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Gao L, Li YJ, Zhao JM, Liao YX, Qin MC, Li JJ, Shi H, Wong NK, Lyu ZP, Shen JG. Mechanism of Reactive Oxygen/Nitrogen Species in Liver Ischemia-Reperfusion Injury and Preventive Effect of Chinese Medicine. Chin J Integr Med 2025; 31:462-473. [PMID: 38941044 DOI: 10.1007/s11655-024-3810-9] [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] [Accepted: 03/04/2024] [Indexed: 06/29/2024]
Abstract
Liver ischemia-reperfusion injury (LIRI) is a pathological process involving multiple injury factors and cell types, with different stages. Currently, protective drugs targeting a single condition are limited in efficacy, and interventions on immune cells will also be accompanied by a series of side effects. In the current bottleneck research stage, the multi-target and obvious clinical efficacy of Chinese medicine (CM) is expected to become a breakthrough point in the research and development of new drugs. In this review, we summarize the roles of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in various stages of hepatic ischemia-reperfusion and on various types of cells. Combined with the current research progress in reducing ROS/RNS with CM, new therapies and mechanisms for the treatment of hepatic ischemia-reperfusion are discussed.
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Affiliation(s)
- Lei Gao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Yun-Jia Li
- The First Affiliated Hospital/the First Clinical Medicine School of Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Jia-Min Zhao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Yu-Xin Liao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Meng-Chen Qin
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Jun-Jie Li
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Hao Shi
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Nai-Kei Wong
- State Key Discipline of Infectious Diseases, Shenzhen Third People's Hospital, the Second Affiliated Hospital, Shenzhen University, Shenzhen, 518112, Guangdong Province, China
| | - Zhi-Ping Lyu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Jian-Gang Shen
- School of Chinese Medicine, the University of Hong Kong, Hong Kong SAR, China.
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Sabry A, Zakaria H, Maher D, Seddik RM, Nada A. Ischemia-Reperfusion Injury at Time-Zero Biopsy as a Prognostic Factor in Predicting Liver Graft Outcome in Egyptian Living Donor Liver Transplanted Patients. Int J Hepatol 2025; 2025:9113107. [PMID: 40224292 PMCID: PMC11991779 DOI: 10.1155/ijh/9113107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 02/07/2025] [Indexed: 04/15/2025] Open
Abstract
Background and Aims: Ischemia-reperfusion injury (IRI) is believed to contribute to the early dysfunction of the graft as well as the survival of the patients following liver transplantation (LT). This study is aimed at ascertaining the role of time-zero biopsies in predicting early graft dysfunction and 5-year patient survival after living donor liver transplantation (LDLT). Patients and Methods: From February 2012 to August 2017, time-zero biopsies were obtained from 60 patients. Histological grading of time-zero biopsies was performed to identify the severity of IRI. Patients were divided into two groups: no or minimal to mild IRI versus moderate to severe IRI. Results: Time-zero biopsies of 60 liver allografts revealed no or minimal to mild IRI (n = 38, 63.3%) (Group 1) versus moderate to severe IRI (n = 22, 36.7%) (Group 2). Group 2 recipients indicated a significant increase in serum bilirubin and a higher incidence of early graft dysfunction. There were significant survival differences between the two groups (p = 0.033), and the rate of death was higher in the moderate to severe IRI group. Recipient age, steatosis, and longer CIT were identified as independent predictors of moderate to severe IRI. Conclusion: Time-zero biopsies with moderate to severe IRI upon biopsy can predict adverse clinical outcomes following LT.
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Affiliation(s)
- Aliaa Sabry
- Department of Hepatology & Gastroenterology, Menoufia University, National Liver Institute, Shebin El-Kom, Menoufia, Egypt
| | - Hazem Zakaria
- Department of Hepatobiliary Surgery, Menoufia University, National Liver Institute, Shebin El-Kom, Menoufia, Egypt
| | - Doha Maher
- Department of Pathology, Menoufia University, National Liver Institute, Shebin El-Kom, Menoufia, Egypt
| | - Randa Mohamed Seddik
- Department of Tropical Medicine, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia, Egypt
| | - Ali Nada
- Department of Hepatology & Gastroenterology, Menoufia University, National Liver Institute, Shebin El-Kom, Menoufia, Egypt
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Sererols-Viñas L, Garcia-Vicién G, Ruiz-Blázquez P, Lee TF, Lee YA, Gonzalez-Sanchez E, Vaquero J, Moles A, Filliol A, Affò S. Hepatic Stellate Cells Functional Heterogeneity in Liver Cancer. Semin Liver Dis 2025; 45:33-51. [PMID: 40043738 DOI: 10.1055/a-2551-0724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/01/2025]
Abstract
Hepatic stellate cells (HSCs) are the liver's pericytes, and play key roles in liver homeostasis, regeneration, fibrosis, and cancer. Upon injury, HSCs activate and are the main origin of myofibroblasts and cancer-associated fibroblasts (CAFs) in liver fibrosis and cancer. Primary liver cancer has a grim prognosis, ranking as the third leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) being the predominant type, followed by intrahepatic cholangiocarcinoma (iCCA). Moreover, the liver hosts 35% of all metastatic lesions. The distinct spatial distribution and functional roles of HSCs across these malignancies represent a significant challenge for universal therapeutic strategies, requiring a nuanced and tailored understanding of their contributions. This review examines the heterogeneous roles of HSCs in liver cancer, focusing on their spatial localization, dynamic interactions within the tumor microenvironment (TME), and emerging therapeutic opportunities, including strategies to modulate their activity, and harness their potential as targets for antifibrotic and antitumor interventions.
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Affiliation(s)
- Laura Sererols-Viñas
- Tumor Microenvironment Plasticity and Heterogeneity Research Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- University of Barcelona, Barcelona, Spain
| | - Gemma Garcia-Vicién
- Tumor Microenvironment Plasticity and Heterogeneity Research Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Paloma Ruiz-Blázquez
- University of Barcelona, Barcelona, Spain
- Tissue Remodeling Fibrosis and Cancer Group, Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain
- Institute of Biomedical Research of Barcelona (IDIBAPS), Barcelona, Spain
- CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain
| | - Ting-Fang Lee
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Youngmin A Lee
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Ester Gonzalez-Sanchez
- HepatoBiliary Tumours Lab, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain
- Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain
| | - Javier Vaquero
- CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain
- HepatoBiliary Tumours Lab, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - Anna Moles
- Tissue Remodeling Fibrosis and Cancer Group, Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain
- Institute of Biomedical Research of Barcelona (IDIBAPS), Barcelona, Spain
- CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain
| | - Aveline Filliol
- Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Silvia Affò
- Tumor Microenvironment Plasticity and Heterogeneity Research Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
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Li Z, Li J, Wu M, Li Z, Zhou J, Lu Y, Xu Y, Qin L, Fan Z. Redox-sensitive epigenetic activation of SUV39H1 contributes to liver ischemia-reperfusion injury. Redox Biol 2024; 78:103414. [PMID: 39603205 PMCID: PMC11635714 DOI: 10.1016/j.redox.2024.103414] [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: 09/18/2024] [Revised: 10/29/2024] [Accepted: 10/30/2024] [Indexed: 11/29/2024] Open
Abstract
Liver ischemia-reperfusion (I/R) injury is a clinically relevant pathophysiological process that determines the effectiveness of life-saving liver transplantation, to which aberrant ROS accumulation plays a key role. In the present study we investigated the role of SUV39H1, a lysine methyltransferases, in this process focusing on regulatory mechanism and translational potential. We report that SUV39H1 expression was up-regulated in the liver tissues of mice subjected to ischemia-reperfusion and in hepatocytes exposed to hypoxia-reoxygenation (H/R) in a redox-sensitive manner. Mechanistically, coactivator associated arginine methyltransferases 1 (CARM1) mediated redox-sensitive Suv39h1 trans-activation by promoting histone H3R17 methylation. Consistently, pharmaceutical CARM1 inhibition attenuated liver I/R injury. In addition, global or hepatocyte conditional Suv39h1 KO mice were protected from liver I/R injury. RNA-seq revealed that aldehyde dehydrogenase 1 family 1a (Aldh1a1) as a novel target for SUV39H1. SUV39H1 directly bound to the Aldh1a1 promoter and repressed Aldh1a1 transcription in H/R-challenged hepatocytes. ALDH1A1 silencing abrogated the protective effects of SUV39H1 deficiency on H/R-inflicted injuries whereas ALDH1A1 over-expression mitigated liver I/R injury in mice. Importantly, administration of a small-molecule SUV39H1 inhibitor achieved similar hepatoprotective effects as SUV39H1 deletion. Finally, increased Suv39h1 expression and decreased Aldh1a1 expression were observed in liver I/R specimens in humans. In conclusion, our data uncover a regulatory role for SUV39H1 in liver I/R injury and serve as proof-of-concept that targeting the SUV39H1-ALDH1A1 axis might be considered as a reasonable approach for the intervention of liver I/R injury.
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Affiliation(s)
- Zilong Li
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China; Institute of Brain Science and Brain-inspired Research, Shandong First Medical University, Jinan, China.
| | - Jichen Li
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Meng Wu
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Zexin Li
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Jiawen Zhou
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Yunjie Lu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yong Xu
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Translational Medicine, Nanjing Medical University, Nanjing, China; Institute of Biomedical Research, College of Agriculture and Biology, Liaocheng University, Liaocheng, China.
| | - Lei Qin
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Zhiwen Fan
- Department of Pathology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
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Wilson EA, Weinberg DL, Patel GP. Intraoperative Anesthetic Strategies to Mitigate Early Allograft Dysfunction After Orthotopic Liver Transplantation: A Narrative Review. Anesth Analg 2024; 139:1267-1282. [PMID: 38442076 DOI: 10.1213/ane.0000000000006902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2024]
Abstract
Orthotopic liver transplantation (OLT) is the most effective treatment for patients with end-stage liver disease (ESLD). Hepatic insufficiency within a week of OLT, termed early allograft dysfunction (EAD), occurs in 20% to 25% of deceased donor OLT recipients and is associated with morbidity and mortality. Primary nonfunction (PNF), the most severe form of EAD, leads to death or retransplantation within 7 days. The etiology of EAD is multifactorial, including donor, recipient, and surgery-related factors, and largely driven by ischemia-reperfusion injury (IRI). IRI is an immunologic phenomenon characterized by dysregulation of cellular oxygen homeostasis and innate immune defenses in the allograft after temporary cessation (ischemia) and later restoration (reperfusion) of oxygen-rich blood flow. The rising global demand for OLT may lead to the use of marginal allografts, which are more susceptible to IRI, and thus lead to an increased incidence of EAD. It is thus imperative the anesthesiologist is knowledgeable about EAD, namely its pathophysiology and intraoperative strategies to mitigate its impact. Intraoperative strategies can be classified by 3 phases, specifically donor allograft procurement, storage, and recipient reperfusion. During procurement, the anesthesiologist can use pharmacologic preconditioning with volatile anesthetics, consider preharvest hyperoxemia, and attenuate the use of norepinephrine as able. The anesthesiologist can advocate for normothermic regional perfusion (NRP) and machine perfusion during allograft storage at their institution. During recipient reperfusion, the anesthesiologist can optimize oxygen exposure, consider adjunct anesthetics with antioxidant-like properties, and administer supplemental magnesium. Unfortunately, there is either mixed, little, or no data to support the routine use of many free radical scavengers. Given the sparse, limited, or at times conflicting evidence supporting some of these strategies, there are ample opportunities for more research to find intraoperative anesthetic strategies to mitigate the impact of EAD and improve postoperative outcomes in OLT recipients.
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Affiliation(s)
- Elizabeth A Wilson
- From the Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia
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Wang P, Pan J, Gong S, Zhang Z, Li B. Yes-associated protein inhibition ameliorates carbon tetrachloride-induced acute liver injury in mice by reducing VDR. Chem Biol Interact 2024; 399:111139. [PMID: 38992766 DOI: 10.1016/j.cbi.2024.111139] [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: 05/23/2024] [Revised: 07/04/2024] [Accepted: 07/08/2024] [Indexed: 07/13/2024]
Abstract
Carbon tetrachloride (CCl4) has a wide range of toxic effects, especially causing acute liver injury (ALI), in which rapid compensation for hepatocyte loss ensures liver survival, but proliferation of surviving hepatocytes (known as endoreplication) may imply impaired residual function. Yes-associated protein (YAP) drives hepatocytes to undergo endoreplication and ploidy, the underlying mechanisms of which remain a mystery. In the present study, we uncover during CCl4-mediated ALI accompanied by increased hepatocytes proliferation and YAP activation. Notably, bioinformatics analyses elucidate that hepatic-specific deletion of YAP substantially ameliorated CCl4-induced hepatic proliferation, effectively decreased the vitamin D receptor (VDR) expression. Additionally, a mouse model of acute liver injury substantiated that inhibition of YAP could suppress hepatocytes proliferation via VDR. Furthermore, we also disclosed that the VDR agonist nullifies CCl4-induced ALI alleviated by the YAP inhibitor in vivo. Importantly, hepatocytes were isolated from mice, and it was spotlighted that the anti-proliferative impact of the YAP inhibitor was abolished by the activation of VDR within these hepatocytes. Similarly, primary hepatic stellate cells (HSCs) were isolated and it was manifested that YAP inhibitor suppressed HSC activation via VDR during acute liver injury. Our findings further elucidate the YAP's role in ALI and may provide new avenues for protection against CCl4-drived acute liver injury.
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Affiliation(s)
- Ping Wang
- Department of Occupational and Environmental Health, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, 215123, China
| | - Jinjing Pan
- Department of Clinical Nutrition, Sheyang County People's Hospital, Yancheng, 224300, China
| | - Shiyi Gong
- Deparment of Nutrition and Food Hygiene, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, 215123, China
| | - Zengli Zhang
- Department of Occupational and Environmental Health, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, 215123, China.
| | - Bingyan Li
- Deparment of Nutrition and Food Hygiene, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, 215123, China.
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7
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Zhou M, Li TS, Abe H, Akashi H, Suzuki R, Bando Y. Expression levels of K ATP channel subunits and morphological changes in the mouse liver after exposure to radiation. World J Exp Med 2024; 14:90374. [PMID: 38948415 PMCID: PMC11212743 DOI: 10.5493/wjem.v14.i2.90374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/28/2024] [Accepted: 03/27/2024] [Indexed: 06/19/2024] Open
Abstract
BACKGROUND ATP sensitive K+ (KATP) channels are ubiquitously distributed in various of cells and tissues, including the liver. They play a role in the pathogenesis of myocardial and liver ischemia. AIM To evaluate the radiation-induced changes in the expression of KATP channel subunits in the mouse liver to understand the potential role of KATP channels in radiation injury. METHODS Adult C57BL/6 mice were randomly exposed to γ-rays at 0 Gy (control, n = 2), 0.2 Gy (n = 6), 1 Gy (n = 6), or 5 Gy (n = 6). The livers were removed 3 and 24 h after radiation exposure. Hematoxylin and eosin staining was used for morphological observation; immunohistochemical staining was applied to determine the expression of KATP channel subunits in the liver tissue. RESULTS Compared with the control group, the livers exposed to 0.2 Gy γ-ray showed an initial increase in the expression of Kir6.1 at 3 h, followed by recovery at 24 h after exposure. Exposure to a high dose of 5.0 Gy resulted in decreased expression of Kir6.1 and increased expression of SUR2B at 24 h. However, the expression of Kir6.2, SUR1, or SUR2A had no remarkable changes at 3 and 24 h after exposure to any of these doses. CONCLUSION The expression levels of Kir6.1 and SUR2B in mouse liver changed differently in response to different radiation doses, suggesting a potential role for them in radiation-induced liver injury.
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Affiliation(s)
- Ming Zhou
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Tao-Sheng Li
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan
| | - Hiroshi Abe
- Sendai Old Age Refresh Station, A Long-term Care Health Facility, Sendai 981-1105, Japan
| | - Hideo Akashi
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Ryoji Suzuki
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Yoshio Bando
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
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Chen Y, Zhang J, Li F. Inhibitory role of remifentanil in hepatic ischemia-reperfusion injury through activation of Fmol/Parkin signaling pathway: A study based on network pharmacology analysis and high-throughput sequencing. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 128:155300. [PMID: 38518639 DOI: 10.1016/j.phymed.2023.155300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 11/13/2023] [Accepted: 12/17/2023] [Indexed: 03/24/2024]
Abstract
BACKGROUND This study was conducted to elucidate the critical molecular pathways underlying the protective effects of remifentanil against hepatic ischemia-reperfusion injury in rats. Our approach integrated network pharmacology analysis with high-throughput sequencing to achieve a comprehensive understanding of the mechanisms involved. STUDY DESIGN/METHODS The study utilized GSE24430 gene expression data from GEO to investigate remifentanil's impact on Hepatic Ischemia-Reperfusion Injury in rats. Weighted Correlation Network Analysis (WGCNA) was employed to pinpoint crucial genes and identify modules of co-expressed genes. Differential analysis with the "Limma" package revealed genes differentially expressed in IRI vs. control groups. PubChem and PharmMapper provided target genes affected by remifentanil. Protein-protein interaction networks were constructed via GeneCards and STRING. Functional analysis pinpointed core genes involved in remifentanil's IRI alleviation. IRI rat models were established, and hepatic injury indicators, liver structure via H&E staining, autophagosome counts via electron microscopy, and gene/protein expression via RT-qPCR and Western blot were assessed. High-throughput sequencing analyzed molecular pathways affected by varying remifentanil doses in IRI rats. RESULTS In the study, we discovered four primary co-expression modules associated with hepatic IRI, and the grey module exhibited the highest correlation with hepatic IRI.A total of sixty-eight genes that were differentially expressed were found to have a connection with hepatic IRI.Network pharmacology analysis found that remifentanil may alleviate hepatic IRI through Fmol.found that the Fmol/Parkin signaling pathway may alleviate hepatic IRI via Additionally, the database autophagy. The established hepatic IRI rat models further confirmed the above findings. CONCLUSION Our study established that remifentanil triggers the Fmol/Parkin signaling cascade, amplifying the expression levels of Fmol and Parkin. This process culminates in the activation of autophagy within hepatic cells, ultimately alleviating hepatic ischemia-reperfusion injury (IRI).
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Affiliation(s)
- Yisi Chen
- Department of Anesthesiology, Huai'an First People's Hospital, Huai'an 223300, China.
| | - Jun Zhang
- Department of Anesthesiology, Huai'an First People's Hospital, Huai'an 223300, China
| | - Fayin Li
- Department of Anesthesiology, Huai'an First People's Hospital, Huai'an 223300, China
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Shen X, Mai R, Han X, Wang Q, Wang Y, Ji T, Tong Y, Chen P, Zhao J, He X, Wen T, Liang R, Lin Y, Luo X, Cai X. BTLA deficiency promotes HSC activation and protects against hepatic ischemia-reperfusion injury. Hepatol Commun 2024; 8:e0449. [PMID: 38840336 PMCID: PMC11155569 DOI: 10.1097/hc9.0000000000000449] [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: 01/19/2024] [Accepted: 03/07/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND AND AIMS Hepatic ischemia-reperfusion injury (IRI) is unavoidable even despite the development of more effective surgical approaches. During hepatic IRI, activated HSC (aHSC) are involved in liver injury and recovery. APPROACH AND RESULT A proportion of aHSC increased significantly both in the mouse liver tissues with IRI and in the primary mouse HSCs and LX-2 cells during hypoxia-reoxygenation. "Loss-of-function" experiments revealed that depleting aHSC with gliotoxin exacerbated liver damage in IRI mice. Subsequently, we found that the transcription of mRNA and the expression of B and T lymphocyte attenuator (BTLA) protein were lower in aHSC compared with quiescent HSCs. Interestingly, overexpression or knockdown of BTLA resulted in opposite changes in the activation of specific markers for HSCs such as collagen type I alpha 1, α-smooth muscle actin, and Vimentin. Moreover, the upregulation of these markers was also observed in the liver tissues of global BLTA-deficient (BTLA-/-) mice and was higher after hepatic IRI. Compared with wild-type mice, aHSC were higher, and liver injury was lower in BTLA-/- mice following IRI. However, the depletion of aHSC reversed these effects. In addition, the depletion of aHSC significantly exacerbated liver damage in BTLA-/- mice with hepatic IRI. Furthermore, the TGF-β1 signaling pathway was identified as a potential mechanism for BTLA to negatively regulate the activation of HSCs in vivo and in vitro. CONCLUSIONS These novel findings revealed a critical role of BTLA. Particularly, the receptor inhibits HSC-activated signaling in acute IRI, implying that it is a potential immunotherapeutic target for decreasing the IRI risk.
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Affiliation(s)
- Xiaoyun Shen
- Key Laboratory of Endoscopic Technology Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - Rongyun Mai
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, P.R. China
| | - Xiao Han
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, P.R. China
| | - Qi Wang
- Key Laboratory of Endoscopic Technology Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - Yifan Wang
- Key Laboratory of Endoscopic Technology Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - Tong Ji
- Key Laboratory of Endoscopic Technology Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - Yifan Tong
- Key Laboratory of Endoscopic Technology Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - Ping Chen
- Key Laboratory of Endoscopic Technology Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - Jia Zhao
- Key Laboratory of Endoscopic Technology Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - Xiaoyan He
- Key Laboratory of Endoscopic Technology Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - Tong Wen
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, P.R. China
| | - Rong Liang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, P.R. China
| | - Yan Lin
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, P.R. China
| | - Xiaoling Luo
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, P.R. China
| | - Xiujun Cai
- Key Laboratory of Endoscopic Technology Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
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Kim JW, Kim YJ. The evidence-based multifaceted roles of hepatic stellate cells in liver diseases: A concise review. Life Sci 2024; 344:122547. [PMID: 38460810 DOI: 10.1016/j.lfs.2024.122547] [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: 12/25/2023] [Revised: 02/21/2024] [Accepted: 03/04/2024] [Indexed: 03/11/2024]
Abstract
Hepatic stellate cells (HSCs) play central roles in liver disease pathogenesis, spanning steatosis to cirrhosis and hepatocellular carcinoma. These cells, located in the liver's sinusoidal space of Disse, transition from a quiescent, vitamin A-rich state to an activated, myofibroblast-like phenotype in response to liver injury. This activation results from a complex interplay of cytokines, growth factors, and oxidative stress, leading to excessive collagen deposition and liver fibrosis, a hallmark of chronic liver diseases. Recently, HSCs have gained recognition for their dynamic, multifaceted roles in liver health and disease. Attention has shifted toward their involvement in various liver conditions, including acute liver injury, alcoholic and non-alcoholic fatty liver disease, and liver regeneration. This review aims to explore diverse functions of HSCs in these acute or chronic liver pathologies, with a focus on their roles beyond fibrogenesis. HSCs exhibit a wide range of actions, including lipid storage, immunomodulation, and interactions with other hepatic and extrahepatic cells, making them pivotal in the hepatic microenvironment. Understanding HSC involvement in the progression of liver diseases can offer novel insights into pathogenic mechanisms and guide targeted therapeutic strategies for various liver conditions.
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Affiliation(s)
- Jong-Won Kim
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Yu Ji Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical School, Jeonbuk National University, Research Institute of Clinical Medicine of Jeonbuk National University - Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, South Korea.
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11
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Zhao J, Ghallab A, Hassan R, Dooley S, Hengstler JG, Drasdo D. A liver digital twin for in silico testing of cellular and inter-cellular mechanisms in regeneration after drug-induced damage. iScience 2024; 27:108077. [PMID: 38371522 PMCID: PMC10869925 DOI: 10.1016/j.isci.2023.108077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 02/22/2023] [Accepted: 09/25/2023] [Indexed: 02/20/2024] Open
Abstract
This communication presents a mathematical mechanism-based model of the regenerating liver after drug-induced pericentral lobule damage resolving tissue microarchitecture. The consequence of alternative hypotheses about the interplay of different cell types on regeneration was simulated. Regeneration dynamics has been quantified by the size of the damage-induced dead cell area, the hepatocyte density and the spatial-temporal profile of the different cell types. We use deviations of observed trajectories from the simulated system to identify branching points, at which the systems behavior cannot be explained by the underlying set of hypotheses anymore. Our procedure reflects a successful strategy for generating a fully digital liver twin that, among others, permits to test perturbations from the molecular up to the tissue scale. The model simulations are complementing current knowledge on liver regeneration by identifying gaps in mechanistic relationships and guiding the system toward the most informative (lacking) parameters that can be experimentally addressed.
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Affiliation(s)
- Jieling Zhao
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
- Group SIMBIOTX, INRIA Saclay, 91120 Palaiseau, France
| | - Ahmed Ghallab
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt
| | - Reham Hassan
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt
| | - Steven Dooley
- Molecular Hepatology Section, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Jan Georg Hengstler
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
| | - Dirk Drasdo
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
- Group SIMBIOTX, INRIA Saclay, 91120 Palaiseau, France
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12
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Yinzhi D, Jianhua H, Hesheng L. The roles of liver sinusoidal endothelial cells in liver ischemia/reperfusion injury. J Gastroenterol Hepatol 2024; 39:224-230. [PMID: 37939704 DOI: 10.1111/jgh.16396] [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: 08/23/2022] [Revised: 09/01/2023] [Accepted: 10/18/2023] [Indexed: 11/10/2023]
Abstract
Liver ischemia/reperfusion injury (IRI) is a major complication after partial hepatectomy and liver transplantation and during hypovolemic shock and hypoxia-related diseases. Liver IRI is a current research hotspot. The early stage of liver IRI is characterized by injury and dysfunction of liver sinusoidal endothelial cells (LSECs), which, along with hepatocytes, are the major cells involved in liver injury. In this review, we elaborate on the roles played by LSECs in liver IRI, including the pathological features of LSECs, LSECs exacerbation of the sterile inflammatory response, LSECs interactions with platelets and the promotion of liver regeneration, and the activation of LSECs autophagy. In addition, we discuss the study of LSECs as therapeutic targets for the treatment of liver IRI and the existing problems when applying LSECs in liver IRI research.
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Affiliation(s)
- Deng Yinzhi
- Hubei Selenium and Human Health Institute, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, China
- Department of Gastroenterology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, China
- Hubei Provincial Key Lab of Selenium Resources and Bioapplications, Enshi, China
| | - He Jianhua
- Department of Gastroenterology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, China
| | - Luo Hesheng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
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13
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Cogliati B, Yashaswini CN, Wang S, Sia D, Friedman SL. Friend or foe? The elusive role of hepatic stellate cells in liver cancer. Nat Rev Gastroenterol Hepatol 2023; 20:647-661. [PMID: 37550577 PMCID: PMC10671228 DOI: 10.1038/s41575-023-00821-z] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/06/2023] [Indexed: 08/09/2023]
Abstract
Liver fibrosis is a substantial risk factor for the development and progression of liver cancer, which includes hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Studies utilizing cell fate mapping and single-cell transcriptomics techniques have identified quiescent perisinusoidal hepatic stellate cells (HSCs) as the primary source of activated collagen-producing HSCs and liver cancer-associated fibroblasts (CAFs) in HCC and liver metastasis, complemented in iCCA by contributions from portal fibroblasts. At the same time, integrative computational analysis of single-cell, single-nucleus and spatial RNA sequencing data have revealed marked heterogeneity among HSCs and CAFs, with distinct subpopulations displaying unique gene expression signatures and functions. Some of these subpopulations have divergent roles in promoting or inhibiting liver fibrogenesis and carcinogenesis. In this Review, we discuss the dual roles of HSC subpopulations in liver fibrogenesis and their contribution to liver cancer promotion, progression and metastasis. We review the transcriptomic and functional similarities between HSC and CAF subpopulations, highlighting the pathways that either promote or prevent fibrosis and cancer, and the immunological landscape from which these pathways emerge. Insights from ongoing studies will yield novel strategies for developing biomarkers, assessing prognosis and generating new therapies for both HCC and iCCA prevention and treatment.
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Affiliation(s)
- Bruno Cogliati
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, SP, Brazil
| | | | - Shuang Wang
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Daniela Sia
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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14
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Rani R, Gandhi CR. Stellate cell in hepatic inflammation and acute injury. J Cell Physiol 2023; 238:1226-1236. [PMID: 37120832 DOI: 10.1002/jcp.31029] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/05/2023] [Accepted: 04/07/2023] [Indexed: 05/02/2023]
Abstract
The perisinusoidal hepatic stellate cells (HSCs) have been investigated extensively for their role as the major fibrogenic cells during chronic liver injury. HSCs also produce numerous cytokines, chemokines, and growth mediators, and express cell adhesion molecules constitutively and in response to stimulants such as endotoxin (lipopolysaccharide). With this property and by interacting with resident and recruited immune and inflammatory cells, HSCs regulate hepatic immune homeostasis, inflammation, and acute injury. Indeed, experiments with HSC-depleted animal models and cocultures have provided evidence for the prominent role of HSCs in the initiation and progression of inflammation and acute liver damage due to various toxic agents. Thus HSCs and/or mediators derived thereof during acute liver damage may be considered as potential therapeutic targets.
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Affiliation(s)
- Richa Rani
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Research & Development, Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio, USA
| | - Chandrashekhar R Gandhi
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Research & Development, Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio, USA
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA
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15
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Crocker CE, Sharmeen R, Tran TT, Khan AM, Li W, Alcorn JL. Surfactant protein a attenuates generalized and localized neuroinflammation in neonatal mice. Brain Res 2023; 1807:148308. [PMID: 36871846 PMCID: PMC10065943 DOI: 10.1016/j.brainres.2023.148308] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 02/24/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023]
Abstract
Surfactant protein A (SP-A) has important roles in innate immunity and modulation of pulmonary and extrapulmonary inflammation. Given SP-A has been detected in rat and human brain, we sought to determine if SP-A has a role in modulating inflammation in the neonatal mouse brain. Neonatal wildtype (WT) and SP-A-deficient (SP-A-/-) mice were subjected to three models of brain inflammation: systemic sepsis, intraventricular hemorrhage (IVH) and hypoxic-ischemic encephalopathy (HIE). Following each intervention, RNA was isolated from brain tissue and expression of cytokine and SP-A mRNA was determined by real-time quantitative RT-PCR analysis. In the sepsis model, expression of most cytokine mRNAs was significantly increased in brains of WT and SP-A-/- mice with significantly greater expression of all cytokine mRNA levels in SP-A-/- mice compared to WT. In the IVH model, expression of all cytokine mRNAs was significantly increased in WT and SP-A-/- mice and levels of most cytokine mRNAs were significantly increased in SP-A-/- mice compared to WT. In the HIE model, only TNF-α mRNA levels were significantly increased in WT brain tissue while all pro-inflammtory cytokine mRNAs were significantly increased in SP-A-/- mice, and all pro-inflammatory cytokine mRNA levels were significantly higher in SP-A-/- mice compared to WT. SP-A mRNA was not detectable in brain tissue of adult WT mice nor in WT neonates subjected to these models. These results suggest that SP-A-/- neonatal mice subjected to models of neuroinflammation are more susceptible to both generalized and localized neuroinflammation compared to WT mice, thus supporting the hypothesis that SP-A attenuates inflammation in neonatal mouse brain.
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Affiliation(s)
- Caroline E Crocker
- Division of Neonatology, Department of Pediatrics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Romana Sharmeen
- Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Thu T Tran
- Division of Neonatology, Department of Pediatrics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Amir M Khan
- Division of Neonatology, Department of Pediatrics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Wen Li
- Division of Clinical and Translational Sciences, Department of Internal Medicine, the University of Texas McGovern Medical School at Houston, Houston, TX 77030, USA; Biostatistics/Epidemiology/Research Design Component, Center for Clinical and Translational Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Joseph L Alcorn
- Division of Neonatology, Department of Pediatrics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Pediatric Research Center, Department of Pediatrics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
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16
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Shen J, Cao J, Chen M, Zhang Y. Recent advances in the role of exosomes in liver fibrosis. J Gastroenterol Hepatol 2023. [PMID: 37114594 DOI: 10.1111/jgh.16203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 04/05/2023] [Accepted: 04/17/2023] [Indexed: 04/29/2023]
Abstract
BACKGROUND AND AIM We aim to summarize the current status of research on the role of exosomes in liver fibrosis. METHODS A review of the relevant literature was performed and the key findings were presented. RESULTS Most studies focused on the role of exosomes derived from mesenchymal stem cells, other types of stem cells, and liver resident cells including hepatocytes, cholangiocytes, and hepatic stellate cells in liver fibrosis. Exosomes have been reported to play an essential role in the inactivation or activation of hepatic stellate cells through the delivery of non-coding RNAs and proteins. In recent years, this exosome cargo has become a research hotspot. CONCLUSIONS Recent studies have indicated the potential therapeutic benefit of exosomes in liver fibrosis.
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Affiliation(s)
- Jiliang Shen
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiasheng Cao
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mingyu Chen
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yaping Zhang
- Department of Anesthesiology, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
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17
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Yoshimoto S, Soyama A, Fukumoto M, Hara T, Hidaka M, Torai S, Kasamatsu H, Ishikawa J, Ohara M, Kobayashi E, Eguchi S. Preliminary observations of an ex vivo normothermic whole blood machine perfusion in an experimental liver transplant porcine model. Transplant Proc 2023:S0041-1345(23)00236-1. [PMID: 37117106 DOI: 10.1016/j.transproceed.2023.03.067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 03/18/2023] [Accepted: 03/29/2023] [Indexed: 04/30/2023]
Abstract
BACKGROUND Even though transplantation is an essential treatment with no viable alternatives, a significant worldwide donor shortage persists. In this study, we assessed the metabolism of livers that underwent extended periods of circulatory death and subsequently conducted functional validation through transplantation to explore the feasibility of using livers from an uncontrolled donor after circulatory death (u-DCD). METHODS A donor model simulating u-DCD was constructed using pigs. The prolonged warm ischemia time (WIT) was set to 60, 120, and 180 minutes, and the liver function was evaluated after 24 hours of perfusion using an originally developed normothermic perfusion system. Based on the results, functional confirmation by transplantation was performed on the 2 groups with prolonged WIT of 60 and 180 minutes. RESULTS Based on the 24-hour perfusion of the liver alone, we evaluated the function by transplanting the WI 60-minute model and 180-minute model (N = 3 each). Warm ischemia was 73.5 ± 3.7 minutes and 188 ± 3 minutes in the 60-minute model and 180-minute model, respectively. In the model with 60 minutes of WI, one case survived until the endpoint, and 2 cases survived between 8 and 12 hours, whereas, in the model with 180 minutes of WI, they died within 6 hours. CONCLUSION We constructed a completely uncontrolled circulatory arrest model without anticoagulation and showed the possibility of using u-DCD livers by ex vivo machine perfusion and transplantation.
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Affiliation(s)
- Syuhei Yoshimoto
- Department of Innovative surgical technology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; R&D Department 3, SCREEN Holdings, Co, Ltd, Kyoto, Japan.
| | - Akihiko Soyama
- Department of Innovative surgical technology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masayuki Fukumoto
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Takanobu Hara
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masaaki Hidaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Shinji Torai
- R&D Department 3, SCREEN Holdings, Co, Ltd, Kyoto, Japan; Department of Organ Fabrication, Keio University School of Medicine, Tokyo, Japan
| | | | - Jun Ishikawa
- R&D Department 3, SCREEN Holdings, Co, Ltd, Kyoto, Japan
| | - Masayuki Ohara
- R&D Department 3, SCREEN Holdings, Co, Ltd, Kyoto, Japan
| | - Eiji Kobayashi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Department of Organ Fabrication, Keio University School of Medicine, Tokyo, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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18
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Ito Y, Hosono K, Amano H. Responses of hepatic sinusoidal cells to liver ischemia–reperfusion injury. Front Cell Dev Biol 2023; 11:1171317. [PMID: 37082623 PMCID: PMC10112669 DOI: 10.3389/fcell.2023.1171317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 03/27/2023] [Indexed: 04/07/2023] Open
Abstract
The liver displays a remarkable regenerative capacity in response to acute liver injury. In addition to the proliferation of hepatocytes during liver regeneration, non-parenchymal cells, including liver macrophages, liver sinusoidal endothelial cells (LSECs), and hepatic stellate cells (HSCs) play critical roles in liver repair and regeneration. Liver ischemia–reperfusion injury (IRI) is a major cause of increased liver damage during liver resection, transplantation, and trauma. Impaired liver repair increases postoperative morbidity and mortality of patients who underwent liver surgery. Successful liver repair and regeneration after liver IRI requires coordinated interplay and synergic actions between hepatic resident cells and recruited cell components. However, the underlying mechanisms of liver repair after liver IRI are not well understood. Recent technological advances have revealed the heterogeneity of each liver cell component in the steady state and diseased livers. In this review, we describe the progress in the biology of liver non-parenchymal cells obtained from novel technological advances. We address the functional role of each cell component in response to liver IRI and the interactions between diverse immune repertoires and non-hematopoietic cell populations during the course of liver repair after liver IRI. We also discuss how these findings can help in the design of novel therapeutic approaches. Growing insights into the cellular interactions during liver IRI would enhance the pathology of liver IRI understanding comprehensively and further develop the strategies for improvement of liver repair.
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19
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Ahmed O, Caravaca AS, Crespo M, Dai W, Liu T, Guo Q, Leiva M, Sabio G, Shavva VS, Malin SG, Olofsson PS. Hepatic stellate cell activation markers are regulated by the vagus nerve in systemic inflammation. Bioelectron Med 2023; 9:6. [PMID: 36997988 PMCID: PMC10064698 DOI: 10.1186/s42234-023-00108-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 03/10/2023] [Indexed: 04/01/2023] Open
Abstract
BACKGROUND The liver is an important immunological organ and liver inflammation is part of the pathophysiology of non-alcoholic steatohepatitis, a condition that may promote cirrhosis, liver cancer, liver failure, and cardiovascular disease. Despite dense innervation of the liver parenchyma, little is known about neural regulation of liver function in inflammation. Here, we study vagus nerve control of the liver response to acute inflammation. METHODS Male C57BL/6 J mice were subjected to either sham surgery, surgical vagotomy, or electrical vagus nerve stimulation followed by intraperitoneal injection of the TLR2 agonist zymosan. Animals were euthanized and tissues collected 12 h after injection. Samples were analyzed by qPCR, RNAseq, flow cytometry, or ELISA. RESULTS Hepatic mRNA levels of pro-inflammatory mediators Ccl2, Il-1β, and Tnf-α were significantly higher in vagotomized mice compared with mice subjected to sham surgery. Differences in liver Ccl2 levels between treatment groups were largely reflected in the plasma chemokine (C-C motif) ligand 2 (CCL2) concentration. In line with this, we observed a higher number of macrophages in the livers of vagotomized mice compared with sham as measured by flow cytometry. In mice subjected to electrical vagus nerve stimulation, hepatic mRNA levels of Ccl2, Il1β, and Tnf-α, and plasma CCL2 levels, were significantly lower compared with sham. Interestingly, RNAseq revealed that a key activation marker for hepatic stellate cells (HSC), Pnpla3, was the most significantly differentially expressed gene between vagotomized and sham mice. Of note, several HSC-activation associated transcripts were higher in vagotomized mice, suggesting that signals in the vagus nerve contribute to HSC activation. In support of this, we observed significantly higher number of activated HSCs in vagotomized mice as compared with sham as measured by flow cytometry. CONCLUSIONS Signals in the cervical vagus nerve controlled hepatic inflammation and markers of HSC activation in zymosan-induced peritonitis.
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Affiliation(s)
- Osman Ahmed
- Department of Medicine Solna, Laboratory of Immunobiology, Division of Cardiovascular Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Biochemistry, Faculty of Medicine, Khartoum University, Khartoum, Sudan
- Department of Medicine Solna, Stockholm Center for Bioelectronic Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - April S Caravaca
- Department of Medicine Solna, Laboratory of Immunobiology, Division of Cardiovascular Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Medicine Solna, Stockholm Center for Bioelectronic Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Maria Crespo
- Spanish National Center for Cardiovascular Research (CNIC), Madrid, Spain
| | - Wanmin Dai
- Department of Medicine Solna, Laboratory of Immunobiology, Division of Cardiovascular Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Medicine Solna, Stockholm Center for Bioelectronic Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Ting Liu
- Department of Medicine Solna, Laboratory of Immunobiology, Division of Cardiovascular Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Medicine Solna, Stockholm Center for Bioelectronic Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Qi Guo
- Department of Medicine Solna, Laboratory of Immunobiology, Division of Cardiovascular Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Medicine Solna, Stockholm Center for Bioelectronic Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Magdalena Leiva
- Department of Immunology, School of Medicine, Complutense University of Madrid, Madrid, Spain
| | - Guadalupe Sabio
- Spanish National Center for Cardiovascular Research (CNIC), Madrid, Spain
| | - Vladimir S Shavva
- Department of Medicine Solna, Laboratory of Immunobiology, Division of Cardiovascular Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Medicine Solna, Stockholm Center for Bioelectronic Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Stephen G Malin
- Department of Medicine Solna, Laboratory of Immunobiology, Division of Cardiovascular Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Peder S Olofsson
- Department of Medicine Solna, Laboratory of Immunobiology, Division of Cardiovascular Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
- Department of Medicine Solna, Stockholm Center for Bioelectronic Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA.
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20
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Yang H, Zhang P, Wang Q, Cheng K, Zhao Y. The research development of STAT3 in hepatic ischemia-reperfusion injury. Front Immunol 2023; 14:1066222. [PMID: 36761734 PMCID: PMC9902876 DOI: 10.3389/fimmu.2023.1066222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 01/10/2023] [Indexed: 01/25/2023] Open
Abstract
Ischemia-reperfusion injury (IRI) is a common complication of surgery, which can cause rapid deterioration of the liver function, increase the risk of graft rejection, and seriously affect the prognosis of patients. The signal transducer and activator of transcription 3 (STAT3) protein has been implicated in pathogenesis of IRI. STAT3 influences the mitochondria through multiple pathways and is also involved in apoptosis and other forms of programmed cell death. STAT3 is associated with Janus kinase (JAK), phosphoinositide-3 kinase (PI3K), and heme oxygenase-1 (HO-1) in liver IRI. The STAT3 pathway plays a dual role in IRI as it can also regulate lipid metabolism which may have potential for treating IRI fatty liver. In this review, we summarize research on the function of STAT3 in liver IRI to provide references for its application in the clinic.
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Affiliation(s)
| | | | | | | | - Yujun Zhao
- Engineering and Technology Research Center for Transplantation Medicine of National Health Comission, Third Xiangya Hospital, Central South University, Changsha, China
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21
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Sun Q, Schwabe RF. Hepatic Stellate Cell Depletion and Genetic Manipulation. Methods Mol Biol 2023; 2669:207-220. [PMID: 37247062 DOI: 10.1007/978-1-0716-3207-9_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Hepatic stellate cells (HSCs) exert key roles in the development of liver disease. Cell-specific genetic labeling, gene knockout and depletion are important for the understanding of the HSC in homeostasis and a wide range of diseases ranging from acute liver injury and liver regeneration to nonalcoholic liver disease and cancer. Here, we will review and compare different Cre-dependent and Cre-independent methods for genetic labeling, gene knockout, HSC tracing and depletion, and their applications to different disease models. We provide detailed protocols for each method including methods to confirm successful and efficient targeting of HSCs.
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Affiliation(s)
- Qiuyan Sun
- Department of Medicine, Columbia University, New York, NY, USA
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22
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Fang M, Zhong C. Vitamin D Receptor Regulates Autophagy to Inhibit Apoptosis and Promote Proliferation in Hepatocyte Injury. J NIPPON MED SCH 2023; 90:89-95. [PMID: 36908130 DOI: 10.1272/jnms.jnms.2023_90-114] [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] [Indexed: 03/13/2023]
Abstract
BACKGROUND Oxidative stress is an important mechanism in liver ischemia/reperfusion (I/R) injury. Hepatocyte apoptosis and proliferation occur in parallel with liver I/R injury, and the degree of apoptosis and proliferation determines the effects on hepatocytes. Vitamin D receptor (VDR) can lessen liver I/R injury, but previous studies focused mostly on inflammation and immunity. METHODS H2O2 was used to induce hepatocyte injury. Before treatment with H2O2, Hep-3B cells were pretreated with paricalcitol (PC) and siRNA-VDR. Rapamycin and chloroquine were also applied in the study. RESULTS The number of apoptotic cells was measured with an annexin V (AV) -fluorescein isothiocyanate apoptosis detection kit. Expression of proteins was measured by western blotting. As compared with the H2O2+Hep-3B group, levels of AV/PI, cleaved caspase-3, and p62 were lower, and expression levels of Bcl-2, proliferating cell nuclear antigen, and VDR were higher, in the PC+H2O2+Hep-3B group. When the VDR gene was silenced by siRNA-VDR in the siRNA-VDR+H2O2+Hep-3B group, expressions of AV/PI, cleaved caspase-3, and p62 were upregulated, and expressions of Bcl-2, proliferating cell nuclear antigen, and VDR were downregulated, as compared with values for the siRNA-NC+H2O2+Hep-3B group. Treatment with rapamycin or chloroquine partially reversed the effect of PC and siRNA-VDR on apoptosis and proliferation. CONCLUSIONS VDR mediates hepatocyte apoptosis and proliferation through autophagy.
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Affiliation(s)
- Mingming Fang
- Department of Neurology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine
- Department of Neurology, Jiangsu Province Academy of Traditional Chinese Medicine
| | - Chen Zhong
- Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences
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Pibiri M, Simbula G. Role of the Hippo pathway in liver regeneration and repair: recent advances. Inflamm Regen 2022; 42:59. [PMID: 36471376 PMCID: PMC9720992 DOI: 10.1186/s41232-022-00235-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 11/09/2022] [Indexed: 12/12/2022] Open
Abstract
Although the signaling pathways involved in normal liver regeneration have been well characterized, less has been done for livers affected by chronic tissue damage. These "abnormal livers" have an impaired regenerative response that leads to liver repair and fibrosis. The tumor suppressor Hippo pathway plays a key role in liver regeneration and repair. On this basis, this review discusses recent studies focusing on the involvement of the Hippo signaling pathway during "normal healthy liver regeneration" (i.e., in a normal liver after 2/3 partial hepatectomy) and "abnormal liver regeneration" (i.e., in a liver damaged by chronic disease). This could be an important question to address with respect to new therapies aimed at improving impaired liver regenerative responses. The studies reported here have shown that activation of the Hippo coactivators YAP/TAZ during normal liver regeneration promotes the formation of a new bile duct network through direct BEC proliferation or/and hepatocyte dedifferentiation to HPCs which can trans-differentiate to BECs. Moreover, YAP/TAZ signaling interaction with other signaling pathways mediates the recruitment and activation of Kupffer cells, which release mitogenic cytokines for parenchymal and/or non-parenchymal cells and engage in phagocytosis of cellular debris. In addition, YAP-mediated activation of stellate cells (HSCs) promotes liver regeneration through the synthesis of extracellular matrix. However, in chronically diseased livers, where the predetermined threshold for proper liver regeneration is exceeded, YAP/TAZ activation results in a reparative process characterized by liver fibrosis. In this condition, YAP/TAZ activation in parenchymal and non-parenchymal cells results in (i) differentiation of quiescent HSCs into myofibroblastic HSCs; (ii) recruitment of macrophages releasing inflammatory cytokines; (iii) polarization of macrophages toward the M2 phenotype. Since accumulation of damaged hepatocytes in chronic liver injury represent a significant risk factor for the development of hepatocarcinoma, this review also discussed the involvement of the Hippo pathway in the clearance of damaged cells.
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Affiliation(s)
- Monica Pibiri
- grid.7763.50000 0004 1755 3242Department of Biomedical Sciences, Oncology and Molecular Pathology Unit, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. Monserrato-Sestu km 0.700, Blocco A. 09042 Monserrato, Cagliari, Italy
| | - Gabriella Simbula
- grid.7763.50000 0004 1755 3242Department of Biomedical Sciences, Oncology and Molecular Pathology Unit, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. Monserrato-Sestu km 0.700, Blocco A. 09042 Monserrato, Cagliari, Italy
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Sharma A, Kudira R, Wang J, Miethke A, Gandhi CR. Differential recruitment of monocyte-derived macrophages in control and stellate cell-depleted mice during recurrent carbon tetrachloride-induced acute liver injury. J Cell Physiol 2022; 237:4215-4225. [PMID: 36098042 PMCID: PMC11296225 DOI: 10.1002/jcp.30877] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 08/04/2022] [Accepted: 08/23/2022] [Indexed: 11/07/2022]
Abstract
Liver depleted of hepatic stellate cells (HSCs) is resistant to ischemia/reperfusion-, concanavalin A-, and acetaminophen-induced acute injury. Whether HSCs regulate carbon tetrachloride (CCl4 )-induced acute liver injury is not known. CCl4 treatment damages pericentral hepatocytes that express CCl4 -metabolizing Cyp2E1 and activates HSCs. We investigated whether HSC-depletion in mice transgenic for thymidine kinase under the glial fibrillary acidic protein promoter (GFAP-TK-Tg) confers resistance to injury and inflammation due to CCl4 rechallenge. GFAP-TK-Tg or wild type (WT) mice were administered 0.16 ml/kg CCl4 (3× at 3 days intervals), then 40 μg/g/day ganciclovir for 10 days. The treatment depletes ~70%-75% HSCs from GFAP-TK-Tg but not WT mice while the liver recovers from earlier CCl4 -induced injury. Mice were then administered CCl4 , and liver injury and inflammation were determined at 24 h. HSC-depleted and HSC-sufficient mice showed similar CCl4 -induced hepatocyte necrosis and oxidative stress. However, increase in F4/80+ macrophages, but not CD68+ cells, was greater in CCl4 rechallenged HSC-depleted compared to HSC-sufficient mice. Expression of tumor necrosis factor-α (TNF-α), CCL2, and CXCL1 increased similarly, whereas increase in interleukin-6 (IL6), IL1β, and IL10 expression was higher in CCl4 rechallenged HSC-depleted compared to HSC-sufficient mice. CCl4 rechallenge of HSC-sufficient mice rapidly activated HSCs causing significant fibrosis with increased expression of Col1a1, transforming growth factor β1 (TGFβ1), tissue inhibitors of metalloproteinases 1 (TIMP1); increase in TIPM1 was much lower and metalloproteinases 13 (MMP13) greater in CCl4 rechallenged HSC-depleted mice. Interestingly, hepatic recruitment of both profibrogenic (Ly6Chi ) and antifibrogenic restorative (Ly6Clo ) macrophages, and neutrophils was significantly greater in CCl4 rechallenged HSC-depleted mice. These data suggest that CCl4 directly damages hepatocytes but HSCs regulate inflammation. Rapid fibrogenesis in CCl4 rechallenged HSC-sufficient mice recovered from earlier injury indicates that even transiently activated HSCs that had reverted to the quiescent phenotype remain primed to become reactivated.
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Affiliation(s)
- Akanksha Sharma
- Department of Pediatrics, Division of Gastroenterology, Hepatology & Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
- Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio, USA
| | - Ramesh Kudira
- Department of Pediatrics, Division of Gastroenterology, Hepatology & Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
| | - Jiang Wang
- Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA
| | - Alexander Miethke
- Department of Pediatrics, Division of Gastroenterology, Hepatology & Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
| | - Chandrashekhar R. Gandhi
- Department of Pediatrics, Division of Gastroenterology, Hepatology & Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
- Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio, USA
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA
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Gut Microbiota Regulation of AHR Signaling in Liver Disease. Biomolecules 2022; 12:biom12091244. [PMID: 36139083 PMCID: PMC9496174 DOI: 10.3390/biom12091244] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 09/01/2022] [Accepted: 09/02/2022] [Indexed: 11/17/2022] Open
Abstract
Liver health plays a vital role in human health and disease. Emerging evidence has shown the importance of the aryl hydrocarbon receptor (AHR) in liver diseases such as alcoholic liver disease, fatty liver disease, and liver failure. As a ligand-activated transcription factor, AHR can be activated by endogenous ligands of microbial metabolites such as tryptophan (Trp), kynurenine (Kyn) or indole derivatives locally or distantly. However, the therapeutic effects of the gut microbiota-regulated AHR pathway remain to be clarified. In this review, we summarize recent progress and examine the role of AHR signaling as a target for gut microbiota intervention in liver diseases. The focus on AHR signaling will identify a promising target in the gut microbiota for better understanding and therapeutic opportunities in liver diseases.
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Ma Y, Jiao Z, Liu X, Zhang Q, Piao C, Xu J, Wang H. Protective effect of adipose-derived stromal cell-secretome attenuate autophagy induced by liver ischemia–reperfusion and partial hepatectomy. STEM CELL RESEARCH & THERAPY 2022; 13:427. [PMID: 35987696 PMCID: PMC9392224 DOI: 10.1186/s13287-022-03109-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 05/03/2022] [Indexed: 11/25/2022]
Abstract
Background The therapeutic effects of adipose-derived mesenchymal stromal cells (ADSCs) may be mainly mediated by their paracrine effects. The ADSC-secretome can ameliorate hepatic ischemia–reperfusion injury (IRI). We explored the therapeutic effect of the ADSC-secretome from the perspective of excessive hepatocyte autophagy induced by hepatic IRI. Methods We established a miniature pig model of hepatic ischemia–reperfusion (I/R) and hepatectomy using a laparoscopic technique and transplanted ADSCs and the ADSC-secretome into the liver parenchyma immediately after surgery. Liver injury and hepatocyte autophagy were evaluated by histopathological examination and assessment of relevant cytokines and other factors. Results The results showed that the ADSC-secretome alleviated the pathological changes of liver tissue and the microstructural damage of hepatocytes after IRI. Moreover, the expression levels of autophagy-related markers including Beclin-1, ATG5, ATG12, and LC3II/LC3I decreased, whereas those of p62 increased during phagophore expansion. Furthermore, the expression levels of markers related to the autophagy inhibition pathway phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR), including PI3K, Akt, and mTOR, increased. Conclusion The ADSC-secretome attenuates hepatic I/R and hepatectomy-induced liver damage by inhibiting autophagy, which is possibly mediated by activation of the PI3K/Akt/mTOR signaling pathway. In addition, there was no significant difference between ADSCs and the ADSC-secretome in the regulation of hepatocyte autophagy. Therefore, ADSCs may improve the excessive autophagy-induced injury of hepatocytes in hepatic I/R and hepatectomy through paracrine effect. Our findings provide new insight into the therapeutic potential of cell-free products, which could replace cell therapy in liver diseases. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03109-2.
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Peng Y, Yin Q, Yuan M, Chen L, Shen X, Xie W, Liu J. Role of hepatic stellate cells in liver ischemia-reperfusion injury. Front Immunol 2022; 13:891868. [PMID: 35967364 PMCID: PMC9366147 DOI: 10.3389/fimmu.2022.891868] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 06/27/2022] [Indexed: 12/13/2022] Open
Abstract
Liver ischemia-reperfusion injury (IRI) is a major complication of liver trauma, resection, and transplantation. IRI may lead to liver dysfunction and failure, but effective approach to address it is still lacking. To better understand the cellular and molecular mechanisms of liver IRI, functional roles of numerous cell types, including hepatocytes, Kupffer cells, neutrophils, and sinusoidal endothelial cells, have been intensively studied. In contrast, hepatic stellate cells (HSCs), which are well recognized by their essential functions in facilitating liver protection and repair, have gained less attention in their role in IRI. This review provides a comprehensive summary of the effects of HSCs on the injury stage of liver IRI and their associated molecular mechanisms. In addition, we discuss the regulation of liver repair and regeneration after IRI by HSCs. Finally, we highlight unanswered questions and future avenues of research regarding contributions of HSCs to IRI in the liver.
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Affiliation(s)
- Yuming Peng
- First Department of General Surgery, Hunan Children’s Hospital, Changsha, China
- Zhaolong Chen Academician Workstation, Changsha, China
- *Correspondence: Yuming Peng, ; Qiang Yin,
| | - Qiang Yin
- First Department of General Surgery, Hunan Children’s Hospital, Changsha, China
- Zhaolong Chen Academician Workstation, Changsha, China
- *Correspondence: Yuming Peng, ; Qiang Yin,
| | - Miaoxian Yuan
- First Department of General Surgery, Hunan Children’s Hospital, Changsha, China
- Zhaolong Chen Academician Workstation, Changsha, China
| | - Lijian Chen
- First Department of General Surgery, Hunan Children’s Hospital, Changsha, China
- Zhaolong Chen Academician Workstation, Changsha, China
| | - Xinyi Shen
- First Department of General Surgery, Hunan Children’s Hospital, Changsha, China
- Zhaolong Chen Academician Workstation, Changsha, China
| | - Weixin Xie
- First Department of General Surgery, Hunan Children’s Hospital, Changsha, China
- Zhaolong Chen Academician Workstation, Changsha, China
| | - Jinqiao Liu
- Department of Ultrasound, Hunan Children’s Hospital, Changsha, China
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Li Y, Palmer A, Lupu L, Huber-Lang M. Inflammatory response to the ischaemia-reperfusion insult in the liver after major tissue trauma. Eur J Trauma Emerg Surg 2022; 48:4431-4444. [PMID: 35831749 DOI: 10.1007/s00068-022-02026-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 05/28/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Polytrauma is often accompanied by ischaemia-reperfusion injury to tissues and organs, and the resulting series of immune inflammatory reactions are a major cause of death in patients. The liver is one of the largest organs in the body, a characteristic that makes it the most vulnerable organ after multiple injuries. In addition, the liver is an important digestive organ that secretes a variety of inflammatory mediators involved in local as well as systemic immune inflammatory responses. Therefore, this review considers the main features of post-traumatic liver injury, focusing on the immuno-pathophysiological changes, the interactions between liver organs, and the principles of treatment deduced. METHODS We focus on the local as well as systemic immune response involving the liver after multiple injuries, with emphasis on the pathophysiological mechanisms. RESULTS An overview of the mechanisms underlying the pathophysiology of local as well as systemic immune responses involving the liver after multiple injuries, the latest research findings, and the current mainstream therapeutic approaches. CONCLUSION Cross-reactivity between various organs and cascade amplification effects are among the main causes of systemic immune inflammatory responses after multiple injuries. For the time being, the pathophysiological mechanisms underlying this interaction remain unclear. Future work will continue to focus on identifying potential signalling pathways as well as target genes and intervening at the right time points to prevent more severe immune inflammatory responses and promote better and faster recovery of the patient.
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Affiliation(s)
- Yang Li
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany
| | - Annette Palmer
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany
| | - Ludmila Lupu
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany
| | - Markus Huber-Lang
- Institute for Clinical and Experimental Trauma Immunology (ITI), University Hospital Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany.
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Kaltenmeier C, Yazdani HO, Handu S, Popp B, Geller D, Tohme S. The Role of Neutrophils as a Driver in Hepatic Ischemia-Reperfusion Injury and Cancer Growth. Front Immunol 2022; 13:887565. [PMID: 35844608 PMCID: PMC9284204 DOI: 10.3389/fimmu.2022.887565] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 06/02/2022] [Indexed: 12/22/2022] Open
Abstract
The innate immune system plays an essential role in the response to sterile inflammation and its association with liver ischemia and reperfusion injury (IRI). Liver IRI often manifests during times of surgical stress such as cancer surgery or liver transplantation. Following the initiation of liver IRI, stressed hepatocytes release damage-associated molecular patterns (DAMPs) which promote the infiltration of innate immune cells which then initiate an inflammatory cascade and cytokine storm. Upon reperfusion, neutrophils are among the first cells that infiltrate the liver. Within the liver, neutrophils play an important role in fueling tissue damage and tumor progression by promoting the metastatic cascade through the formation of Neutrophil Extracellular Traps (NETs). NETs are composed of web-like DNA structures containing proteins that are released in response to inflammatory stimuli in the environment. Additionally, NETs can aid in mediating liver IRI, promoting tumor progression, and most recently, in mediating early graft rejection in liver transplantation. In this review we aim to summarize the current knowledge of innate immune cells, with a focus on neutrophils, and their role in mediating IRI in mouse and human diseases, including cancer and transplantation. Moreover, we will investigate the interaction of Neutrophils with varying subtypes of other cells. Furthermore, we will discuss the role and different treatment modalities in targeting Neutrophils and NETs to prevent IRI.
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Affiliation(s)
- Christof Kaltenmeier
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Hamza O. Yazdani
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Sanah Handu
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Brandon Popp
- Lake Erie College of Osteopathic Medicine, Erie, PA, United States
| | - David Geller
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Samer Tohme
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- *Correspondence: Samer Tohme,
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Rani R, Sharma A, Wang J, Kumar S, Polaki US, Gandhi CR. Endotoxin-Stimulated Hepatic Stellate Cells Augment Acetaminophen-Induced Hepatocyte Injury. THE AMERICAN JOURNAL OF PATHOLOGY 2022; 192:518-535. [PMID: 34954210 PMCID: PMC8895430 DOI: 10.1016/j.ajpath.2021.11.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 10/27/2021] [Accepted: 11/29/2021] [Indexed: 12/11/2022]
Abstract
Acetaminophen (APAP)-induced liver injury is influenced by inflammatory Gram-negative bacterial endotoxin [lipopolysaccharide (LPS)], mechanisms of which are not completely understood. Because LPS-stimulated perisinusoidal hepatic stellate cells (HSCs) produce cytokines that affect survival of hepatocytes, this study investigated their role in APAP-induced liver injury. Fed (nonstarved) rats were administered 5 mg/kg LPS or phosphate-buffered saline (PBS) vehicle, followed by 200 mg/kg APAP or PBS an hour later, and euthanized at 6 hours. Control rats received PBS at both time points. Both LPS and APAP caused mild hepatocyte injury (apoptosis), as assessed by histopathology, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, and caspase-3 activation. The liver injury was augmented in rats administered LPS + APAP, in association with increased nuclear translocation of interferon-regulatory factor-1 (IRF1). In vitro, APAP augmented LPS/HSC-conditioned medium-induced inhibition of DNA and protein synthesis, apoptosis, and nuclear IRF1 in hepatocytes. LPS-stimulated HSCs produced interferon-β (IFN-β), and LPS/HSC + APAP-induced hepatocyte apoptosis was inhibited by anti-IFN-β antibody. Finally, HSC-depleted mice produced significantly lower IFN-β and tumor necrosis factor-α, exhibited less oxidative stress, and were protected from excessive injury due to high APAP dose (600 mg/kg), as well as LPS (5 mg/kg overnight) followed by APAP. In co-culture with or without LPS, HSCs increased expression of proinflammatory cytokines by Kupffer cells. These results suggest that HSCs play a critical role in APAP-induced liver injury without or with LPS preconditioning, and it involves INF-β-IRF1 signaling.
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Affiliation(s)
- Richa Rani
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Research & development, Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio
| | - Akanksha Sharma
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Research & development, Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio
| | - Jiang Wang
- Department of Pathology, University of Cincinnati, Cincinnati, Ohio
| | - Sudhir Kumar
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Research & development, Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio
| | - Usha S Polaki
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Research & development, Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio
| | - Chandrashekhar R Gandhi
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Research & development, Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio; Department of Surgery, University of Cincinnati, Cincinnati, Ohio; Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
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31
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Jin L, Li J, Yang S, Zhang R, Hu C, Chen Y, Tian Z, Ma W, Feng Y, Liu N, Liu J, Yang Y, Chen T, Zhao Y, He Y, Yan T. MAPK p38/Ulk1 pathway inhibits autophagy and induces IL-1β expression in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 2022; 322:G360-G367. [PMID: 35018817 DOI: 10.1152/ajpgi.00230.2021] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
In the past, hepatic stellate cells (HSCs) were considered to be noninflammatory cells and to contribute to liver fibrosis by producing extracellular matrix. Recently, it was found that HSCs can also secrete cytokines and chemokines and therefore participate in hepatic inflammation. Autophagy participates in many immune response processes in immune cells. It is unclear whether autophagy is involved in inflammatory cytokine induction in HSCs. MAPK p38, Ulk1 phosphorylation, and the Ulk1-Atg13 complex were analyzed in HSC-T6 cells after LPS treatment. The relationship between autophagy inhibition and inflammation was investigated in primary rat HSCs. We discovered that LPS inhibited autophagy through MAPK p38. The activation of MAPK p38 induced Ulk1 phosphorylation, which disrupted the Ulk1-Atg13 complex and therefore inhibited autophagy. Furthermore, in primary rat HSCs, we demonstrated that autophagy inhibition regulated IL-1β induction, which depended on the MAPK p38/Ulk1 pathway. Our results reveal a continuous signaling pathway, MAPK p38-Ulk1 phosphorylation-Ulk1-Atg13 disruption, which inhibits autophagy and induces IL-1β expression in HSCs.NEW & NOTEWORTHY LPS inhibits autophagy in a concentration- and dose-dependent manner in HSC-T6 cells. MAPK p38 induces phosphorylation of Ulk1, which disrupts the Ulk1-Atg13 complex and is therefore required for the inhibition of autophagy by LPS. LPS induces IL-1β expression via the MAPK p38/Ulk1 pathway in HSCs.
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Affiliation(s)
- Li Jin
- Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Juan Li
- Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - ShuJuan Yang
- Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,The Eighth Hospital, Xi'an, Shaanxi, China
| | - Rou Zhang
- Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - ChunHua Hu
- Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yi Chen
- Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Zhen Tian
- Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - WenQi Ma
- Department of Ultrasound, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - YaLi Feng
- Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Na Liu
- Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Department of Infectious Diseases, Yan'an University Affiliated Hospital, Yan'an, Shaanxi, China
| | - JinFeng Liu
- Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yuan Yang
- Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - TianYan Chen
- Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - YingRen Zhao
- Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - YingLi He
- Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - TaoTao Yan
- Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China
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Shi Q, Zhao G, Wei S, Guo C, Wu X, Zhao RC, Di G. Pterostilbene alleviates liver ischemia/reperfusion injury via PINK1-mediated mitophagy. J Pharmacol Sci 2022; 148:19-30. [PMID: 34924126 DOI: 10.1016/j.jphs.2021.09.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 09/11/2021] [Accepted: 09/16/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatic ischemia/reperfusion (I/R) injury contributes to morbidity and mortality during liver resection or transplantation, with limited effective treatments available. Here, we investigated the potential benefits and underlying mechanisms of pterostilbene (Pt), a natural component of blueberries and grapes, in preventing hepatic I/R injury. Male C57BL/6 mice subjected to partial warm hepatic I/R and human hepatocyte cell line L02 cells exposed to anoxia/reoxygenation (A/R) were used as in vivo and in vitro models, respectively. Our findings showed that pretreatment with Pt ameliorated hepatic I/R injury by improving liver histology, decreasing hepatocyte apoptosis, and reducing plasma ALT and AST levels. Likewise, cell apoptosis, mitochondrial membrane dysfunction, and mitochondrial ROS overproduction in L02 cells triggered by the A/R challenge in vitro were reduced due to Pt administration. Mechanistically, Pt treatment efficiently enhanced mitophagy and upregulated PINK1, Parkin, and LC3B expression. Notably, the protective effect of Pt was largely abrogated after cells were transfected with PINK1 siRNA. Moreover, Pt pretreatment promoted hepatocyte proliferation and liver regeneration in the late phase of hepatic I/R. In conclusion, our findings provide evidence that Pt exerts hepatoprotective effects in hepatic I/R injury by upregulating PINK1-mediated mitophagy.
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Affiliation(s)
- Qiangqiang Shi
- College of Basic Medicine, Qingdao University, Qingdao, China
| | - Guangfen Zhao
- Department of Medicine, The Liaocheng Third People's Hospital, Liaocheng, China
| | - Susu Wei
- College of Basic Medicine, Qingdao University, Qingdao, China
| | - Chuanlong Guo
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, China
| | - Xianggen Wu
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, China
| | | | - Guohu Di
- College of Basic Medicine, Qingdao University, Qingdao, China.
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Deneysel İskemi/Reperfüzyon Modelinde İlioprostun Karaciğer Dokusu Üzerindeki Koruyucu Etkisi. ANADOLU KLINIĞI TIP BILIMLERI DERGISI 2021. [DOI: 10.21673/anadoluklin.1030797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Hepatic interferon regulatory factor 8 expression mediates liver ischemia/reperfusion injury in mice. Biochem Pharmacol 2021; 192:114728. [PMID: 34400126 DOI: 10.1016/j.bcp.2021.114728] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 08/07/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023]
Abstract
Hepatic ischemia/reperfusion (I/R) injury is an inevitable complication of hepatic surgery occasioned by liver transplantation and resection. The progression from liver ischemia to reperfusion injury is accompanied by abnormal metabolism, Kupffer cell activation, neutrophil recruitment and the release of cytokines. Activation of several interferon regulatory factors (IRFs) has been reported to either enhance or restrict I/R progression, but the role of IRF8 in the regulation of I/R injury progression is still unknown. In this study, we explore the IRF8 function in the I/R-mediated liver injury using overexpressed hepatic IRF8 and knockout mice. According to our results, IRF8 knockout mice had significantly lower inflammatory cells infiltration, inflammatory cytokines release and serum aspartate aminotransferase/alanine aminotransferase levels that improved the necrotic injury after I/R, unlike the control mice. Conversely, the overexpression of IRF8 in WT mice markedly aggravated the liver structure damage and its abnormal function. We further showed that IRF8-mediated inflammatory cells infiltration were partly dependent on early autophagy and NF-κΒ signal pathway during I/R. AAV8-IRF8-I/R mice pretreated with autophagy inhibitor hydroxychloroquine and NF-κΒ signal pathway inhibitor secukinumab could drastically reverse the IRF8-mediated increase of neutrophil infiltration and chemokine release at different degrees. This work uncovered a critical role of IRF8 in the modulation of the hepatic microenvironment and as a potential target in the initial treatment of I/R injury.
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Betsou A, Lambropoulou M, Georgakopoulou AE, Kostomitsopoulos N, Konstandi O, Anagnostopoulos K, Tsalikidis C, Simopoulos CE, Valsami G, Tsaroucha AK. The hepatoprotective effect of silibinin after hepatic ischemia/reperfusion in a rat model is confirmed by immunohistochemistry and qRT-PCR. J Pharm Pharmacol 2021; 73:1274-1284. [PMID: 33847359 DOI: 10.1093/jpp/rgab062] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 03/19/2021] [Indexed: 01/18/2023]
Abstract
OBJECTIVES We investigated the positive effect of silibinin after IV administration as silibinin-hydroxypropyl-β-cyclodextrin lyophilized product, by measuring gene expression and liver tissue protein levels of tumor necrosis factor-α, interleukin-6, monocyte chemoattractant protein-1, matrix metalloproteinases matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases-2. METHODS 63 Wistar rats of age 13.24±4.40 weeks underwent ischemia/reperfusion (I/R) injury of the liver. The animals were randomized into three groups: Sham (S; n = 7); Control (C; n-28); silibinin (Si; n-28). The C and Si groups underwent 45 min ischemia. Si received silibinin-hydroxypropyl-β-cyclodextrin intravenously immediately before reperfusion at a dose of 5 mg/kg. Both groups were further divided into 4 subgroups, based on euthanasia time (i.e., 60, 120, 180 and 240 min). KEY FINDINGS qRT-PCR results confirmed the statistically significant reduction of the expression of the pro-inflammatory factors at 240 min after I/R injury (tumor necrosis factor-α: P < 0.05; MCR1: P < 0.05) and matrix metalloproteinases (matrix metalloproteinases 2: P < 0.05; matrix metalloproteinases 3: P < 0.05) and the increase of tissue inhibitor of matrix metalloproteinases-2 in liver tissue in the Si group. Moreover, results of immunohistochemistry levels confirmed that at 240 min pro-inflammatory factors (tumor necrosis factor-α: P < 0.05; MCR1: P < 0.05) and matrix metalloproteinases ( matrix metalloproteinases 2: P < 0.05; matrix metalloproteinases 3: P < 0.05) had a statistically significantly lower expression in the Si group while tissue inhibitor of matrix metalloproteinases-2 had a higher expression. CONCLUSIONS Silibinin may have a beneficial effect on the protection of the liver.
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Affiliation(s)
- Afrodite Betsou
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Maria Lambropoulou
- Laboratory of Histology-Embryology, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | | | | | - Ourania Konstandi
- Faculty of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Christos Tsalikidis
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
- 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Constantinos E Simopoulos
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
- 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Georgia Valsami
- School of Health Sciences, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Alexandra K Tsaroucha
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
- 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
- Laboratory of Experimental Surgery and Surgical Research, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
- Laboratory of Bioethics, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
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Abstract
Liver sinusoidal endothelial cells (LSECs) form the wall of the hepatic sinusoids. Unlike other capillaries, they lack an organized basement membrane and have cytoplasm that is penetrated by open fenestrae, making the hepatic microvascular endothelium discontinuous. LSECs have essential roles in the maintenance of hepatic homeostasis, including regulation of the vascular tone, inflammation and thrombosis, and they are essential for control of the hepatic immune response. On a background of acute or chronic liver injury, LSECs modify their phenotype and negatively affect neighbouring cells and liver disease pathophysiology. This Review describes the main functions and phenotypic dysregulations of LSECs in liver diseases, specifically in the context of acute injury (ischaemia-reperfusion injury, drug-induced liver injury and bacterial and viral infection), chronic liver disease (metabolism-associated liver disease, alcoholic steatohepatitis and chronic hepatotoxic injury) and hepatocellular carcinoma, and provides a comprehensive update of the role of LSECs as therapeutic targets for liver disease. Finally, we discuss the open questions in the field of LSEC pathobiology and future avenues of research.
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Yu Q, Cheng P, Wu J, Guo C. PPARγ/NF-κB and TGF-β1/Smad pathway are involved in the anti-fibrotic effects of levo-tetrahydropalmatine on liver fibrosis. J Cell Mol Med 2021; 25:1645-1660. [PMID: 33438347 PMCID: PMC7875896 DOI: 10.1111/jcmm.16267] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 12/10/2020] [Accepted: 12/22/2020] [Indexed: 12/19/2022] Open
Abstract
Liver fibrosis is a necessary stage in the development of chronic liver diseases to liver cirrhosis. This study aims to investigate the anti‐fibrotic effects of levo‐tetrahydropalmatine (L‐THP) on hepatic fibrosis in mice and cell models and its underlying mechanisms. Two mouse hepatic fibrosis models were generated in male C57 mice by intraperitoneal injection of carbon tetrachloride (CCl4) for 2 months and bile duct ligation (BDL) for 14 days. Levo‐tetrahydropalmatine was administered orally at doses of 20 and 40 mg/kg. An activated LX2 cell model induced by TGF‐β1 was also generated. The results showed that levo‐tetrahydropalmatine alleviated liver fibrosis by inhibiting the formation of extracellular matrix (ECM) and regulating the balance between TIMP1 and MMP2 in the two mice liver fibrosis models and cell model. Levo‐tetrahydropalmatine inhibited activation and autophagy of hepatic stellate cells (HSCs) by modulating PPARγ/NF‐κB and TGF‐β1/Smad pathway in vivo and in vitro. In conclusion, levo‐tetrahydropalmatine attenuated liver fibrosis by inhibiting ECM deposition and HSCs autophagy via modulation of PPARγ/NF‐κB and TGF‐β1/Smad pathway.
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Affiliation(s)
- Qiang Yu
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai, China.,Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ping Cheng
- Department of Gerontology, Shanghai Minhang District Central Hospital, Shanghai, China
| | - Jianye Wu
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Chuanyong Guo
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai, China.,Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
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NAMPT/SIRT1 Attenuate Ang II-Induced Vascular Remodeling and Vulnerability to Hypertension by Inhibiting the ROS/MAPK Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:1974265. [PMID: 33488923 PMCID: PMC7791967 DOI: 10.1155/2020/1974265] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 11/24/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023]
Abstract
Hypertension is characterized by endothelial dysfunction, vascular remodeling, and rearrangement of the extracellular matrix. Besides, the pathogenesis of hypertension is closely related to excess generation of reactive oxygen species (ROS). Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis that influences the activity of NAD-dependent enzymes, such as sirtuins, which possess NAD-dependent protein deacetylase activity and cleave NAD during the deacetylation cycle. Recently, NAMPT has been shown to play a crucial role in various diseases associated with oxidative stress. However, the function and regulation of NAMPT in hypertension have not been extensively explored. In the present study, we identified NAMPT as a crucial regulator of hypertension, because NAMPT expression was significantly downregulated in both patients with hypertension and experimental animals. NAMPT knockout (NAMPT+/-) mice exhibited a significantly higher blood pressure and ROS levels after stimulation with angiotensin II (Ang II) than wild-type mice, and the administration of recombinant human NAMPT (rhNAMPT) reversed this effect. In vivo, overexpression of NAMPT protected against angiotensin II- (Ang II-) induced hypertension by inhibiting ROS production via sirtuin 1 in mouse aortic endothelial cells (MAECs) and mouse aortic vascular smooth muscle cells (MOVAs). In turn, NAMPT alleviated the ROS-induced mitogen-activated protein kinase (MAPK) pathway. In conclusion, NAMPT might be a novel biomarker and a therapeutic target in hypertension.
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Xu JB, Gao GC, Yuan MJ, Huang X, Zhou HY, Zhang Y, Zheng YX, Wu Z, Feng JM, Wu JM. Lignans from Schisandra chinensis ameliorate alcohol and CCl 4-induced long-term liver injury and reduce hepatocellular degeneration via blocking ETBR. JOURNAL OF ETHNOPHARMACOLOGY 2020; 258:112813. [PMID: 32259665 DOI: 10.1016/j.jep.2020.112813] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/27/2020] [Accepted: 03/28/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Chemical hepatotoxicity, especially alcoholic liver injury (ALI), commonly occurs in young and middle-aged people who drink heavily. ALI is extremely harmful and can induce severe disease states, such as hepatitis, liver fibrosis, cirrhosis, or liver cancer, which are similar to CCl4-induced liver disease states in animals. In recent studies, the pathological changes of hepatocytes and the hepatic stellate cell have shown a significant connection between endoplasmic reticulum (ER) stress and the development of liver pathology in patients. However, the detailed pathological mechanism needs to be further studied. Schisandra chinensis, (S. chinensis), a fruit-bearing vine used in Traditional Chinese Medicine (TCM), has been used to treat chronic or acute diseases, including liver disease. S. chinensis-derived lignans (SCDLs) in particular have been shown to alleviate liver pathological changes. AIM OF THE STUDY This study sought to elucidate the mechanisms underlying SCDL-mediated hepatoprotection. MATERIALS AND METHODS We first used in silico target prediction and computational simulation methods to identify putative lignan-binding targets relative to the hepatoprotective effect. A gene microarray analysis was performed to identify differently expressed genes that might have significance in the disease pathological process. We then used histological analyses in a mice hepatotoxicity model to test the effectiveness of SCDLs in vivo, and a hepatocellular toxicity model to analyze the candidate-compound-mediated hepatoprotection and expression states of the key targets in vitro. RESULTS The in silico analysis results indicated that endothelin receptor B (ETBR/EDNRB) is likely a significant node during the liver pathological change process and a promising key target for the SCDL compound schisantherin D on the hepatoprotective effect; experimental studies showed that schisantherin D alleviated the EtOH- and ET-1-induced HL-7702 cell (belongs to liver parenchymal cell lines) injury ratio, decreased the expression of ETBR, and inhibited ECMs and ET-1 secretion in LX-2 cells (one form of hepatic stellate cells). SCDLs ameliorated EtOH- and CCl4-induced fibrosis formation in mice liver tissue. Liver tissue western blots of SCDL-treated mice showed downregulated α-SMA, ETBR, PLCβ, CHOP, Bax, and the apoptotic factors of cleaved-caspase 12, cleaved-caspase 9, and cleaved-caspase 3 hinted at an anti-apoptosis and hepatoprotective effect. The SCDL treatment also elevated serum glutathione (GSH) and reduced the serum-transforming growth factor-β1 (TGF-β1) level. CONCLUSION The findings indicated that SCDLs prevent hepatotoxicity via their anti-fibrotic, anti-oxidant, and anti-apoptosis properties. ETBR may be the key factor in promoting chemical hepatotoxicity.
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Affiliation(s)
- Jin-Biao Xu
- Department of Pharmacy, College of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Guang-Chun Gao
- Department of Pharmacy, College of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Ming-Jing Yuan
- Department of Pharmacy, College of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Xuan Huang
- Department of Pharmacy, College of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Hong-Yu Zhou
- Department of Pharmacy, College of Medicine, Jiaxing University, Jiaxing, 314001, China
| | - Yang Zhang
- School of Biology and Food Engineering, Changshu Institute of Technology, Changshu, 215500, China
| | - Ya-Xin Zheng
- School of Pharmacy, Key Laboratory of Sichuan Province for Specific Structure of Small Molecule Drugs, Chengdu Medical College, Chengdu, 610500, China
| | - Zhe Wu
- School of Chemical and Pharmaceutical Engineering, Jilin Institute of Chemical Technology, Jilin, 132022, China
| | - Jun-Miao Feng
- School of Chemical and Pharmaceutical Engineering, Jilin Institute of Chemical Technology, Jilin, 132022, China
| | - Ji-Ming Wu
- Department of Pharmacy, College of Medicine, Jiaxing University, Jiaxing, 314001, China.
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40
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Yang T, Feng Y, Zhang Y, Wang W, Zhang S, Yang S, Hong M. Kweichow Moutai ameliorates alcohol-induced liver fibrosis in mice by targeting the NFκB pathway. Food Sci Nutr 2020; 8:4214-4222. [PMID: 32884702 PMCID: PMC7455936 DOI: 10.1002/fsn3.1716] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 05/21/2020] [Accepted: 05/26/2020] [Indexed: 01/15/2023] Open
Abstract
Previous epidemiological and histopathological studies have demonstrated that long-term computation of Kweichow Moutai liquor (Moutai) could induce fatty liver disease but few of these patients with fatty liver will develop hepatic fibrosis or cirrhosis. Moutai liquor has a different brewing technique from other white wine, which may generate various microorganisms in the unique geographical conditions and may produce plenty of vitamins, amino acids, and several essential microelements. In the current study, we evaluated the potential protective effect of Moutai liquor in alcohol-induced liver fibrosis mouse model. Both in vivo and in vitro studies were performed for exploring the possible mechanisms in suppressing liver fibrosis by Moutai. We demonstrated that Moutai treatment induced hepatic stellate cell (HSC) apoptosis and suppressed collagen deposition, as well as attenuated hepatic fibrosis. The antifibrosis mechanism of Moutai was possibly related with the inhibition of Kupffer cell and HSC activation via suppressing NFκB nuclear translocation and preventing the expression of pro-inflammatory cytokines. It is worth noting that although Moutai attenuates liver fibrosis, it still causes lipid metabolic abnormalities in mouse liver and induces fatty liver. Kweichow Moutai may ameliorate alcohol-induced liver fibrosis in mice by targeting the NFκB pathway.
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Affiliation(s)
- Tao Yang
- Department of General SurgeryThe First Affiliated Hospital of Jinzhou Medical UniversityJinzhouChina
| | - Yu Feng
- Department of TraumatologyGeneral Hospital of Ningxia Medical UniversityYinchuanChina
| | - Yifan Zhang
- Department of General SurgeryThe First Affiliated Hospital of Jinzhou Medical UniversityJinzhouChina
| | - Wei Wang
- Department of General SurgeryThe First Affiliated Hospital of Jinzhou Medical UniversityJinzhouChina
| | - Shutian Zhang
- Department of General SurgeryThe First Affiliated Hospital of Jinzhou Medical UniversityJinzhouChina
| | - Sijin Yang
- Southwestern Medical University Affiliated Chinese Medicine HospitalLuzhouChina
| | - Ming Hong
- Science and Technology Innovation CenterGuangzhou University of Chinese MedicineGuangzhouChina
- Institute of Clinical PharmacologyGuangzhou University of Chinese MedicineGuangzhouChina
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Zhou J, Chen J, Wei Q, Saeb-Parsy K, Xu X. The Role of Ischemia/Reperfusion Injury in Early Hepatic Allograft Dysfunction. Liver Transpl 2020; 26:1034-1048. [PMID: 32294292 DOI: 10.1002/lt.25779] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 03/15/2020] [Accepted: 04/06/2020] [Indexed: 12/13/2022]
Abstract
Liver transplantation (LT) is the only available curative treatment for patients with end-stage liver disease. Early allograft dysfunction (EAD) is a life-threatening complication of LT and is thought to be mediated in large part through ischemia/reperfusion injury (IRI). However, the underlying mechanisms linking IRI and EAD after LT are poorly understood. Most previous studies focused on the clinical features of EAD, but basic research on the underlying mechanisms is insufficient, due, in part, to a lack of suitable animal models of EAD. There is still no consensus on definition of EAD, which hampers comparative analysis of data from different LT centers. IRI is considered as an important risk factor of EAD, which can induce both damage and adaptive responses in liver grafts. IRI and EAD are closely linked and share several common pathways. However, the underlying mechanisms remain largely unclear. Therapeutic interventions against EAD through the amelioration of IRI is a promising strategy, but most approaches are still in preclinical stages. To further study the mechanisms of EAD and promote collaborations between LT centers, optimized animal models and unified definitions of EAD are urgently needed. Because IRI and EAD are closely linked, more attention should be paid to the underlying mechanisms and the fundamental relationship between them. Ischemia/reperfusion-induced adaptive responses may play a crucial role in the prevention of EAD, and more preclinical studies and clinical trials are urgently needed to address the current limitation of available therapeutic interventions.
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Affiliation(s)
- Junbin Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Jian Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Qiang Wei
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Kourosh Saeb-Parsy
- Department of Surgery, University of Cambridge, Cambridge, United Kingdom.,Cambridge National Institute of Health Research Biomedical research Centre, Cambridge, United Kingdom
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
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Wang C, Li Y, Li H, Zhang Y, Ying Z, Wang X, Zhang T, Zhang W, Fan Z, Li X, Ma J, Pan X. Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells. Front Cell Dev Biol 2020; 8:601. [PMID: 32793588 PMCID: PMC7387415 DOI: 10.3389/fcell.2020.00601] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 06/19/2020] [Indexed: 12/11/2022] Open
Abstract
It is a well-documented event that fibroblast growth factors (FGFs) regulate liver development and homeostasis in autocrine, paracrine, and endocrine manners via binding and activating FGF receptors (FGFRs) tyrosine kinase in hepatocytes. Recent research reveals that hepatic stellate cells (HSCs) play a fundamental role in liver immunology. However, how FGF signaling in HSCs regulates liver inflammation remains unclear. Here, we report that FGF promoted NF-κB signaling, an inflammatory pathway, in human HSCs, which was associated with FGFR1 expression. Both FGF and NF-κB signaling in HSCs were compromised by FGFR1 tyrosine kinase inhibitor. After stimulating HSCs with proinflammatory cytokines, expression of multiple FGF ligands was significantly increased. However, disruption of FGF signaling with FGFR inhibitors prominently reduced the apoptosis, inflammatory response, NF-κB nuclear translocation, and expression of matrix metalloproteinase-9 (MMP-9) induced by TNFα in HSCs. Interestingly, FGF21 significantly alleviated the inflammation responses in the concanavalin A (Con A)-induced acutely injured liver. Unlike canonic FGFs that elicit signals through activating the FGFR–heparan sulfate complex, FGF21 activates the FGFR–KLB complex and elicits a different set of signals. Therefore, the finding here indicates the urgency of developing pathway-specific inhibitors that only suppress canonical FGF, but not non-canonical FGF21, signaling for alleviating inflammation in the liver, which is presented in all stages of diseased liver.
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Affiliation(s)
- Cong Wang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yuelong Li
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Hao Li
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yali Zhang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Zhangguo Ying
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xuye Wang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Tingting Zhang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Wenshu Zhang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Zhichao Fan
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xiaokun Li
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Jisheng Ma
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xuebo Pan
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
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Gandhi CR. Pro- and Anti-fibrogenic Functions of Gram-Negative Bacterial Lipopolysaccharide in the Liver. Front Med (Lausanne) 2020; 7:130. [PMID: 32373617 PMCID: PMC7186417 DOI: 10.3389/fmed.2020.00130] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 03/24/2020] [Indexed: 12/14/2022] Open
Abstract
Extensive research performed over several decades has identified cells participating in the initiation and progression of fibrosis, and the numerous underlying inter- and intra-cellular signaling pathways. However, liver fibrosis continues to be a major clinical challenge as the precise targets of treatment are still elusive. Activation of physiologically quiescent perisinusoidal hepatic stellate cells (HSCs) to a myofibroblastic proliferating, contractile and fibrogenic phenotype is a critical event in the pathogenesis of chronic liver disease. Thus, elucidation of the mechanisms of the reversal to quiescence or inhibition of activated HSCs, and/or their elimination via apoptosis has been the focus of intense investigation. Lipopolysaccharide (LPS), a gut-resident Gram-negative bacterial endotoxin, is a powerful pro-inflammatory molecule implicated in hepatic injury, inflammation and fibrosis. In both acute and chronic liver injury, portal venous levels of LPS are elevated due to increased intestinal permeability. LPS, via CD14 and Toll-like receptor 4 (TLR4) and its adapter molecules, stimulates macrophages, neutrophils and several other cell types to produce inflammatory mediators as well as factors that can activate HSCs and stimulate their fibrogenic activity. LPS also stimulates synthesis of pro- and anti-inflammatory cytokines/chemokines, growth mediators and molecules of immune regulation by HSCs. However, LPS was found to arrest proliferation of activated HSCs and to convert them into non-fibrogenic phenotype. Interestingly, LPS can elicit responses in HSCs independent of CD14 and TLR4. Identifying and/or developing non-inflammatory but anti-fibrogenic mimetics of LPS could be relevant for treating liver fibrosis.
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Affiliation(s)
- Chandrashekhar R Gandhi
- Divisions of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Cincinnati VA Medical Center, Cincinnati, OH, United States
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Czigany Z, Lurje I, Schmelzle M, Schöning W, Öllinger R, Raschzok N, Sauer IM, Tacke F, Strnad P, Trautwein C, Neumann UP, Fronek J, Mehrabi A, Pratschke J, Schlegel A, Lurje G. Ischemia-Reperfusion Injury in Marginal Liver Grafts and the Role of Hypothermic Machine Perfusion: Molecular Mechanisms and Clinical Implications. J Clin Med 2020; 9:E846. [PMID: 32244972 PMCID: PMC7141496 DOI: 10.3390/jcm9030846] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/09/2020] [Accepted: 03/11/2020] [Indexed: 12/19/2022] Open
Abstract
Ischemia-reperfusion injury (IRI) constitutes a significant source of morbidity and mortality after orthotopic liver transplantation (OLT). The allograft is metabolically impaired during warm and cold ischemia and is further damaged by a paradox reperfusion injury after revascularization and reoxygenation. Short-term and long-term complications including post-reperfusion syndrome, delayed graft function, and immune activation have been associated with IRI. Due to the current critical organ shortage, extended criteria grafts are increasingly considered for transplantation, however, with an elevated risk to develop significant features of IRI. In recent years, ex vivo machine perfusion (MP) of the donor liver has witnessed significant advancements. Here, we describe the concept of hypothermic (oxygenated) machine perfusion (HMP/HOPE) approaches and highlight which allografts may benefit from this technology. This review also summarizes clinical applications and the main aspects of ongoing randomized controlled trials on hypothermic perfusion. The mechanistic aspects of IRI and hypothermic MP-which include tissue energy replenishment, optimization of mitochondrial function, and the reduction of oxidative and inflammatory damage following reperfusion-will be comprehensively discussed within the context of current preclinical and clinical evidence. Finally, we highlight novel trends and future perspectives in the field of hypothermic MP in the context of recent findings of basic and translational research.
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Affiliation(s)
- Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (Z.C.); (U.P.N.)
| | - Isabella Lurje
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Moritz Schmelzle
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Wenzel Schöning
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Robert Öllinger
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Nathanael Raschzok
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Igor M. Sauer
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
| | - Pavel Strnad
- Department of Gastroenterology, Metabolic Disorders and Intensive Care, University Hospital RWTH Aachen, 52074 Aachen, Germany; (P.S.); (C.T.)
| | - Christian Trautwein
- Department of Gastroenterology, Metabolic Disorders and Intensive Care, University Hospital RWTH Aachen, 52074 Aachen, Germany; (P.S.); (C.T.)
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (Z.C.); (U.P.N.)
| | - Jiri Fronek
- Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic;
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany;
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Andrea Schlegel
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, UK;
| | - Georg Lurje
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (Z.C.); (U.P.N.)
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
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Cell release during perfusion reflects cold ischemic injury in rat livers. Sci Rep 2020; 10:1102. [PMID: 31980677 PMCID: PMC6981218 DOI: 10.1038/s41598-020-57589-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 12/28/2019] [Indexed: 12/13/2022] Open
Abstract
The global shortage of donor organs has made it crucial to deeply understand and better predict donor liver viability. However, biomarkers that effectively assess viability of marginal grafts for organ transplantation are currently lacking. Here, we showed that hepatocytes, sinusoidal endothelial, stellate, and liver-specific immune cells were released into perfusates from Lewis rat livers as a result of cold ischemia and machine perfusion. Perfusate comparison analysis of fresh livers and cold ischemic livers showed that the released cell profiles were significantly altered by the duration of cold ischemia. Our findings show for the first time that parenchymal cells are released from organs under non-proliferative pathological conditions, correlating with the degree of ischemic injury. Thus, perfusate cell profiles could serve as potential biomarkers of graft viability and indicators of specific injury mechanisms during organ handling and transplantation. Further, parenchymal cell release may have applications in other pathological conditions beyond organ transplantation.
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Buchwald JE, Xu J, Bozorgzadeh A, Martins PN. Therapeutics administered during ex vivo liver machine perfusion: An overview. World J Transplant 2020; 10:1-14. [PMID: 32110510 PMCID: PMC7031625 DOI: 10.5500/wjt.v10.i1.1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 10/26/2019] [Accepted: 12/06/2019] [Indexed: 02/06/2023] Open
Abstract
Although the use of extended criteria donors has increased the pool of available livers for transplant, it has also introduced the need to develop improved methods of protection against ischemia-reperfusion injury (IRI), as these "marginal" organs are particularly vulnerable to IRI during the process of procurement, preservation, surgery, and post-transplantation. In this review, we explore the current basic science research investigating therapeutics administered during ex vivo liver machine perfusion aimed at mitigating the effects of IRI in the liver transplantation process. These various categories of therapeutics are utilized during the perfusion process and include invoking the RNA interference pathway, utilizing defatting cocktails, and administering classes of agents such as vasodilators, anti-inflammatory drugs, human liver stem cell-derived extracellular vesicles, and δ-opioid agonists in order to reduce the damage of IRI. Ex vivo machine perfusion is an attractive alternative to static cold storage due to its ability to continuously perfuse the organ, effectively deliver substrates and oxygen required for cellular metabolism, therapeutically administer pharmacological or cytoprotective agents, and continuously monitor organ viability during perfusion. The use of administered therapeutics during machine liver perfusion has demonstrated promising results in basic science studies. While novel therapeutic approaches to combat IRI are being developed through basic science research, their use in clinical medicine and treatment in patients for liver transplantation has yet to be explored.
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Affiliation(s)
- Julianna E Buchwald
- Division of Transplantation, Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01655, United States
| | - Jing Xu
- Division of Transplantation, Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01655, United States
| | - Adel Bozorgzadeh
- Division of Transplantation, Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01655, United States
| | - Paulo N Martins
- Division of Transplantation, Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01655, United States
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da Silva Meirelles L, Marson RF, Solari MIG, Nardi NB. Are Liver Pericytes Just Precursors of Myofibroblasts in Hepatic Diseases? Insights from the Crosstalk between Perivascular and Inflammatory Cells in Liver Injury and Repair. Cells 2020; 9:cells9010188. [PMID: 31940814 PMCID: PMC7017158 DOI: 10.3390/cells9010188] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 12/31/2019] [Accepted: 01/08/2020] [Indexed: 12/13/2022] Open
Abstract
Cirrhosis, a late form of liver disease, is characterized by extensive scarring due to exacerbated secretion of extracellular matrix proteins by myofibroblasts that develop during this process. These myofibroblasts arise mainly from hepatic stellate cells (HSCs), liver-specific pericytes that become activated at the onset of liver injury. Consequently, HSCs tend to be viewed mainly as myofibroblast precursors in a fibrotic process driven by inflammation. Here, the molecular interactions between liver pericytes and inflammatory cells such as macrophages and neutrophils at the first moments after injury and during the healing process are brought into focus. Data on HSCs and pericytes from other tissues indicate that these cells are able to sense pathogen- and damage-associated molecular patterns and have an important proinflammatory role in the initial stages of liver injury. On the other hand, further data suggest that as the healing process evolves, activated HSCs play a role in skewing the initial proinflammatory (M1) macrophage polarization by contributing to the emergence of alternatively activated, pro-regenerative (M2-like) macrophages. Finally, data suggesting that some HSCs activated during liver injury could behave as hepatic progenitor or stem cells will be discussed.
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Affiliation(s)
- Lindolfo da Silva Meirelles
- PPGBioSaúde and School of Medicine, Lutheran University of Brazil, Av. Farroupilha 8001, 92425-900 Canoas, RS, Brazil
| | - Renan Fava Marson
- PPGBioSaúde, Lutheran University of Brazil, Av. Farroupilha 8001, 92425-900 Canoas, RS, Brazil
| | - Maria Inês Gonzalez Solari
- Institute of Cardiology of Rio Grande do Sul, Av Princesa Isabel 370, 90620-001 Porto Alegre, RS, Brazil
| | - Nance Beyer Nardi
- Institute of Cardiology of Rio Grande do Sul, Av Princesa Isabel 370, 90620-001 Porto Alegre, RS, Brazil
- Correspondence: ; Tel.: +55-51-3230-3600
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Zhou M, Yoshikawa K, Akashi H, Miura M, Suzuki R, Li TS, Abe H, Bando Y. Localization of ATP-sensitive K + channel subunits in rat liver. World J Exp Med 2019; 9:14-31. [PMID: 31938690 PMCID: PMC6955576 DOI: 10.5493/wjem.v9.i2.14] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 09/05/2019] [Accepted: 11/21/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND ATP-sensitive K+ (KATP) channels were originally found in cardiac myocytes by Noma in 1983. KATP channels were formed by potassium ion-passing pore-forming subunits (Kir6.1, Kir6.2) and regulatory subunits SUR1, SU2A and SUR2B. A number of cells and tissues have been revealed to contain these channels including hepatocytes, but detailed localization of these subunits in different types of liver cells was still uncertain.
AIM To investigate the expression of KATP channel subunits in rat liver and their localization in different cells of the liver.
METHODS Rabbit anti-rat SUR1 peptide antibody was raised and purified by antigen immunoaffinity column chromatography. Four of Sprague-Dawley rats were used for liver protein extraction for immunoblot analysis, seven of them were used for immunohistochemistry both for the ABC method and immunofluorescence staining. Four of Wistar rats were used for the isolation of hepatic stellate cells (HSCs) and Kupffer cells for both primary culture and immunocytochemistry.
RESULTS Immunoblot analysis showed that the five kinds of KATP channel subunits, i.e. Kir6.1, Kir6.2, SUR1, SUR2A, and SUR2B, were detected in liver. Immunohistochemical staining showed that Kir6.1 and Kir6.2 were weakly to moderately expressed in parenchymal cells and sinusoidal lining cells, while SUR1, SUR2A, and SUR2B were mainly localized to sinusoidal lining cells, such as HSCs, Kupffer cells, and sinusoidal endothelial cells. Immunoreactivity for SUR2A and SUR2B was expressed in the hepatocyte membrane. Double immunofluorescence staining further showed that the pore-forming subunits Kir6.1 and/or Kir6.2 colocalized with GFAP in rat liver sections and primary cultured HSCs. These KATP channel subunits also colocalized with CD68 in liver sections and primary cultured Kupffer cells. The SUR subunits colocalized with GFAP in liver sections and colocalized with CD68 both in liver sections and primary cultured Kupffer cells. In addition, five KATP channel subunits colocalized with SE-1 in sinusoidal endothelial cells.
CONCLUSION Observations from the present study indicated that KATP channel subunits expressed in rat liver and the diversity of KATP channel subunit composition might form different types of KATP channels. This is applicable to hepatocytes, HSCs, various types of Kupffer cells and sinusoidal endothelial cells.
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Affiliation(s)
- Ming Zhou
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Kiwamu Yoshikawa
- Department of Cell Biology and Morphology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Hideo Akashi
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Mitsutaka Miura
- Department of Cell Biology and Morphology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Ryoji Suzuki
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Tao-Sheng Li
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan
| | - Hiroshi Abe
- TRUST, A Long-Term Care Health Facility, Sendai 980-0011, Japan
| | - Yoshio Bando
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
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Takahashi T, Yoshioka M, Uchinami H, Nakagawa Y, Otsuka N, Motoyama S, Yamamoto Y. Hepatic Stellate Cells Play a Functional Role in Exacerbating Ischemia-Reperfusion Injury in Rat Liver. Eur Surg Res 2019; 60:74-85. [PMID: 31132769 DOI: 10.1159/000499750] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 03/20/2019] [Indexed: 11/19/2022]
Abstract
PURPOSE The involvement of hepatic stellate cells (HSCs) with ischemia-reperfusion (I/R) injury in rat liver was examined using gliotoxin, which is known to induce HSC apoptosis. METHODS Male Sprague-Dawley rats were used. HSC was represented by a glial fibrillary acidic protein (GFAP)-positive cell. Liver ischemia was produced by cross-clamping the hepatoduodenal ligament. The degree of I/R injury was evaluated by a release of aminotransferases. Sinusoidal diameter and sinusoidal perfusion rates were examined using intravital fluorescence microscopy. RESULTS Gliotoxin significantly decreased the number of GFAP-positive cells 48 h after dosing (2.50 ± 0.19% [mean ± SD] in the nontreated group vs. 1.91 ± 0.46% in the gliotoxin-treated group). Liver damage was significantly suppressed by the pretreatment with gliotoxin. Sinusoidal diameters in zone 3 were wider in the gliotoxin group (10.25 ± 0.35 µm) than in the nontreated group (8.21 ± 0.50 µm). The sinusoidal perfusion rate was maintained as well in the gliotoxin group as in normal livers, even after I/R. CONCLUSIONS Pretreatment with gliotoxin significantly reduced the number of HSCs in the liver and further suppressed liver injury following I/R. It is strongly suggested that HSCs play a functional role in exacerbating the degree of I/R injury of the liver.
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Affiliation(s)
- Tomokazu Takahashi
- Department of Gastroenterological Surgery, Akita University Graduate School of Medicine, Akita, Japan
| | - Masato Yoshioka
- Department of Gastroenterological Surgery, Akita University Graduate School of Medicine, Akita, Japan,
| | - Hiroshi Uchinami
- Department of Gastroenterological Surgery, Akita University Graduate School of Medicine, Akita, Japan
| | - Yasuhiko Nakagawa
- Department of Gastroenterological Surgery, Akita University Graduate School of Medicine, Akita, Japan
| | - Naohiko Otsuka
- Department of Gastroenterological Surgery, Akita University Graduate School of Medicine, Akita, Japan
| | - Satoru Motoyama
- Department of Comprehensive Cancer Control, Akita University Graduate School of Medicine, Akita, Japan
| | - Yuzo Yamamoto
- Department of Gastroenterological Surgery, Akita University Graduate School of Medicine, Akita, Japan
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Li J, Zhao YR, Tian Z. Roles of hepatic stellate cells in acute liver failure: From the perspective of inflammation and fibrosis. World J Hepatol 2019; 11:412-420. [PMID: 31183002 PMCID: PMC6547291 DOI: 10.4254/wjh.v11.i5.412] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 05/14/2019] [Accepted: 05/21/2019] [Indexed: 02/06/2023] Open
Abstract
Acute liver failure (ALF) usually results in hepatocellular dysfunction and coagulopathy and carries a high mortality rate. Hepatic stellate cells (HSCs) are famous for their role in liver fibrosis. Although some recent studies revealed that HSCs might participate in the pathogenesis of ALF, the accurate mechanism is still not fully understood. This review focuses on the recent advances in understanding the functions of HSCs in ALF and revealed both protective and promotive roles during the pathogenesis of ALF: HSC activation participates in the maintenance of cell attachment and the architecture of liver tissue via extracellular matrix production and assists liver regeneration by producing growth factors; and HSC inflammation plays a role in relaying inflammation signaling from sinusoids to parenchyma via secretion of inflammatory cytokines. A better understanding of roles of HSCs in the pathogenesis of ALF may lead to improvements and novel strategies for treating ALF patients.
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Affiliation(s)
- Juan Li
- Department of Infectious Diseases, Institute of Hepatology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Ying-Ren Zhao
- Department of Infectious Diseases, Institute of Hepatology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Zhen Tian
- Department of Infectious Diseases, Institute of Hepatology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
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