradient ethanol precipitation separation. HSWP-1a was an α-(1,4)-D-glucan; HSWP-1b and HSWP-1d mainly consisted of mannoglucans with a backbone composed of 1,4-linked α-D-Glcp and 1,4,6-linked α-D-Manp residues branched at O-6 of the 1,4-linked α-D-Glcp with a 1-linked α-D-Glcp as a side chain; and HSWP-1c mainly contained galactomannoglucans. These polysaccharide fractions protected HIBECs from a TGF-β1-induced EMT, according to HIBEC morphological changes, cell viability, decreased E-cadherin and ZO-1 expression, and increased vimentin and collagen I expression. Furthermore, the effects of the polysaccharides might be mediated by inhibiting the activation of the TGF-β/Smad signaling pathway, which attenuated hepatic bile duct fibrosis and potential PBC effects.
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Affiliation(s)
- Mengmeng Yang
- Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China; Medical college, Qinghai University, Xining 810001, China
| | - Lin Rong
- CAS Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Xining 810001, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xingfang Zhang
- Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China; Medical college, Qinghai University, Xining 810001, China
| | - Guoqiang Li
- CAS Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Xining 810001, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qiannan Wang
- Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China; CAS Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Xining 810001, China
| | - Cen Li
- Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China; CAS Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Xining 810001, China
| | - Yuancan Xiao
- Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China; CAS Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Xining 810001, China
| | - Lixin Wei
- CAS Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Xining 810001, China.
| | - Hongtao Bi
- Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China.
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Zheng Q, Li M, Chen L, Zhang C, Zhao Y, Liu G, Yang F, Zhan J. Potential therapeutic target of EGF on bile duct ligation model and biliary atresia children. Pediatr Res 2023; 94:1297-1307. [PMID: 37138025 DOI: 10.1038/s41390-023-02592-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 02/26/2023] [Accepted: 03/20/2023] [Indexed: 05/05/2023]
Abstract
BACKGROUND The pathogenesis of liver fibrosis in biliary atresia (BA) is unclear. Epidermal growth factor (EGF) plays a vital role in liver fibrosis. This study aims to investigate the expression of EGF and the mechanisms of its pro-fibrotic effects in BA. METHODS EGF levels in serum and liver samples of BA and non-BA children were detected. Marker proteins of EGF signaling and epithelial-mesenchymal transition (EMT) in liver sections were evaluated. Effects of EGF on intrahepatic cells and the underlying mechanisms were explored in vitro. Bile duct ligation (BDL) mice with/without EGF antibody injection were used to verify the effects of EGF on liver fibrosis. RESULTS Serum levels and liver expression of EGF elevated in BA. Phosphorylated EGF receptor (p-EGFR) and extracellular regulated kinase 1/2 (p-ERK1/2) increased. In addition, EMT and proliferation of biliary epithelial cells were present in BA liver. In vitro, EGF induced EMT and proliferation of HIBEpic cells and promoted IL-8 expression in L-02 cells by phosphorylating ERK1/2. And EGF activated LX-2 cells. Furthermore, EGF antibody injection reduced p-ERK1/2 levels and alleviated liver fibrosis in BDL mice. CONCLUSION EGF is overexpressed in BA. It aggravates liver fibrosis through EGF/EGFR-ERK1/2 pathway, which may be a therapeutic target for BA. IMPACT The exact pathogenesis of liver fibrosis in BA is unknown, severely limiting the advancement of BA treatment strategies. This study revealed that serum and liver tissue levels of EGF were increased in BA, and its expression in liver tissues was correlated with the degree of liver fibrosis. EGF may promote EMT and proliferation of biliary epithelial cells and induce IL-8 overexpression in hepatocytes through EGF/EGFR-ERK1/2 signaling pathway. EGF can also activate HSCs in vitro. The EGF/EGFR-ERK1/2 pathway may be a potential therapeutic target for BA.
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Affiliation(s)
- Qipeng Zheng
- Graduate College, Tianjin Medical University, Tianjin, 300070, China
- Department of General Surgery, Tianjin Children's Hospital, Tianjin, 300134, China
| | - Mengdi Li
- Graduate College, Tianjin Medical University, Tianjin, 300070, China
- Department of General Surgery, Tianjin Children's Hospital, Tianjin, 300134, China
| | - Lingzhi Chen
- Graduate College, Tianjin Medical University, Tianjin, 300070, China
- Department of General Surgery, Tianjin Children's Hospital, Tianjin, 300134, China
| | - Cong Zhang
- Graduate College, Tianjin Medical University, Tianjin, 300070, China
- Department of General Surgery, Tianjin Children's Hospital, Tianjin, 300134, China
| | - Yilin Zhao
- Graduate College, Tianjin Medical University, Tianjin, 300070, China
- Department of General Surgery, Tianjin Children's Hospital, Tianjin, 300134, China
| | - Gengxin Liu
- Graduate College, Tianjin Medical University, Tianjin, 300070, China
- Department of General Surgery, Tianjin Children's Hospital, Tianjin, 300134, China
| | - Fang Yang
- Graduate College, Tianjin Medical University, Tianjin, 300070, China
- Department of General Surgery, Tianjin Children's Hospital, Tianjin, 300134, China
| | - Jianghua Zhan
- Department of General Surgery, Tianjin Children's Hospital, Tianjin, 300134, China.
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Wang L, Wang J, Ren G, Sun S, Nishikawa K, Yu J, Zhang C. Ameliorative effects of the Coptis inflorescence extract against lung injury in diabetic mice by regulating AMPK/NEU1 signaling. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 118:154963. [PMID: 37516057 DOI: 10.1016/j.phymed.2023.154963] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 06/23/2023] [Accepted: 07/08/2023] [Indexed: 07/31/2023]
Abstract
BACKGROUND In diabetic patients, complications are the leading cause of death and disability, while diabetic lung damage has received little research. The Coptis inflorescence extract (CE) has hypoglycemic properties, but the mechanism of its protective role on diabetic lung injury is understood. PURPOSE This study aims to explore the protective actions and molecular mechanism of CE and its active ingredients in diabetic lung disease. METHOD Twenty-nine metabolites were identified in the metabolomic profile of CE using HPLC-ESI/MS, and high-content substances of berberine (BBR) and linarin (LIN) were isolated from CE using column chromatography. The potential targets and molecular mechanisms of CE against diabetic lung damage were systematically investigated by network pharmacology and in vitro experimental validation. RESULTS CE significantly improved lung function and pathology. CE (360 mg/kg) or metformin treatment significantly improved lipid metabolism disorders, including decreased HDL-C and elevated serum TG, TC, and LDL-C levels. Furthermore, CE's chemical composition was determined using the HPLC-QTOF-MS method. CE identified five compounds as candidate active compounds (Berberine, Linarin, Palmatine, Worenine, and Coptisine). Network pharmacology analysis predicted CE contained five active compounds and target proteins, that AMPK, TGFβ1, and Smad might be the key targets in treating diabetic lung injury. Then we investigated the therapeutic effect of bioactive compounds of CE on diabetic lung damage through in vivo and in vitro experiments. Intragastric administration with BBR (50 mg/kg) or LIN (20 mg/kg) suppressed weight loss, hyperglycemia, and dyslipidemia, significantly alleviating lung inflammation in diabetic mice. Further mechanism research revealed that LIN or BBR inhibited alveolar epithelial-mesenchymal transition induced by high glucose by regulating AMPK/NEU-mediated signaling pathway. CONCLUSION In conclusion, the administration of CE can effectively alleviate diabetic lung damage, providing a scientific basis for lowering blood sugar to moisturize lung function. BBR and LIN, the main components of CE, can effectively alleviate diabetic lung damage by regulating AMPK/NEU1 Signaling and inhibiting the TGF-β1 level, which may be a critical mechanism of its effects.
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Affiliation(s)
- Lei Wang
- Sino-Jan Joint Lab of Natural Health Products Research, School of Traditional Chinese Medicines, China Pharmaceutical University, Nanjing, China; State Key Laboratory of Natural Medicines, School of Traditional Chinese Medicines, China Pharmaceutical University, Nanjing, China
| | - Jiaoyang Wang
- Sino-Jan Joint Lab of Natural Health Products Research, School of Traditional Chinese Medicines, China Pharmaceutical University, Nanjing, China
| | - Guoqing Ren
- Sino-Jan Joint Lab of Natural Health Products Research, School of Traditional Chinese Medicines, China Pharmaceutical University, Nanjing, China; State Key Laboratory of Natural Medicines, School of Traditional Chinese Medicines, China Pharmaceutical University, Nanjing, China
| | - Siyang Sun
- Sino-Jan Joint Lab of Natural Health Products Research, School of Traditional Chinese Medicines, China Pharmaceutical University, Nanjing, China
| | - Kazuo Nishikawa
- Kampo Medicine Pharmacology Research Laboratory, Graduate School of Pharmaceutical Sciences, Yokohama University of Pharmacy, Yokohama-city 2408501, Japan
| | - Jing Yu
- Kampo Medicine Pharmacology Research Laboratory, Graduate School of Pharmaceutical Sciences, Yokohama University of Pharmacy, Yokohama-city 2408501, Japan.
| | - Chaofeng Zhang
- Sino-Jan Joint Lab of Natural Health Products Research, School of Traditional Chinese Medicines, China Pharmaceutical University, Nanjing, China; State Key Laboratory of Natural Medicines, School of Traditional Chinese Medicines, China Pharmaceutical University, Nanjing, China.
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Chusilp S, Balsamo F, Li B, Vejchapipat P, Pierro A. Development of liver inflammatory injury in biliary atresia: from basic to clinical research. Pediatr Surg Int 2023; 39:207. [PMID: 37249714 DOI: 10.1007/s00383-023-05489-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/13/2023] [Indexed: 05/31/2023]
Abstract
Biliary atresia (BA) is a severe cholangiopathy in infants. It is characterized by inflammatory fibro-obliteration of the intra- and extrahepatic bile ducts. Although the restoration of bile flow can be successful after Kasai operation, the rapid progression of liver fibrosis can continue, leading to cirrhosis. It is believed that the progression of liver fibrosis in BA is exacerbated by complicated mechanisms other than the consequence of bile duct obstruction. The fibrogenic cascade in BA liver can be divided into three stages, including liver inflammatory injury, myofibroblast activation, and fibrous scar formation. Recent studies have revealed that the activation of an immune response following bile duct injury plays an important role in promoting the inflammatory process, the releasing of inflammatory cytokines, and the development of fibrogenesis in BA liver. In this article, we summarized the evidence regarding liver inflammatory injury and the possible mechanisms that explain the rapid progression of liver fibrosis in BA.
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Affiliation(s)
- Sinobol Chusilp
- Division of General and Thoracic Surgery, Translational Medicine Program, University of Toronto, The Hospital for Sick Children, 1526-555 University Ave, Toronto, ON, M5G 1X8, Canada
- Division of Pediatric Surgery, Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Felicia Balsamo
- Division of General and Thoracic Surgery, Translational Medicine Program, University of Toronto, The Hospital for Sick Children, 1526-555 University Ave, Toronto, ON, M5G 1X8, Canada
| | - Bo Li
- Division of General and Thoracic Surgery, Translational Medicine Program, University of Toronto, The Hospital for Sick Children, 1526-555 University Ave, Toronto, ON, M5G 1X8, Canada
| | - Paisarn Vejchapipat
- Division of Pediatric Surgery, Department of Surgery, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Agostino Pierro
- Division of General and Thoracic Surgery, Translational Medicine Program, University of Toronto, The Hospital for Sick Children, 1526-555 University Ave, Toronto, ON, M5G 1X8, Canada.
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Wang D, Yang S, Zhao Y, Zhang Y, Hua K, Gu Y, Li S, Liao J, Yang T, Zhao J, Huang J. Identifying and validating molecular subtypes of biliary atresia using multiple high-throughput data integration analysis. Front Immunol 2023; 13:1008246. [PMID: 36713418 PMCID: PMC9878701 DOI: 10.3389/fimmu.2022.1008246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 12/29/2022] [Indexed: 01/13/2023] Open
Abstract
Background Biliary atresia (BA) is the most common form of severe neonatal obstructive jaundice. The etiology and pathogenesis of BA are multifactorial, and different factors may interact to produce heterogeneous pathological features and clinical outcomes. Despite different pathological features, all patients received the same treatment strategy. This study performed integrative clustering analysis based on multiple high-throughput datasets to identify the molecular subtypes of BA and provide a new treatment strategy for personalized treatment of the different subtypes of BA. Methods The RNA sequence dataset GSE122340 in the Gene Expression Omnibus (GEO) database was downloaded; 31 BA and 20 control normal liver tissues were collected at our center for transcriptome sequencing, and clinical and follow-up data of BA patients were available. Molecular subtypes were identified using integrated unsupervised cluster analysis involving gene expression, biliary fibrosis, and immune enrichment scores based on the transcriptome dataset, and the results were validated using independent datasets. Results Based on the results of the integrated unsupervised clustering analysis, four molecular subtypes were identified: autoimmune, inflammatory, virus infection-related, and oxidative stress. The autoimmune subtype with a moderate prognosis was dominated by autoimmune responses and morphogenesis, such as the Fc-gamma receptor and Wnt signaling pathway. The biological process of the inflammatory subtype was mainly the inflammatory response, with the best prognosis, youngest age at surgery, and lowest liver stiffness. The virus infection-related subtype had the worst prognosis and was enriched for a variety of biological processes such as viral infection, immunity, anatomical morphogenesis, and epithelial mesenchymal transition. The oxidative stress subtype was characterized by the activation of oxidative stress and various metabolic pathways and had a poor prognosis. The above results were verified independently in the validation sets. Conclusions This study identified four molecular subtypes of BA with distinct prognosis and biological processes. According to the pathological characteristics of the different subtypes, individualized perioperative and preoperative treatment may be a new strategy to improve the prognosis of BA.
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Modeling bile duct ischemia and reoxygenation injury in human cholangiocyte organoids for screening of novel cholangio-protective agents. EBioMedicine 2023; 88:104431. [PMID: 36608526 PMCID: PMC9826934 DOI: 10.1016/j.ebiom.2022.104431] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 12/16/2022] [Accepted: 12/19/2022] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Ischemia of the bile duct is a common feature in liver disease and transplantation, which represents a major cause of morbidity and mortality, especially after liver transplantation. Detailed knowledge of its pathogenesis remains incomplete due to the lack of appropriate in vitro models. METHODS To recapitulate biliary damage induced by ischemia and reperfusion in vitro, human intrahepatic cholangiocyte organoids (ICOs) were grown at low oxygen levels of 1% up to 72 h, followed by re-oxygenation at normal levels. FINDINGS ICOs stressed by ischemia and subsequent re-oxygenation represented the dynamic change in biliary cell proliferation, upregulation of epithelial-mesenchymal transition (EMT)-associated markers, and the evocation of phase-dependent cell death programs similar to what is described in patients. Clinical-grade alpha-1 antitrypsin was identified as a potent inhibitor of both ischemia-induced apoptosis and necroptosis. INTERPRETATION These findings demonstrate that ICOs recapitulate ischemic cholangiopathy in vitro and enable drug assessment studies for the discovery of new therapeutics for ischemic cholangiopathies. FUNDING Dutch Digestive FoundationMLDS D16-26; TKI-LSH (Topconsortium Kennis en Innovatie-Life Sciences & Health) grant RELOAD, EMC-LSH19002; Medical Delta program "Regenerative Medicine 4D"; China Scholarship Council No. 201706230252.
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Haritha CV, Lingaraju MC, Mathesh K, Jadhav SE, Shyamkumar TS, Aneesha VA, Parida S, Singh TU, Kumar D. PRE-084 ameliorates adenine-induced renal fibrosis in rats. Tissue Cell 2022; 79:101905. [PMID: 36063652 DOI: 10.1016/j.tice.2022.101905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 08/12/2022] [Accepted: 08/19/2022] [Indexed: 11/30/2022]
Abstract
2-(4-morpholinoethyl)- 1-phenylcyclohexane-1-carboxylate hydrochloride (PRE-084) is a selective sigma 1 receptor agonist. It has been shown that PRE-084 protected various tissues from experimental injury. However, no reports are available on its effect on renal fibrosis. Rat model of adenine-induced chronic kidney disease was chosen to study this. Adenine feeding in rats caused renal dysfunction as shown by increased serum creatinine and reduced creatinine clearance along with increased high molecular weight (HMW) urine protein excretion. Further, adenine feeding induced profibrotic changes in the kidney as reflected by increased expression of alpha-smooth muscle actin (α-SMA), fibroblast specific protein-1 (FSP-1) and matrix metalloproteinase-2 (MMP-2) activity; reduced cytokeratin expression. Further, there was excess deposition of extracellular matrix in the kidney, a striking character of fibrosis. However, administration of PRE-084 to adenine fed rats led to reduction in creatinine and proteinuria parameters partly. This was accompanied by reduced expression of α-SMA, FSP-1 and MMP-2 activity and slight restoration of cytokeratin levels leading to reduced extracellular matrix deposition in the kidney. These data demonstrate that PRE-084 partly ameliorated renal dysfunction and exhibited anti-fibrotic potential in the kidney of adenine fed rats.
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Affiliation(s)
- C V Haritha
- Division of Pharmacology and Toxicology, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, India
| | | | - Karikalan Mathesh
- Centre for Wildlife Conservation Management and Disease Surveillance, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, India
| | - Sunil E Jadhav
- Division of Animal Nutrition, ICAR-Indian Veterinary Research Institute, Izatnagar, 243122, India
| | - T S Shyamkumar
- Division of Pharmacology and Toxicology, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, India
| | - V A Aneesha
- Division of Pharmacology and Toxicology, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, India
| | - Subhashree Parida
- Division of Pharmacology and Toxicology, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, India
| | - Thakur Uttam Singh
- Division of Pharmacology and Toxicology, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, India
| | - Dinesh Kumar
- Division of Pharmacology and Toxicology, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, India
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11
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Ma Y, Lu L, Tan K, Li Z, Guo T, Wu Y, Wu W, Zheng L, Fan F, Mo J, Gong Z. Reduced peroxisome proliferator-activated receptor-α and bile acid nuclear receptor NR1H4/FXR may affect the hepatic immune microenvironment of biliary atresia. Front Immunol 2022; 13:875593. [PMID: 36090996 PMCID: PMC9454303 DOI: 10.3389/fimmu.2022.875593] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 08/03/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Biliary atresia (BA) is a childhood liver disease characterized by fibrous obstruction and obstruction of the extrahepatic biliary system and is one of the most common and serious biliary disorders in infants. Significant inflammation and fibrosis of the liver and biliary tract are the most prominent features, regardless of the initial damage to the BA. Abnormalities in innate or adaptive immunity have been found in human patients and mouse models of BA. We previously reported that children with BA had abnormal lipid metabolism, including free serum carnitine. OBJECTIVE To study gene and protein expression levels of the hepatic peroxisome proliferator-activated receptor-α (PPARα) signaling pathway and farnesoid X receptor (FXR) in BA and BA fibrosis, and assess their clinical values. METHODS Low expression of PPARα and NR1H4 (FXR) in BA were validated in the Gene Expression Omnibus database. Functional differences were determined by gene set enrichment analysis based on of PPARα and NR1H4 expression. BA patients from GSE46960 were divided into two clusters by using consensus clustering according to PPARα, NR1H4, and SMAD3 expression levels, and immunoinfiltration analysis was performed. Finally, 58 cases treated in our hospital were used for experimental verification. (IHC: 10 Biliary atresia, 10 choledochal cysts; PCR: 10 Biliary atresia, 14 choledochal cysts; WB: 10 Biliary atresia, 4 choledochal cysts). RESULTS Bioinformatics analysis showed that the expression of PPARα, CYP7A1 and NR1H4 (FXR) in the biliary atresia group was significantly lower than in the control group. More BA-specific pathways, including TGFβ signaling pathway, P53 signaling pathway, PI3K-AKT-mTOR signaling pathway, etc., are enriched in BA patients with low PPARα and NR1H4 expression. In addition, low NR1H4 expression is abundant in inflammatory responses, IL6/STAT3 signaling pathways, early estrogen responses, IL2 STAT5 signaling pathways, and TGFβ signaling pathways. The TGFβ signaling pathway was significant in both groups. According to the expression of PPARα, NR1H4 and SMAD3, a key node in TGFβ pathway, BA patients were divided into two clusters using consensus clustering. In cluster 2, SMAD3 expression was high, and PPARα and NR1H4 expression were low. In contrast to cluster 1, immune cell infiltration was higher in cluster 2, which was confirmed by immunohistochemistry. The mRNA and protein levels of PPARα and NR1H4 in BA patients were lower than in the control group by immunohistochemistry, Western blot analysis and real-time PCR. CONCLUSIONS The downregulation of PPARα and NR1H4 (FXR) signaling pathway may be closely related to biliary atresia.
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Affiliation(s)
- Yingxuan Ma
- Department of General Surgery, Children’s Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai, China
| | - Li Lu
- Department of General Surgery, Children’s Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai, China
| | - Kezhe Tan
- Department of General Surgery, Children’s Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai, China
| | - Zhi Li
- Pathology Department, Children’s Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai, China
| | - Ting Guo
- Department of General Surgery, Children’s Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai, China
| | - Yibo Wu
- Department of General Surgery, Children’s Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Wu
- Department of General Surgery, Children’s Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai, China
| | - Lulu Zheng
- Department of General Surgery, Children’s Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai, China
| | - Feilong Fan
- Department of General Surgery, Children’s Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai, China
| | - Jiayu Mo
- Department of General Surgery, Children’s Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai, China
| | - Zhenhua Gong
- Department of General Surgery, Children’s Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai, China
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12
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Siyu P, Junxiang W, Qi W, Yimao Z, Shuguang J. The Role of GLI in the Regulation of Hepatic Epithelial-Mesenchymal Transition in Biliary Atresia. Front Pediatr 2022; 10:861826. [PMID: 35692978 PMCID: PMC9178093 DOI: 10.3389/fped.2022.861826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 05/06/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE To study the regulatory role of GLI1/GLI2, a nuclear transcription factor of the Sonic hedgehog (Shh) signaling pathway, in epithelial-mesenchymal transition (EMT) related to hepatic fibrosis in patients with biliary atresia (BA). METHODS The messenger RNA (mRNA) and protein expression levels of GLI1/GLI2, Snail/Slug, and other Shh- and EMT-related cytokines were tested in the liver tissues of BA patients and animals. Then, GLI1/GLI2 was silenced and overexpressed in mouse intrahepatic bile duct epithelial cells (mIBECs) and BA animals to investigate changes in the mRNA and protein expression of EMT key factors and liver fibrosis indicators. After silencing and overexpression of GLI1/GLI2, immunofluorescence was used to detect the expression of cytokeratin-19 (CK19) and α-smooth muscle actin (α-SMA) in mIBECs, and hematoxylin and eosin (HE) staining and Masson staining were used to observe the degree of liver fibrosis in the BA animals. RESULTS Compared with the control, the mRNA and protein expression levels of GLI2, Snail, vimentin, and α-SMA were significantly increased and those of E-cadherin were significantly decreased in liver tissue from BA patients and animals. Overexpression of GLI2 increased the mRNA and protein expression levels of Snail, vimentin, and α-SMA and that of E-cadherin was significantly decreased in mIBECs and BA animals. After GLI2 silencing, the opposite pattern was observed. Immunofluorescence detection showed enhanced expression of the bile duct epithelial cell marker CK19 in mIBECs after GLI2 silencing and enhanced expression of the mesenchymal cell marker α-SMA after GLI2 overexpression. HE and Masson staining suggested that the GLI2-overexpressing group had a significantly higher degree of fibrosis. CONCLUSION The Shh signaling pathway plays an important role in fibrogenesis in BA. GLI2 can significantly regulate EMT in mIBECs and livers of BA mice.
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Affiliation(s)
- Pu Siyu
- Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Wang Junxiang
- Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Wang Qi
- Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Zhang Yimao
- Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Jin Shuguang
- Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu, China
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Nambiyar K, Ahuja A, Bhardwaj M. A study of epithelial-mesenchymal transition immunohistochemical markers in primary oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol 2021; 132:680-686. [PMID: 34511347 DOI: 10.1016/j.oooo.2021.05.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 03/20/2021] [Accepted: 05/30/2021] [Indexed: 10/21/2022]
Abstract
OBJECTIVE To analyze markers of epithelial-mesenchymal transition (EMT) in oral squamous cell carcinoma (SCC) using E-cadherin, epithelial membrane antigen (EMA), vimentin, and smooth muscle actin (SMA), and their association with tumor metastasis and grade. STUDY DESIGN This was a retrospective study, which included 45 diagnosed cases of primary oral SCC with known lymph node status, taken from the archives of the Department of Pathology along with their clinical profile. Histomorphologic evaluation and immunohistochemical (IHC) analysis for E-cadherin, EMA, vimentin, and SMA were performed. IHC expression of these markers was compared with tumor differentiation as well as lymph node metastasis. RESULTS We observed that reduced E-cadherin expression and positive expression of SMA were significantly higher in tumors having lymph node metastasis and loss of tumor differentiation, respectively. Reduced EMA expression was associated with the presence of lymph node metastasis but not with the histologic differentiation. Vimentin positivity did not show any correlation with lymph node metastasis or histologic differentiation. CONCLUSIONS This study emphasizes the importance of EMT in the pathogenesis of oral SCC. The use of biomarkers like E-cadherin, EMA, and SMA might be a valuable tool for predicting patient outcomes and therapy.
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Affiliation(s)
- Kaniyappan Nambiyar
- Assistant Professor, Department of Pathology, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. Ram Manohar Lohia Hospital, New Delhi, India
| | - Arvind Ahuja
- Professor, Department of Pathology, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. Ram Manohar Lohia Hospital, New Delhi, India.
| | - Minakshi Bhardwaj
- Professor, Department of Pathology, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. Ram Manohar Lohia Hospital, New Delhi, India
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Chusilp S, Lee C, Li B, Lee D, Yamoto M, Ganji N, Vejchapipat P, Pierro A. Human amniotic fluid stem cells attenuate cholangiocyte apoptosis in a bile duct injury model of liver ductal organoids. J Pediatr Surg 2021; 56:11-16. [PMID: 33129508 DOI: 10.1016/j.jpedsurg.2020.09.043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 09/22/2020] [Indexed: 11/17/2022]
Abstract
PURPOSE Biliary atresia (BA) is a fibro-obliterative cholangiopathy that involves both extrahepatic and intrahepatic bile ducts in infants. Cholangiocyte apoptosis has an influence on the fibrogenesis process of bile ducts and the progression of liver fibrosis in BA. Human amniotic fluid stem cells (hAFSCs) are multipotent cells that have ability to inhibit cell apoptosis. We aimed to investigate whether hAFSCs have the potential to attenuate cholangiocyte apoptosis and injury induced fibrogenic response in our ex vivo bile duct injury model of liver ductal organoids. METHODS The anti-apoptotic effect of hAFSCs was tested in the acetaminophen-induced injury model of neonatal mouse liver ductal organoids (AUP #42681) by using direct and indirect co-culture systems. Cell apoptosis and proliferation were evaluated by immunofluorescent staining. Expression of fibrogenic cytokines was analyzed by RT-qPCR. Data were compared using one-way ANOVA with post hoc test. RESULTS In our injury model, liver ductal organoids that were treated with hAFSCs in both direct and indirect co-culture systems had a significantly smaller number of apoptotic cholangiocytes and decreased expression of fibrogenic cytokines, transforming growth factor beta-1 (TGF-β1) and platelet-derived growth factor-BB (PDGF-BB). Moreover, hAFSCs increased cholangiocyte proliferation in injured organoids. CONCLUSION hAFSCs have the ability to protect the organoids from injury by decreasing cholangiocyte apoptosis and promoting cholangiocyte proliferation. This protective ability of hAFSCs leads to inhibition of the fibrogenic response in the injured organoids. hAFSCs have high therapeutic potential to attenuate liver fibrogenesis in cholangiopathic diseases such as BA.
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Affiliation(s)
- Sinobol Chusilp
- Division of General and Thoracic Surgery, Translational Medicine Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Pediatric Surgery, Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Carol Lee
- Division of General and Thoracic Surgery, Translational Medicine Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Bo Li
- Division of General and Thoracic Surgery, Translational Medicine Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Dorothy Lee
- Division of General and Thoracic Surgery, Translational Medicine Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Masaya Yamoto
- Division of General and Thoracic Surgery, Translational Medicine Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Niloofar Ganji
- Division of General and Thoracic Surgery, Translational Medicine Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Paisarn Vejchapipat
- Division of Pediatric Surgery, Department of Surgery, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Agostino Pierro
- Division of General and Thoracic Surgery, Translational Medicine Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
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15
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Chen Y, Fan Y, Guo DY, Xu B, Shi XY, Li JT, Duan LF. Study on the relationship between hepatic fibrosis and epithelial-mesenchymal transition in intrahepatic cells. Biomed Pharmacother 2020; 129:110413. [PMID: 32570119 DOI: 10.1016/j.biopha.2020.110413] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 06/08/2020] [Accepted: 06/13/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatic fibrosis is a pathophysiological process, which causes excessive extracellular matrix (ECM) deposition resulting from persistent liver damage. Myofibroblasts are the core cells that produce ECM. It is known that epithelial-mesenchymal transition (EMT) is not a simple transition of cells from the epithelial to mesenchymal state. Instead, it is a process, in which epithelial cells temporarily lose cell polarity, transform into interstitial cell-like morphology, and acquire migration ability. Hepatocytes, hepatic stellate cells, and bile duct cells are the types of intrahepatic cells found in the liver. They can be transformed into myofibroblasts via EMT and play important roles in the development of hepatic fibrosis through a maze of regulations involving various pathways. The aim of the present study is to explore the relationship between the relevant regulatory factors and the EMT signaling pathways in the various intrahepatic cells.
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Affiliation(s)
- Yang Chen
- The Basic Medical College of Shaanxi University of Chinese Medicine, Xianyang 712046, China.
| | - Yu Fan
- The Basic Medical College of Shaanxi University of Chinese Medicine, Xianyang 712046, China; Shaanxi Province Key Laboratory of Basic and New Herbal Medicament Research, Xianyang 712046, China.
| | - Dong-Yan Guo
- Shaanxi Province Key Laboratory of Basic and New Herbal Medicament Research, Xianyang 712046, China.
| | - Bing Xu
- The Medical Technical College of Shaanxi University of Chinese Medicine, Xianyang 712046, China.
| | - Xiao-Yan Shi
- The Basic Medical College of Shaanxi University of Chinese Medicine, Xianyang 712046, China.
| | - Jing-Tao Li
- The First Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang 712000, China.
| | - Li-Fang Duan
- The Basic Medical College of Shaanxi University of Chinese Medicine, Xianyang 712046, China.
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16
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Abstract
The treatment of biliary atresia (BA) is predominantly surgical with firstly an attempt at restoration of bile flow from the native liver by wide excision of the obstructed, obliterated extrahepatic biliary tree to the level of the porta hepatis and a portoenterostomy using a long Roux loop-Kasai portoenterostomy (KPE). Liver transplantation is reserved for those that fail this and for those where surgery is considered futile for reasons of age or stage of disease. As the aetiology of BA remains ill-defined, so adjuvant treatment has been largely based on pragmatism, trial and error. Systematic analysis of the few randomized placebo-controlled trial data and less well-controlled cohort studies have suggested benefit from post-operative high-dose steroids and ursodeoxycholic acid (UDCA) while the benefit of long-term prophylactic antibiotics, bile acid sequestrants (e.g., colestyramine) or probiotics remains unproven. Newer modalities such as antiviral therapy (AVT), immunoglobulin, FXR agonists (e.g., obeticholic acid), ileal bile acid transporter (IBAT) antagonists (e.g., maralixibat) remain unproven. This article reviews the current evidence for the efficacy of adjuvant medical therapy in BA.
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Affiliation(s)
- Jessica Burns
- Department of Paediatric Surgery, King's College Hospital, London, UK
| | - Mark Davenport
- Department of Paediatric Surgery, King's College Hospital, London, UK
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Ardalani H, Sengupta S, Harms V, Vickerman V, Thomson JA, Murphy WL. 3-D culture and endothelial cells improve maturity of human pluripotent stem cell-derived hepatocytes. Acta Biomater 2019; 95:371-381. [PMID: 31362140 DOI: 10.1016/j.actbio.2019.07.047] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 07/19/2019] [Accepted: 07/25/2019] [Indexed: 12/18/2022]
Abstract
Human-induced pluripotent stem cell (hiPSC)-derived hepatocytes (iHEP) offer an attractive alternative to primary human hepatocytes (PHH) for drug toxicity studies, as PHHs are limited in supply, vary in their metabolic activity between donors, and rapidly lose their functionality in vitro. However, one of the major drawbacks with iHEP cells in drug safety studies is their decreased phenotypic maturity, with lower liver specific enzyme activity compared with that of PHH. Here we evaluated the effects of 3D culture and non-parenchymal cells on the maturation of iHEPs. We describe a serum-free, chemically defined 3D in vitro model using iHEP cells, which is compatible with automation and conventional assay plates. The iHEP cells cultured in this model form polarized aggregates with functional bile canaliculi and strongly increased expression of albumin, urea and genes encoding phase I and II drug metabolism enzymes and bile transporters. Cytochrome P450-mediated metabolism is significantly higher in 3D iHEP aggregates compared to 2D iHEP culture. Furthermore, addition of human liver sinusoidal endothelial cells (sECs) and iPS-derived endothelial cells (iECs) improved mature hepatocyte function and CYP450 enzyme activity. Also, ECs formed endothelial networks within the hepatic 3D cultures, mimicking aspects of an in vivo architecture. Collectively, these results suggest that the iHEP/EC aggregates described here may have the potential to be used for many applications, including as an in vitro model to study liver diseases associated with sinusoidal endothelial cells. STATEMENT OF SIGNIFICANCE: iPS-derived hepatocytes provide an inexhaustible source of cells for drug screening, toxicology studies and cell-based therapies, but lack mature phenotype of adult primary human hepatocytes (PHH). Herein, we show that 3D culture of iPS-derived hepatocytes and their co-culture with human sinusoidal endothelial cells (sECs) to improve their maturity.
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Affiliation(s)
- Hamisha Ardalani
- Department of Biomedical Engineering, University of Wisconsin-Madison, WI, USA; Morgridge Institute for Research, Madison, WI, USA
| | | | - Victoria Harms
- Molecular and Environmental Toxicology Program, University of Wisconsin-Madison, WI, USA
| | | | - James A Thomson
- Morgridge Institute for Research, Madison, WI, USA; Cell and Regenerative Biology, University of Wisconsin-Madison, WI, USA; Department of Molecular, Cellular, and Developmental Biology, University of California-Santa Barbara, CA, USA
| | - William L Murphy
- Department of Biomedical Engineering, University of Wisconsin-Madison, WI, USA; Department of Orthopedics and Rehabilitation, University of Wisconsin-Madison, WI, USA.
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Abstract
BACKGROUND Biliary atresia (BA) is the most common cause of obstructive jaundice in infants. Although the Kasai procedure has greatly improved the prognosis, most patients still need liver transplantation (LT) for long-term survival. The pathogenesis of BA has not been fully clarified, and liver fibrosis in BA is far beyond biliary obstructive cirrhosis. DATA SOURCES Literature reviews were underwent through PubMed. Persistent inflammation, immune response, biliary epithelial-mesenchymal transition, matrix deposition, decompensated angiogenesis, and unique biliary structure development all contribute to the fibrosis process. Observed evidences in such fields have been collected and form the backbone of this review. RESULTS Interactions of the multiple pathways accelerate this process. CONCLUSIONS Understanding the mechanisms of the liver fibrosis in BA may pave the way to improved survival after the Kasai procedure.
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Affiliation(s)
- Wen-Jun Shen
- Department of Pediatric Surgery, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102, China
| | - Gong Chen
- Department of Pediatric Surgery, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102, China
| | - Min Wang
- Department of Pediatric Surgery, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102, China
| | - Shan Zheng
- Department of Pediatric Surgery, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102, China.
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Tang YM, Yu HY. Progress in research of mechanism of biliary epithelial cell injury in primary biliary cholangitis. Shijie Huaren Xiaohua Zazhi 2019; 27:36-42. [DOI: 10.11569/wcjd.v27.i1.36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by chronic biliary cholestasis and progressive intrahepatic and small bile duct non- suppurative inflammation with early infiltration of inflammatory cells around biliary epithelial cells (BECs). BECs lining the bile duct express multiple receptors for pathogen-associated molecular patterns and can activate intracellular signaling pathways and participate in immune regulation. The etiology and pathogenesis of PBC are not fully understood yet, but the key step found in its pathogenesis is the targeted destruction of biliary cells. Since bile duct epithelial cells participate in a series of intrahepatic immune regulation processes, bile duct epithelial cell injury is an important mechanism involved in the development of intrahepatic inflammation in PBC. Therefore, understanding the mechanism of BEC injury can help us find some new targets for the treatment of PBC. This article briefly reviews the progress in the research of mechanism of biliary epithelial cell injury in PBC.
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Affiliation(s)
- Ying-Mei Tang
- Department of Gastroenterology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
| | - Hai-Yan Yu
- Department of Gastroenterology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
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20
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Toll-like receptor 4 shRNA attenuates lipopolysaccharide-induced epithelial-mesenchymal transition of intrahepatic biliary epithelial cells in rats. Biomed Pharmacother 2018; 107:1210-1217. [PMID: 30257335 DOI: 10.1016/j.biopha.2018.08.071] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Revised: 07/26/2018] [Accepted: 08/15/2018] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND AND AIM Intrahepatic biliary epithelial cells (IBECs) of the bile duct in liver tissue of patients with hepatolithiasis promoted the development of diseases through epithelial-mesenchymal transition (EMT). This study investigated whether lipopolysaccharide (LPS), a cell-wall constituent of gram-negative bacteria, could induce EMT of IBECs and toll-like receptor 4 (TLR4) had a regulatory role via activating the nuclear factor-κB (NF-κB)/Snail signaling pathway during this process in vivo. METHODS TLR4 short hairpin RNA (shRNA) adenovirus or negative control shRNA (NC shRNA) adenovirus (1 × 109 plaque-forming unit (PFU), respectively) was injected into the caudal vein of rats. After 96 h, 1 mg/kg LPS was infused retrogradely into the common bile duct for 48 h per rat. The effects of TLR4 shRNA on LPS-induced EMT were determined by evaluating the histopathological changes in IBECs using hematoxylin and eosin staining and the changes in the levels of EMT markers, TLR4, NF-κB p65, pNF-κB p65, and Snail using real-time polymerase chain reaction and Western blot analysis. RESULTS Compared with normal saline treatment, a loss of epithelial cell markers (E-cadherin and cytokeratin 7) and a gain of mesenchymal cell markers (N-cadherin and matrix metalloproteinase 2) were revealed. The levels of TLR4, NF-κB phosphorylation, and Snail significantly increased after LPS treatment, whereas pretreatment with TLR4 shRNA inhibited the LPS-induced EMT by downregulating the NF-κB/Snail signaling pathway. CONCLUSIONS LPS induced the EMT of IBECs by activating TLR4. The RNAi-mediated knockdown of TLR4 suppressed EMT occurrence via downregulating the NF-κB/Snail signaling pathway, implicating TLR4 as a new target for human hepatolithiasis.
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Zhang RZ, Zeng XH, Lin ZF, Ming-Fu, Tong YL, Lui VCH, Tam PKH, Lamb JR, Xia HM, Chen Y. Downregulation of Hes1 expression in experimental biliary atresia and its effects on bile duct structure. World J Gastroenterol 2018; 24:3260-3272. [PMID: 30090006 PMCID: PMC6079292 DOI: 10.3748/wjg.v24.i29.3260] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Revised: 06/03/2018] [Accepted: 06/25/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To analyze the expression and function of the Notch signaling target gene Hes1 in a rhesus rotavirus-induced mouse biliary atresia model.
METHODS The morphologies of biliary epithelial cells in biliary atresia patients and in a mouse model were examined by immunohistochemical staining. Then, the differential expression of Notch signaling pathway-related molecules was investigated. Further, the effects of the siRNA-mediated inhibition of Hes1 expression were examined using a biliary epithelial cell 3D culture system.
RESULTS Both immature (EpCAM+) and mature (CK19+) biliary epithelial cells were detected in the livers of biliary atresia patients without a ductile structure and in the mouse model with a distorted bile duct structure. The hepatic expression of transcripts for most Notch signaling molecules were significantly reduced on day 7 but recovered to normal levels by day 14, except for the target molecule Hes1, which still exhibited lower mRNA and protein levels. Expression of the Hes1 transcriptional co-regulator, RBP-Jκ was also reduced. A 3D gel culture system promoted the maturation of immature biliary epithelial cells, with increased expression of CK19+ cells and the formation of a duct-like structure. The administration of Hes1 siRNA blocked this process. As a result, the cells remained in an immature state, and no duct-like structure was observed.
CONCLUSION Our data indicated that Hes1 might contribute to the maturation and the cellular structure organization of biliary epithelial cells, which provides new insight into understanding the pathology of biliary atresia.
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Affiliation(s)
- Rui-Zhong Zhang
- Department of Pediatric Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
| | - Xin-Hao Zeng
- Department of Pediatric Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
| | - Ze-Feng Lin
- Department of Pediatric Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
| | - Ming-Fu
- Department of Pediatric Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
| | - Yan-Lu Tong
- Department of Pediatric Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
| | - Vincent CH Lui
- Department of Surgery and Pathology, University of Hong Kong, Hong Kong, China
| | - Paul KH Tam
- Department of Surgery and Pathology, University of Hong Kong, Hong Kong, China
| | - Jonathan R Lamb
- Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London SW7 2AZ, United Kingdom
| | - Hui-Min Xia
- Department of Pediatric Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
| | - Yan Chen
- Department of Pediatric Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
- Department of Surgery and Pathology, University of Hong Kong, Hong Kong, China
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Chen CM, Juan SH, Pai MH, Chou HC. Hyperglycemia induces epithelial-mesenchymal transition in the lungs of experimental diabetes mellitus. Acta Histochem 2018; 120:525-533. [PMID: 29934127 DOI: 10.1016/j.acthis.2018.06.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 06/13/2018] [Accepted: 06/14/2018] [Indexed: 02/06/2023]
Abstract
Diabetes mellitus (DM) reduces lung function and increases the risk of asthma, chronic obstructive pulmonary disease, pneumonia, and pulmonary fibrosis. Epithelial-mesenchymal transition (EMT) plays a crucial role in the development of pulmonary fibrosis. The pathogenesis of pulmonary fibrosis in diabetes remains unknown. We investigated the effects of hyperglycemia on EMT in the lungs of gerbils with streptozotocin (STZ)-induced diabetes. Diabetic gerbils exhibited a significantly lower volume fraction of the alveolar airspace and significantly higher septal thickness, volume fraction of the alveolar wall, and lung injury scores than did nondiabetic gerbils. The percentage of 8-hydroxy-2'-deoxyguanosine-positive cells and transforming growth factor-β-positive cells was significantly higher, the expression of E-cadherin was significantly lower, and the expression of N-cadherin was significantly higher in diabetic gerbils than in nondiabetic gerbils. These EMT characteristics were associated with a significant increase in α-smooth muscle actin (SMA) expression and collagen deposition in the lungs of diabetic gerbils. The increased α-SMA expression was co-localized with surfactant protein-C in alveolar type II cells in hyperglycemic animals. In conclusion, our study demonstrates that hyperglycemia induces EMT and contributes to lung fibrosis in an experimental DM model.
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Udomsinprasert W, Vejchapipat P, Klaikeaw N, Chongsrisawat V, Poovorawan Y, Honsawek S. Hepatic autotaxin overexpression in infants with biliary atresia. PeerJ 2018; 6:e5224. [PMID: 30065861 PMCID: PMC6063256 DOI: 10.7717/peerj.5224] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 06/22/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Autotaxin (ATX) is a secreted glycoprotein that is involved in the development of hepatic fibrogenesis via the enzymatic production of lysophosphatidic acid. The aim of this study was to investigate hepatic expression of ATX in biliary atresia (BA) compared with non-BA liver controls and to examine the association between ATX expression and clinical outcome in BA. METHODS Liver specimens from BA infants (n = 20) were compared with samples from infants who underwent liver biopsy for reasons other than BA (n = 14) and served as controls. Relative mRNA and protein expression of ATX were quantified using real-time polymerase chain reaction (PCR) and immunohistochemistry. Masson's Trichrome staining was performed to determine the degree of liver fibrosis. RESULTS Quantitative real-time PCR demonstrated overexpression of ATX mRNA in BA livers. In immunohistochemical evaluation, ATX was positively stained on the hepatic parenchyma and the biliary epithelium in BA patients, as compared to non-BA controls. The immunostaining score of ATX in BA livers was also significantly higher than that observed in non-BA livers (P < 0.001). Subgroup analysis revealed that ATX expression in the patients with poor outcomes was significantly greater than in those with good outcomes (P = 0.03). Additionally, there was a positive correlation between hepatic ATX expression and Metavir fibrosis stage in BA livers (r = 0.79, P < 0.001). DISCUSSION This study found that mRNA and protein expression of ATX were increased in BA livers. High hepatic ATX expression at the time of Kasai operation was associated with liver fibrosis and outcome in BA, suggesting that ATX may serve a role as a promising biomarker of the prognosis in biliary atresia.
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Affiliation(s)
- Wanvisa Udomsinprasert
- Osteoarthritis and Musculoskeleton Research Unit, Department of Biochemistry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Chulalongkorn University, Bangkok, Thailand
- Department of Biochemistry, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Paisarn Vejchapipat
- Department of Surgery, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Chulalongkorn University, Bangkok, Thailand
| | - Naruemon Klaikeaw
- Department of Pathology, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Chulalongkorn University, Bangkok, Thailand
| | - Voranush Chongsrisawat
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand
| | - Sittisak Honsawek
- Osteoarthritis and Musculoskeleton Research Unit, Department of Biochemistry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Chulalongkorn University, Bangkok, Thailand
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Chen L, Chen R, Kemper S, Cong M, You H, Brigstock DR. Therapeutic effects of serum extracellular vesicles in liver fibrosis. J Extracell Vesicles 2018; 7:1461505. [PMID: 29696080 PMCID: PMC5912192 DOI: 10.1080/20013078.2018.1461505] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Accepted: 04/02/2018] [Indexed: 12/15/2022] Open
Abstract
The lack of approved therapies for hepatic fibrosis seriously limits medical management of patients with chronic liver disease. Since extracellular vesicles (EVs) function as conduits for intercellular molecular transfer, we investigated if EVs from healthy individuals have anti-fibrotic properties. Hepatic fibrogenesis or fibrosis in carbon tetrachloride (CCl4)- or thioacetic acid-induced liver injury models in male or female mice were suppressed by serum EVs from normal mice (EVN) but not from fibrotic mice (EVF). CCl4-treated mice undergoing EVN therapy also exhibited reduced levels of hepatocyte death, inflammatory infiltration, circulating AST/ALT levels and hepatic or circulating pro-inflammatory cytokines. Hepatic histology, liver function tests or circulating proinflammatory cytokine levels were unaltered in control mice receiving EVN. As determined using PKH26-labelled EVN, principal target cells included hepatic stellate cells (HSC; a normally quiescent fibroblastic cell that undergoes injury-induced activation and produces fibrosis during chronic injury) or hepatocytes which showed increased EVN binding after, respectively, activation or exposure to CCl4. In vitro, EVN decreased proliferation and fibrosis-associated molecule expression in activated HSC, while reversing the inhibitory effects of CCl4 or ethanol on hepatocyte proliferation. In mice, microRNA-34c, -151-3p, -483-5p, -532-5p and -687 were more highly expressed in EVN than EVF and mimics of these microRNAs (miRs) individually suppressed fibrogenic gene expression in activated HSC. A role for these miRs in contributing to EVN actions was shown by the ability of their corresponding antagomirs to individually and/or collectively block the therapeutic effects of EVN on activated HSC or injured hepatocytes. Similarly, the activated phenotype of human LX-2 HSC was attenuated by serum EVs from healthy human subjects and contained higher miR-34c, -151-3p, -483-5p or -532-5p than EVs from hepatic fibrosis patients. In conclusion, serum EVs from normal healthy individuals are inherently anti-fibrogenic and anti-fibrotic, and contain microRNAs that have therapeutic actions in activated HSC or injured hepatocytes. Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; CCl4: carbon tetrachloride; CCN2: connective tissue growth factor; E: eosin; EGFP: enhanced green fluorescent protein; EVs: extracellular vesicles; EVF: serum EVs from mice with experimental hepatic fibrosis; EVN: serum EVs from normal mice; H: hematoxylin; HSC: hepatic stellate cell; IHC: immunohistochemistry; IL: interleukin; MCP-1: monocyte chemotactic protein-1; miR: microRNA; mRNA: messenger RNA; NTA: nanoparticle tracking analysis; PCNA: proliferating cell nuclear antigen; qRT-PCR: quantitative real-time polymerase chain reaction; SDS-PAGE: sodium dodecyl sulphate – polyacrylamide gel electrophoresis; αSMA: alpha smooth muscle actin; TAA: thioacetic acid; TG: transgenic; TGF-β: transforming growth factor beta; TEM: transmission electron microscopy; TNFα: tumour necrosis factor alpha.
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Affiliation(s)
- Li Chen
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - Ruju Chen
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - Sherri Kemper
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - Min Cong
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - David R Brigstock
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.,Department of Surgery, Wexner Medical Center, The Ohio State University, Columbus, OH, USA
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Zhu Y, Tang Q, Wang G, Han R. Tanshinone IIA Protects Hippocampal Neuronal Cells from Reactive Oxygen Species Through Changes in Autophagy and Activation of Phosphatidylinositol 3-Kinase, Protein Kinas B, and Mechanistic Target of Rapamycin Pathways. Curr Neurovasc Res 2018; 14:132-140. [PMID: 28260507 PMCID: PMC5543574 DOI: 10.2174/1567202614666170306105315] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Revised: 02/18/2017] [Accepted: 02/20/2017] [Indexed: 12/29/2022]
Abstract
Background: Tanshinone IIA is a key active ingredient of danshen, which is derived from the dried root or rhizome of Salviae miltiorrhizae Bge. The tanshinone IIA has protective effects against the focal cerebral ischemic injury. However, the underlying mechanisms remain unclear. Methods: An in vitro model of cerebral ischemia was established by subjecting cultures of hippocampal neuronal cells to oxygen-glucose deprivation followed by reperfusion (OGD/R). The probes of 5-(and-6)-chloromethyl-2’,7’-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H2DCFDA) and 5’,6,6’-tetrachloro-1,1’,3,3’-tetraethylbenzimidazolylcarbocyanine,iodide (JC-1) were used to determine the mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) production. Western-blot was used to detect the expression of proteins in HT-22 cells. Results: The results of cell proliferative assays showed that the tanshinone IIA attenuated OGD/R-mediated neuronal cell death, with the evidence of increased cell viability. In addition, OGD/R exposure led to increase the levels of intracellular reactive oxygen species (ROS), which were significantly suppressed by tanshinone IIA treatment. Furthermore, tanshinone IIA treatment inhibited elevations in MMP and autophagy following exposure to OGD/R. Additionally, OGD/R promoted cell death with concomitant inhibiting phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/ mammalian target of Rapamycin (mTOR) pathway, which was reversed by tanshinone IIA. Conclusion: These results suggest that the tanshinone IIA protects against OGD/R-mediated cell death in HT-22 cells, in part, due to activating PI3K/Akt/mTOR pathway.
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Affiliation(s)
- Yingchun Zhu
- Department of Neurology Disease, the Affiliated Anhui Provincial Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Qiqiang Tang
- Department of Neurology Disease, the Affiliated Anhui Provincial Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Guopin Wang
- Department of Neurology Disease, the Affiliated Anhui Provincial Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Ruodong Han
- Department of Intensive Care Division, The People's Hospital of Bozhou, Bozhou 236800, Anhui, China
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26
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Abstract
Fibrosis of the liver is an inherent wound healing response to chronic liver injury. Regeneration of liver epithelium and restoration of normal liver structure were generally involved in this process. Although the liver has a striking capacity to adapt to damage through tissue repair, excessive accumulation of extracellular matrix during this process often leads to scar tissue formation and subsequent fibrosis. Epithelial to mesenchymal transition (EMT) enables a polarized epithelial cell to undergo multiple changes biochemically and to bear a mesenchymal cell phenotype. EMT plays a critical role in tissue and organ development and embryogenesis. In the liver, it is proposed that epithelial cells can acquire fibroblastic phonotype via EMT and contribute to fibrogenesis. This made EMT a potential target for antifibrotic strategies. Following an original passion, many investigators devote themselves to exploring this mechanism in liver fibrosis. However, as research continues, this hypothesis became highly controversial. The exact contribution of EMT to fibrogenesis was challenged due to the contradictory results from related studies. In this review, we summarized the recent advances regarding EMT in hepatic fibrosis and discussed the potentially involved liver cell types and pathways in order to reach rational and helpful conclusions.
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Affiliation(s)
- Kangkang Yu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Qian Li
- Department of General Surgery, Qingdao Municipal Hospital, Qingdao, People's Republic of China
| | - Guangfeng Shi
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Ning Li
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People's Republic of China,Address for correspondence: Dr. Ning Li, Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai – 200040, People's Republic of China. E-mail:
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Molecular signature of active fibrogenesis prevails in biliary atresia after successful portoenterostomy. Surgery 2017; 162:548-556. [PMID: 28655415 DOI: 10.1016/j.surg.2017.04.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 04/11/2017] [Accepted: 04/20/2017] [Indexed: 01/05/2023]
Abstract
BACKGROUND In biliary atresia mechanisms of progressive liver injury leading to need of liver transplantation after successful portoenterostomy remain unknown. A better understanding is a prerequisite for development of novel therapies to extend native liver survival, and we aimed to unravel molecular characteristics of liver injury after successful portoenterostomy. METHODS Liver biopsies obtained from 28 biliary atresia children during successful portoenterostomy and at median age 3.0 years were studied. Biopsies were analyzed for histology and immunohistochemical expression of collagen 1, myofibroblast marker α-smooth muscle actin, and cytokeratin-7 positive ductal reactions. Hepatic ribonucleic acid (RNA) expression of growth factors and inflammatory cytokines was evaluated. Intestinal failure patients with comparable liver fibrosis and nonfibrotic gallstone patients and donor livers were controls. RESULTS After successful portoenterostomy, histologic cholestasis resolved and portal inflammation reduced, while fibrosis along with ductal reactions and overexpression of collagen and α-smooth muscle actin persisted. At follow-up, liver RNA expression of collagen and platelet-derived growth factor was increased, whereas RNA expression of various inflammatory cytokines remained low. Disappearance of periductal α-smooth muscle actin expression after successful portoenterostomy (36% of patients) associated with contracted ductal reactions and reduced progression of fibrosis, collagen accumulation, platelet-derived growth factor RNA expression, and serum levels of bile acids and bilirubin. Fibrosis progressed less rapidly in syndromic than in isolated biliary atresia patients. CONCLUSION These findings suggest that instead of inflammation, molecular signature of active fibrogenesis in association with ductal reactions prevails in long-term native liver survivors with biliary atresia. Patients should be stratified for isolated and syndromic disease forms in interventional studies.
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28
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Martínez-Ramírez AS, Díaz-Muñoz M, Butanda-Ochoa A, Vázquez-Cuevas FG. Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT). Purinergic Signal 2017; 13:1-12. [PMID: 27900516 PMCID: PMC5334205 DOI: 10.1007/s11302-016-9550-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 11/21/2016] [Indexed: 12/18/2022] Open
Abstract
The epithelium-mesenchymal transition (EMT) is an important process of cell plasticity, consisting in the loss of epithelial identity and the gain of mesenchymal characteristics through the coordinated activity of a highly regulated informational program. Although it was originally described in the embryonic development, an important body of information supports its role in pathology, mainly in cancerous and fibrotic processes. The purinergic system of inter-cellular communication, mainly based in ATP and adenosine acting throughout their specific receptors, has emerged as a potent regulator of the EMT in several pathological entities. In this context, cellular signaling associated to purines is opening the understanding of a new element in the complex regulatory network of this phenotypical differentiation process. In this review, we have summarized recent information about the role of ATP and adenosine in EMT, as a growing field with high therapeutic potential.
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Affiliation(s)
- A S Martínez-Ramírez
- Departamento de Neurobiología Celular y Molecular. Instituto de Neurobiología, Universidad Nacional Autónoma de México, Boulevard Juriquilla, 3001, CP 76230, Juriquilla Querétaro, Mexico
| | - M Díaz-Muñoz
- Departamento de Neurobiología Celular y Molecular. Instituto de Neurobiología, Universidad Nacional Autónoma de México, Boulevard Juriquilla, 3001, CP 76230, Juriquilla Querétaro, Mexico
| | - A Butanda-Ochoa
- Departamento de Biología Celular y del Desarrollo. Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510, México, D.F., Mexico
| | - F G Vázquez-Cuevas
- Departamento de Neurobiología Celular y Molecular. Instituto de Neurobiología, Universidad Nacional Autónoma de México, Boulevard Juriquilla, 3001, CP 76230, Juriquilla Querétaro, Mexico.
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29
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Harada K. Immunopathology of Biliary Atresia. PATHOLOGY OF THE BILE DUCT 2017:121-137. [DOI: 10.1007/978-981-10-3500-5_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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30
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Zou XZ, Liu T, Gong ZC, Hu CP, Zhang Z. MicroRNAs-mediated epithelial-mesenchymal transition in fibrotic diseases. Eur J Pharmacol 2016; 796:190-206. [PMID: 27916556 DOI: 10.1016/j.ejphar.2016.12.003] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Revised: 11/24/2016] [Accepted: 12/01/2016] [Indexed: 12/19/2022]
Abstract
MicroRNAs (miRNAs), a large family of small and highly conserved non-coding RNAs, regulate gene expression through translational repression or mRNA degradation. Aberrant expression of miRNAs underlies a spectrum of diseases including organ fibrosis. Recent evidence suggests that miRNAs contribute to organ fibrosis through mediating epithelial-mesenchymal transition (EMT). Alleviation of EMT has been proposed as a promising strategy against fibrotic diseases given the key role of EMT in fibrosis. miRNAs impact the expression of specific ligands, receptors, and signaling pathways, thus modulating EMT and consequently influencing fibrosis. This review summarizes the current knowledge concerning how miRNAs regulate EMT and highlights the specific roles that miRNAs-regulated EMT plays in fibrotic diseases as diverse as pulmonary fibrosis, hepatic fibrosis, renal fibrosis and cardiac fibrosis. It is desirable that a more comprehensive understanding of the functions of miRNAs-regulated EMT will facilitate the development of novel diagnostic and therapeutic strategies for various debilitating organ fibrosis.
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Affiliation(s)
- Xiao-Zhou Zou
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China
| | - Ting Liu
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China
| | - Zhi-Cheng Gong
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Chang-Ping Hu
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, Hunan 410078, China.
| | - Zheng Zhang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, Hunan 410078, China.
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31
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Myers JS, von Lersner AK, Sang QXA. Proteomic Upregulation of Fatty Acid Synthase and Fatty Acid Binding Protein 5 and Identification of Cancer- and Race-Specific Pathway Associations in Human Prostate Cancer Tissues. J Cancer 2016; 7:1452-64. [PMID: 27471561 PMCID: PMC4964129 DOI: 10.7150/jca.15860] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Accepted: 05/23/2016] [Indexed: 12/25/2022] Open
Abstract
Protein profiling studies of prostate cancer have been widely used to characterize molecular differences between diseased and non-diseased tissues. When combined with pathway analysis, profiling approaches are able to identify molecular mechanisms of prostate cancer, group patients by cancer subtype, and predict prognosis. This strategy can also be implemented to study prostate cancer in very specific populations, such as African Americans who have higher rates of prostate cancer incidence and mortality than other racial groups in the United States. In this study, age-, stage-, and Gleason score-matched prostate tumor specimen from African American and Caucasian American men, along with non-malignant adjacent prostate tissue from these same patients, were compared. Protein expression changes and altered pathway associations were identified in prostate cancer generally and in African American prostate cancer specifically. In comparing tumor to non-malignant samples, 45 proteins were significantly cancer-associated and 3 proteins were significantly downregulated in tumor samples. Notably, fatty acid synthase (FASN) and epidermal fatty acid-binding protein (FABP5) were upregulated in human prostate cancer tissues, consistent with their known functions in prostate cancer progression. Aldehyde dehydrogenase family 1 member A3 (ALDH1A3) was also upregulated in tumor samples. The Metastasis Associated Protein 3 (MTA3) pathway was significantly enriched in tumor samples compared to non-malignant samples. While the current experiment was unable to detect statistically significant differences in protein expression between African American and Caucasian American samples, differences in overrepresentation and pathway enrichment were found. Structural components (Cytoskeletal Proteins and Extracellular Matrix Protein protein classes, and Biological Adhesion Gene Ontology (GO) annotation) were overrepresented in African American but not Caucasian American tumors. Additionally, 5 pathways were enriched in African American prostate tumors: the Small Cell Lung Cancer, Platelet-Amyloid Precursor Protein, Agrin, Neuroactive Ligand-Receptor Interaction, and Intrinsic pathways. The protein components of these pathways were either basement membrane proteins or coagulation proteins.
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Affiliation(s)
- Jennifer S Myers
- 1. Department of Chemistry & Biochemistry, Florida State University, Tallahassee, FL, USA
| | - Ariana K von Lersner
- 1. Department of Chemistry & Biochemistry, Florida State University, Tallahassee, FL, USA
| | - Qing-Xiang Amy Sang
- 1. Department of Chemistry & Biochemistry, Florida State University, Tallahassee, FL, USA.; 2. Institute of Molecular Biophysics, Florida State University, Tallahassee, FL, USA
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Kerola A, Lampela H, Lohi J, Heikkilä P, Mutanen A, Hagström J, Tervahartiala T, Sorsa T, Haglund C, Jalanko H, Pakarinen MP. Increased MMP-7 expression in biliary epithelium and serum underpins native liver fibrosis after successful portoenterostomy in biliary atresia. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2016; 2:187-98. [PMID: 27499927 PMCID: PMC4958739 DOI: 10.1002/cjp2.50] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 04/24/2016] [Indexed: 12/14/2022]
Abstract
The molecular mechanisms underlying progressive liver fibrosis following surgical treatment of biliary atresia (BA) remain unclear. Our aim was to address hepatic gene and protein expression and serum levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) after successful portoenterostomy (PE), and relate them to histological signs of liver injury, clinical follow‐up data and biochemical markers of hepatic function. LIver biopsies and serum samples were obtained from 25 children after successful PE at median age of 3.3 years. Serum MMP concentrations were determined by enzyme‐linked immune sorbent assay. Hepatic gene expression of MMPs and TIMPs was analyzed using real‐time reverse‐transcription PCR. Liver expression of MMP‐7 and cytokeratin‐7 was studied using immunohistochemistry. Despite effective clearance of biochemical and histological cholestasis following PE, BA patients showed increased hepatic gene expression of MMP‐7 (29‐fold, p < 0.001), MMP‐2 (3.1‐fold, p < 0.001), MMP‐14 (1.7‐fold, p = 0.007), and TIMP‐1 (1.8‐fold, p < 0.001), when compared to controls. Similar to a biliary epithelial marker cytokeratin‐7, expression of MMP‐7 localized in biliary epithelium of bile ducts and ductal proliferations and periportal hepatocytes and was increased (p < 0.001) in relation to controls. BA patients had 6‐fold higher serum levels of MMP‐7 (p < 0.001), which correlated positively with hepatic MMP‐7 gene (r = 0.548, p = 0.007) and protein (r = 0.532, p = 0.007) expression. Patients showed a positive correlation between biliary MMP‐7 expression and Metavir fibrosis stage (r = 0.605, p = 0.001) and portal fibrosis grade (r = 0.606, p = 0.001). Neither similarly increased MMP‐7 expression nor correlation with liver fibrosis was observed in patients with intestinal failure‐associated liver disease and comparable Metavir stage. In conclusion, our findings support an unique role of altered hepatic expression of MMP‐7 in the progression of liver fibrosis after successful PE and introduce a potential therapeutic target to pharmacologically extend native liver survival by inhibiting MMP‐7 hyperactivity. Serum MMP‐7 may be a valuable postoperative prognostic tool in BA.
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Affiliation(s)
- Anna Kerola
- Pediatric Surgery and Pediatric Transplantation Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki and Helsinki University HospitalHelsinkiFinland; Department of SurgeryNorth Karelia Central HospitalJoensuuFinland
| | - Hanna Lampela
- Pediatric Surgery and Pediatric Transplantation Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki and Helsinki University HospitalHelsinkiFinland; Gastroenterological Surgery, University of Helsinki and Helsinki University HospitalHelsinkiFinland
| | - Jouko Lohi
- Pathology, University of Helsinki and Helsinki University Hospital Helsinki Finland
| | - Päivi Heikkilä
- Pathology, University of Helsinki and Helsinki University Hospital Helsinki Finland
| | - Annika Mutanen
- Pediatric Surgery and Pediatric Transplantation Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki and Helsinki University Hospital Helsinki Finland
| | - Jaana Hagström
- Pathology and Oral Pathology University of Helsinki and Helsinki University Hospital Helsinki Finland
| | - Taina Tervahartiala
- Oral and Maxillofacial Diseases University of Helsinki and Helsinki University Hospital Helsinki Finland
| | - Timo Sorsa
- Oral and Maxillofacial DiseasesUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland; Division of Periodontology, Department of Dental MedicineKarolinska InstitutetHuddingeSweden
| | - Caj Haglund
- Department of SurgeryUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland; Research Programs Unit, Translational Cancer Biology, University of Helsinki and Helsinki University HospitalHelsinkiFinland
| | - Hannu Jalanko
- Pediatric Nephrology and Transplantation, University of Helsinki and Helsinki University Hospital Helsinki Finland
| | - Mikko P Pakarinen
- Pediatric Surgery and Pediatric Transplantation Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki and Helsinki University Hospital Helsinki Finland
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Chang YC, Lin CW, Yu CC, Wang BY, Huang YH, Hsieh YC, Kuo YL, Chang WW. Resveratrol suppresses myofibroblast activity of human buccal mucosal fibroblasts through the epigenetic inhibition of ZEB1 expression. Oncotarget 2016; 7:12137-49. [PMID: 26934322 PMCID: PMC4914274 DOI: 10.18632/oncotarget.7763] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 02/18/2016] [Indexed: 01/18/2023] Open
Abstract
Oral submucous fibrosis (OSF) is a precancerous condition of the oral mucosa without specific therapeutic drugs. We previously demonstrated that the zinc finger E-box binding homeobox 1 (ZEB1) plays a pathogenic role in the induction of the myofibroblast activity of buccal mucosal fibroblasts (BMFs) and contributes to the pathogenesis of OSF. Resveratrol is a natural polyphenolic flavonoid with anti-fibrosis activity in various tissues and has the capability to inhibit ZEB1 in oral cancer cells. We examined the effect of resveratrol on the myofibroblast activity of human primary fibrotic BMFs (fBMFs) derived from OSF tissues. With the collagen contraction assay, resveratrol displayed anti-myofibroblast activity in three fBMF lines. Resveratrol also inhibited the expression of fibrogenic genes at the mRNA and protein levels in a dose- and time-dependent manner. The downregulation of ZEB1 in fBMFs by resveratrol was mediated by epigenetic mechanisms, such as the upregulated expression of miR-200c and the enhancer of zeste homolog 2 (EZH2), as well as the trimethylated lysine 27 of histone H3 (H3K27me3). Resveratrol also increased the binding of H3K27me3 to the ZEB1 promoter. The knockdown of EZH2 in fBMFs caused the upregulation of ZEB1 and suppressed the inhibitory effect of resveratrol. Furthermore, the reversed expression pattern between EZH2 and ZEB1 was observed in 6/8 OSF tissues with twofold upregulation of ZEB1 expression compared with the adjacent normal mucosa. In conclusion, our data suggest that resveratrol epigenetically inhibits ZEB1 expression to suppress the myofibroblast activity of fBMFs and may serve as a dietary supplement for OSF patients.
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Affiliation(s)
- Yu-Chao Chang
- 1 School of Dentistry, Chung Shan Medical University, Taichung, Taiwan,2 Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Cheng-Wei Lin
- 3 School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan
| | - Cheng-Chia Yu
- 1 School of Dentistry, Chung Shan Medical University, Taichung, Taiwan,2 Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan,4 Institute of Oral Science, Chung Shan Medical University, Taichung, Taiwan
| | - Bing-Yen Wang
- 5 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan,6 Division of Throacic Surgery, Department of Surgery, Changhua Christian Hospital, Changhua County, Taiwan,7 School of Medicine, National Yang-Ming University, Taipei City, Taiwan
| | - Yu-Hao Huang
- 3 School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan
| | - Yang-Chih Hsieh
- 3 School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan
| | - Yu-Liang Kuo
- 8 School of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung, Taiwan,9 Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung City, Taiwan
| | - Wen-Wei Chang
- 3 School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan,10 Department of Medical Research, Chung Shan Medical University Hospital, Taichung City, Taiwan
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Dong R, Zheng S. Interleukin-8: A critical chemokine in biliary atresia. J Gastroenterol Hepatol 2015; 30:970-6. [PMID: 25611432 DOI: 10.1111/jgh.12900] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/10/2015] [Indexed: 12/15/2022]
Abstract
Biliary atresia (BA) is characterized by periductular inflammation and fibrosis and is associated with the progressive obliteration of the bile ducts. The induction and maintenance of systemic and local inflammatory responses plays a pivotal role in this process. Interleukin-8 (IL-8) is an important mediator of inflammation and the immune response in human disease. IL-8 is overexpressed in BA, and its expression positively correlates with inflammation and liver fibrosis. In this review, we focus on the available evidence, recent insights, and future clinical and preclinical possibilities regarding the role of IL-8 in BA.
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Affiliation(s)
- Rui Dong
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China; Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
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