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Nachmany I, Nevo S, Edelheit S, Sarusi-Portuguez A, Friedlander G, Salame TM, Pavlov V, Yakubovsky O, Pencovich N. Myeloid derived suppressor cells mediate hepatocyte proliferation and immune suppression during liver regeneration following resection. Genes Immun 2024; 25:483-491. [PMID: 39488626 DOI: 10.1038/s41435-024-00303-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 10/06/2024] [Accepted: 10/22/2024] [Indexed: 11/04/2024]
Abstract
Liver regeneration following resection is a complex process relying on coordinated pathways and cell types in the remnant organ. Myeloid-Derived Suppressor Cells (MDSCs) have a role in liver regeneration-related angiogenesis but other roles they may play in this process remain to be elucidated. In this study, we sought to examine the effect of G-MDSCs on hepatocytes proliferation and immune modulation during liver regeneration. Global gene expression profiling of regenerating hepatocytes in mice with CD11b+Ly6G+ MDSCs (G-MDSCs) depletion revealed disrupted transcriptional progression from day one to day two after major liver resection. Key genes and pathways related to hepatocyte proliferation and immune response were differentially expressed upon MDSC depletion. Hepatocytes cellularity increased when co-cultured with G-MDSCs, or treated with amphiregulin, which G-MDSCs upregulate during regeneration. Cytometry by time-of-flight (CyTOF) analysis of the intra-liver immune milieu upon MDSC depletion during regeneration demonstrated increased natural killer cell proportions, alongside changes in other immune cell populations. Taken together, these results provide evidence that MDSCs contribute to early liver regeneration by promoting hepatocyte proliferation and modulating the intra-liver immune response, and illuminate the multifaceted role of MDSCs in liver regeneration.
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Affiliation(s)
- Ido Nachmany
- The Laboratory of Molecular Biology, Department of Surgery and Transplantation, Sheba Medical Center, Tel-Hashomer, Faculty of Medicine and Medical Sciences, Tel-Aviv University, Tel-Aviv, Israel
| | - Shir Nevo
- The Laboratory of Molecular Biology, Department of Surgery and Transplantation, Sheba Medical Center, Tel-Hashomer, Faculty of Medicine and Medical Sciences, Tel-Aviv University, Tel-Aviv, Israel
| | - Sarit Edelheit
- The Laboratory of Molecular Biology, Department of Surgery and Transplantation, Sheba Medical Center, Tel-Hashomer, Faculty of Medicine and Medical Sciences, Tel-Aviv University, Tel-Aviv, Israel
| | - Avital Sarusi-Portuguez
- The Mantoux Bioinformatics institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Gilgi Friedlander
- The Mantoux Bioinformatics institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Tomer-Meir Salame
- Mass Cytometry Unit, Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - Vera Pavlov
- The Laboratory of Molecular Biology, Department of Surgery and Transplantation, Sheba Medical Center, Tel-Hashomer, Faculty of Medicine and Medical Sciences, Tel-Aviv University, Tel-Aviv, Israel
| | - Oran Yakubovsky
- The Laboratory of Molecular Biology, Department of Surgery and Transplantation, Sheba Medical Center, Tel-Hashomer, Faculty of Medicine and Medical Sciences, Tel-Aviv University, Tel-Aviv, Israel
| | - Niv Pencovich
- The Laboratory of Molecular Biology, Department of Surgery and Transplantation, Sheba Medical Center, Tel-Hashomer, Faculty of Medicine and Medical Sciences, Tel-Aviv University, Tel-Aviv, Israel.
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Wang Q, Long Z, Zhu F, Li H, Xiang Z, Liang H, Wu Y, Dai X, Zhu Z. Integrated analysis of lncRNA/circRNA-miRNA-mRNA in the proliferative phase of liver regeneration in mice with liver fibrosis. BMC Genomics 2023; 24:417. [PMID: 37488484 PMCID: PMC10364436 DOI: 10.1186/s12864-023-09478-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 06/22/2023] [Indexed: 07/26/2023] Open
Abstract
BACKGROUND Non-coding RNAs play important roles in liver regeneration; however, their functions and mechanisms of action in the regeneration of fibrotic liver have not been elucidated. We aimed to clarify the expression patterns and regulatory functions of lncRNAs, circRNAs, miRNAs, and mRNAs in the proliferative phase of fibrotic liver regeneration. METHODS Based on a mouse model of liver fibrosis with 70% hepatectomy, whole-transcriptome profiling was performed using high-throughput sequencing on samples collected at 0, 12, 24, 48, and 72 h after hepatectomy. Hub genes were selected by weighted gene co-expression network analysis and subjected to enrichment analysis. Integrated analysis was performed to reveal the interactions of differentially expressed (DE) lncRNAs, circRNAs, miRNAs, and mRNAs, and to construct lncRNA-mRNA cis- and trans-regulatory networks and lncRNA/circRNA-miRNA-mRNA ceRNA regulatory networks. Real-Time quantitative PCR was used to validate part of the ceRNA network. RESULTS A total of 1,329 lncRNAs, 48 circRNAs, 167 miRNAs, and 6,458 mRNAs were differentially expressed, including 812 hub genes. Based on these DE RNAs, we examined several mechanisms of ncRNA regulatory networks, including lncRNA cis and trans interactions, circRNA parental genes, and ceRNA pathways. We constructed a cis-regulatory core network consisting of 64 lncRNA-mRNA pairs (53 DE lncRNAs and 58 hub genes), a trans-regulatory core network consisting of 103 lncRNA-mRNA pairs (18 DE lncRNAs and 85 hub genes), a lncRNA-miRNA-mRNA ceRNA core regulatory network (20 DE lncRNAs, 12 DE miRNAs, and 33 mRNAs), and a circRNA-miRNA-mRNA ceRNA core regulatory network (5 DE circRNAs, 5 DE miRNAs, and 39 mRNAs). CONCLUSIONS These results reveal the expression patterns of lncRNAs, circRNAs, miRNAs, and mRNAs in the proliferative phase of fibrotic liver regeneration, as well as core regulatory networks of mRNAs and non-coding RNAs underlying liver regeneration. The findings provide insights into molecular mechanisms that may be useful in developing new therapeutic approaches to ameliorate diseases that are characterized by liver fibrosis, which would be beneficial for the prevention of liver failure and treatment of liver cancer.
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Affiliation(s)
- Qian Wang
- The First Affiliated Hospital, Department of Reproductive Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Zhangtao Long
- The First Affiliated Hospital, Department of Hepatobiliary Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Fengfeng Zhu
- The First Affiliated Hospital, Department of Hepatobiliary Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Huajian Li
- The First Affiliated Hospital, Department of Hepatobiliary Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Zhiqiang Xiang
- The First Affiliated Hospital, Department of Hepatobiliary Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Hao Liang
- The First Affiliated Hospital, Department of Hepatobiliary Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Yachen Wu
- The First Affiliated Hospital, Department of Hepatobiliary Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xiaoming Dai
- The First Affiliated Hospital, Department of Hepatobiliary Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| | - Zhu Zhu
- The First Affiliated Hospital, Department of Hepatobiliary Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
- The First Affiliated Hospital, Department of Education and Training, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
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Liu Z, Zhu H, Wang W, Xu J, Que S, Zhuang L, Qian J, Wang S, Yu J, Zhang F, Yin S, Xie H, Zhou L, Geng L, Zheng S. Metabonomic Profile of Macrosteatotic Allografts for Orthotopic Liver Transplantation in Patients With Initial Poor Function: Mechanistic Investigation and Prognostic Prediction. Front Cell Dev Biol 2020; 8:826. [PMID: 32984324 PMCID: PMC7484052 DOI: 10.3389/fcell.2020.00826] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 08/03/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Our previous study revealled amplified hazardous effects of macrosteatosis (MaS) on graft failure (GF) in recipients with severe liver damage in short post-operative days, with vague mechanism inside. AIM We aimed to uncover the molecular mechanism of donor MaS on GF, and construct the predictive model to monitor post-transplant prognosis based on "omics" perspective. METHODS Ultra-performance liquid chromatography coupled to mass spectrometry metabolomic analysis was performed in allograft tissues from 82 patients with initial poor function (IPF) from multi-liver transplant (LT) centers. Pathway analysis was performed by on-line toolkit Metaboanalyst (v 3.0). Predictive model was constructed based on combinative metabonomic and clinical data extracted by stepwised cox proportional analysis. RESULTS Principle component analysis (PCA) analysis revealled stratification on metabolic feature in organs classified by MaS status. Differential metabolits both associated with MaS and GF were significantly enriched on pathway of glycerophospholipid metabolism (P < 0.05). Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) involved in glycerophospholipid metabolism was significantly decreased in cases with MaS donors and GF (P < 0.05). Better prediction was observed on graft survival by combinative model (area under the curve = 0.91) and confirmed by internal validation. CONCLUSION Metabonomic features of allografts can be clearly distinguished by MaS status in patients with IPF. Dysfunction on glycerophospholipid metabolism was culprit to link donor MaS and final GF. Decrement on PC and PE exerted the fatal effects of MaS on organ failure. Metabonomic data might help for monitoring long-term graft survival after LT.
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Affiliation(s)
- Zhengtao Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Hai Zhu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wenchao Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jun Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | | | - Li Zhuang
- Shulan Hospital (Hangzhou), Hangzhou, China
| | - Junjie Qian
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shuai Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jian Yu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Feng Zhang
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shengyong Yin
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Haiyang Xie
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lei Geng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Organ Transplantation, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Shulan Hospital (Hangzhou), Hangzhou, China
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Jia JJ, Xie HY, Li JH, He Y, Jiang L, He N, Zhou L, Wang W, Zheng SS. Graft protection of the liver by hypothermic machine perfusion involves recovery of graft regeneration in rats. J Int Med Res 2019; 47:427-437. [PMID: 30791830 PMCID: PMC6384453 DOI: 10.1177/0300060518787726] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Objective This study was performed to evaluate the impact and underlying mechanisms of hypothermic machine perfusion (HMP) on half-size liver graft regeneration. Methods Forty rats were randomly assigned to five groups: two in vitro groups (static cold storage [SCS] and HMP) and three in vivo groups (orthotopic liver transplantation, SCS, and HMP). Perfusates and plasma samples were collected for analysis of hepatic enzymes. Liver tissue was obtained for evaluation of histology, immunohistochemistry (Ki67 and proliferating cell nuclear antigen [PCNA]), and the regeneration rate. Cell cycle genes were analyzed by quantitative real-time polymerase chain reaction, and cyclin D1 and cyclin E1 were semiquantified by western blot. Results HMP improved histopathological outcomes and decreased hepatic enzyme release. The expression of Ki67 and PCNA demonstrated a greater proliferation activity in the HMP than SCS group, and the expression of almost all cell cycle genes was elevated following HMP. Western blot results showed higher protein levels of cyclin D1 and cyclin E1 in the HMP than SCS group. Conclusions Our findings suggest for the first time that half-size liver graft protection by HMP involves recovery of graft regeneration.
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Affiliation(s)
- Jun-Jun Jia
- 1 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,*These authors contributed equally to this work
| | - Hai-Yang Xie
- 1 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,2 Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China.,3 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.,*These authors contributed equally to this work
| | - Jian-Hui Li
- 1 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yong He
- 1 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Li Jiang
- 1 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ning He
- 1 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,2 Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China
| | - Lin Zhou
- 1 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,2 Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China.,3 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Weilin Wang
- 1 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,2 Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China.,3 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Shu-Sen Zheng
- 1 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,2 Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China.,3 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
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Partial Inhibition of HO-1 Attenuates HMP-Induced Hepatic Regeneration against Liver Injury in Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:9108483. [PMID: 29849924 PMCID: PMC5925174 DOI: 10.1155/2018/9108483] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Accepted: 02/21/2018] [Indexed: 01/06/2023]
Abstract
We found better liver graft regeneration with hypothermic machine perfusion (HMP) compared with static cold storage (SCS) for the first time in our pilot study, but the underlying mechanisms are unknown. Upregulated heme oxygenase- (HO-) 1 expression has been reported to play a pivotal role in promoting hepatocyte proliferation. Here, we evaluated the novel role of HO-1 in liver graft protection by HMP. Rats with a heterozygous knockout of HO-1 (HO-1+/-) were generated and subjected to 3 h of SCS or HMP pre-half-size liver transplantation (HSLT) in vivo or 6 h of SCS or HMP in vitro; control rats were subjected to the same conditions (HO-1+/+). We found that HSLT induced significant elevation of the HO-1 protein level in the regenerated liver and that HO-1 haplodeficiency resulted in decreased proliferation post-HSLT. Compared with SCS, HMP induced significant elevation of the HO-1 protein level along with better liver recovery, both of which were reduced by HO-1 haplodeficiency. HO-1 haplodeficiency-induced decreased proliferation was responsible for the attenuated regenerative ability of HMP. Mechanistically, HO-1 haploinsufficiency resulted in suppression of hepatocyte growth factor (HGF)/Akt activity. Our results suggest that inhibition of HO-1 mitigates HMP-induced liver recovery effects related to proliferation, in part, by downregulating the HGF-Akt axis.
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Mikiewicz M, Otrocka-Domagała I, Paździor-Czapula K, Rotkiewicz T. Influence of long-term, high-dose dexamethasone administration on proliferation and apoptosis in porcine hepatocytes. Res Vet Sci 2017; 112:141-148. [PMID: 28391056 DOI: 10.1016/j.rvsc.2017.03.018] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 03/20/2017] [Accepted: 03/29/2017] [Indexed: 10/25/2022]
Abstract
The aim of this study was to examine the influence of long-term, high-dose dexamethasone administration on the liver, with particular emphasis on hepatocyte proliferation and apoptosis, using a swine model. The study included 48 large, female Polish breed pigs aged 3months (weighing ca. 30kg) divided into groups I (control; n=24) and II (dexamethasone; n=24) that receiving intra-muscular injections of monosodium phosphate dexamethasone for 29days. The pigs were euthanized on days subsequent to the experiment. Immediately after the euthanasia, the pig livers were sampled, fixed, and processed routinely for histopathology, histochemistry, and immunohistochemistry (for proliferating cell nuclear antigen, Bcl-2, and caspase-3). Apoptosis was visualized by terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL). Dexamethasone administration gradually caused hepatocyte glycogen degeneration and finally lipid degeneration, accompanied by sinusoid and central vein dilatation and nuclear chromatin condensation. The proliferating cell nuclear antigen index, mean number of argyrophilic nucleolar organizer regions and proliferation index of argyrophilic nucleolar organizer regions were lower, while Bcl-2 expression was higher in group II compared with group I. The results from this study suggest that safe high-dose dexamethasone administration time is difficult to establish. Long-term, high-dose dexamethasone administration can cause pronounced morphological changes in hepatocytes by diminishing their transcriptional and proliferation activity but also protects them from apoptosis by potentially affecting Bcl-2 expression.
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Affiliation(s)
- Mateusz Mikiewicz
- Department of Pathological Anatomy, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland.
| | - Iwona Otrocka-Domagała
- Department of Pathological Anatomy, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Katarzyna Paździor-Czapula
- Department of Pathological Anatomy, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Tadeusz Rotkiewicz
- Department of Pathological Anatomy, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
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de Jonge J, Olthoff KM. Liver regeneration. BLUMGART'S SURGERY OF THE LIVER, BILIARY TRACT AND PANCREAS, 2-VOLUME SET 2017:93-109.e7. [DOI: 10.1016/b978-0-323-34062-5.00006-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Jorns C, Nowak G, Nemeth A, Zemack H, Mörk L, Johansson H, Gramignoli R, Watanabe M, Karadagi A, Alheim M, Hauzenberger D, van Dijk R, Bosma PJ, Ebbesen F, Szakos A, Fischler B, Strom S, Ellis E, Ericzon B. De Novo Donor-Specific HLA Antibody Formation in Two Patients With Crigler-Najjar Syndrome Type I Following Human Hepatocyte Transplantation With Partial Hepatectomy Preconditioning. Am J Transplant 2016; 16:1021-30. [PMID: 26523372 PMCID: PMC5061095 DOI: 10.1111/ajt.13487] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 08/05/2015] [Accepted: 08/06/2015] [Indexed: 01/25/2023]
Abstract
Clinical hepatocyte transplantation is hampered by low engraftment rates and gradual loss of function resulting in incomplete correction of the underlying disease. Preconditioning with partial hepatectomy improves engraftment in animal studies. Our aim was to study safety and efficacy of partial hepatectomy preconditioning in clinical hepatocyte transplantation. Two patients with Crigler-Najjar syndrome type I underwent liver resection followed by hepatocyte transplantation. A transient increase of hepatocyte growth factor was seen, suggesting that this procedure provides a regenerative stimulus. Serum bilirubin was decreased by 50%, and presence of bilirubin glucuronides in bile confirmed graft function in both cases; however, graft function was lost due to discontinuation of immunosuppressive therapy in one patient. In the other patient, serum bilirubin gradually increased to pretransplant concentrations after ≈600 days. In both cases, loss of graft function was temporally associated with emergence of human leukocyte antigen donor-specific antibodies (DSAs). In conclusion, partial hepatectomy in combination with hepatocyte transplantation was safe and induced a robust release of hepatocyte growth factor, but its efficacy on hepatocyte engraftment needs to be evaluated with additional studies. To our knowledge, this study provides the first description of de novo DSAs after hepatocyte transplantation associated with graft loss.
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Affiliation(s)
- C. Jorns
- Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Transplantation Surgery, Karolinska InstituteKarolinska University Hospital HuddingeStockholmSweden
| | - G. Nowak
- Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Transplantation Surgery, Karolinska InstituteKarolinska University Hospital HuddingeStockholmSweden
| | - A. Nemeth
- Division of Pediatrics, Karolinska InstituteKarolinska University Hospital HuddingeStockholmSweden
| | - H. Zemack
- Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Transplantation Surgery, Karolinska InstituteKarolinska University Hospital HuddingeStockholmSweden
| | - L.‐M. Mörk
- Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Transplantation Surgery, Karolinska InstituteKarolinska University Hospital HuddingeStockholmSweden
| | - H. Johansson
- Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Transplantation Surgery, Karolinska InstituteKarolinska University Hospital HuddingeStockholmSweden
| | - R. Gramignoli
- Department of Laboratory Medicine, Division of Pathology, Karolinska InstituteKarolinska University Hospital HuddingeStockholmSweden
| | - M. Watanabe
- Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Transplantation Surgery, Karolinska InstituteKarolinska University Hospital HuddingeStockholmSweden
| | - A. Karadagi
- Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Transplantation Surgery, Karolinska InstituteKarolinska University Hospital HuddingeStockholmSweden
| | - M. Alheim
- Division of Clinical Immunology and Transfusion, Karolinska InstituteKarolinska University Hospital HuddingeStockholmSweden
| | - D. Hauzenberger
- Division of Clinical Immunology and Transfusion, Karolinska InstituteKarolinska University Hospital HuddingeStockholmSweden
| | - R. van Dijk
- Tytgat Institute for Liver and Intestinal ResearchAcademic Medical CenterAmsterdamThe Netherlands
| | - P. J. Bosma
- Tytgat Institute for Liver and Intestinal ResearchAcademic Medical CenterAmsterdamThe Netherlands
| | - F. Ebbesen
- Department of PediatricsAalborg University HospitalAalborgDenmark
| | - A. Szakos
- Department of Laboratory Medicine, Division of Pathology, Karolinska InstituteKarolinska University Hospital HuddingeStockholmSweden
| | - B. Fischler
- Division of Pediatrics, Karolinska InstituteKarolinska University Hospital HuddingeStockholmSweden
| | - S. Strom
- Department of Laboratory Medicine, Division of Pathology, Karolinska InstituteKarolinska University Hospital HuddingeStockholmSweden
| | - E. Ellis
- Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Transplantation Surgery, Karolinska InstituteKarolinska University Hospital HuddingeStockholmSweden
| | - B.‐G. Ericzon
- Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Transplantation Surgery, Karolinska InstituteKarolinska University Hospital HuddingeStockholmSweden
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Hashmi SK, Baranov E, Gonzalez A, Olthoff K, Shaked A. Genomics of liver transplant injury and regeneration. Transplant Rev (Orlando) 2014; 29:23-32. [PMID: 24746681 DOI: 10.1016/j.trre.2014.01.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Accepted: 01/19/2014] [Indexed: 12/21/2022]
Abstract
While improved surgical techniques, post-operative care, and immunosuppression regimens have reduced morbidity and mortality associated with orthotopic liver transplantation (OLT), further improvement of outcomes requires personalized treatment and a better understanding of genomic mechanisms involved. Gene expression profiles of ischemia/reperfusion (I/R) injury, regeneration, and rejection, may suggest mechanisms for development of better predictive tools and treatments. The liver is unique in its regenerative potential, recovering lost mass and function after injury from ischemia, resection, and rejection. I/R injury, an inevitable consequence of perfusion cessation, cold storage, and reperfusion, is regulated by the interaction of the immune system, inflammatory cytokines, and reduced microcirculatory blood flow in the liver. Rejection, a common post-operative complication, is mediated by the recipient's immune system through T-cell-dependent responses activating proinflammatory and apoptotic pathways. Characterizing distinctive gene expression signatures for these events can identify therapies to reduce injury, promote regeneration, and improve outcomes. While certain markers of liver injury and regeneration have been observed in animals, many of these are unverified in human studies. Further investigation of these genomic signatures and mechanisms through new technology offers promise, but continues to pose a significant challenge. An overview of the current fund of knowledge in this area is reviewed.
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Affiliation(s)
- Sohaib Khalid Hashmi
- Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Esther Baranov
- Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Ana Gonzalez
- Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Kim Olthoff
- Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
| | - Abraham Shaked
- Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
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10
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Ramirez CB, Doria C, Frank AM, Armenti ST, Marino IR. Completely steroid-free immunosuppression in liver transplantation: a randomized study. Clin Transplant 2013; 27:463-71. [PMID: 23621629 DOI: 10.1111/ctr.12119] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2013] [Indexed: 01/11/2023]
Abstract
INTRODUCTION Corticosteroids (CS) have been standard immunosuppression to prevent and treat rejection. However, CS are associated with increased risk of infection, obesity, hypertension, hyperlipidemia, diabetes, and accelerated hepatitis C virus (HCV) recurrence post-orthotopic liver transplantation (OLT). This study assesses the safety and efficacy of CS-free immunosuppressive regimen in adult OLT. METHODS A two-yr, prospective, randomized study of CS with delayed withdrawal (CS) or CS-free regimen with basiliximab, tacrolimus, and enteric-coated mycophenolate sodium (EC-MPS) was performed in 39 patients (CS=20; CS-free=19). CS group received intra-operative methylprednisolone weaned by six months. HCV patients had HCV PCR pre-OLT and 0.5, one, three, and six months post-OLT. Protocol liver biopsies were performed at OLT, 2 and 24 wk post-OLT or when indicated. RESULTS Rejection occurred in two patients. Patient survival at one yr (100% vs. 95%), three yr (85% vs. 63%), and five yr (80% vs. 63%) post-OLT were similar between CS and CS-free group, respectively. Death-censored graft survival at one yr (100% vs. 95%), three yr (85% vs. 63%), and five yr (75% vs. 63%) were also similar. The risk of new-onset DM, hypertension, hypercholesterolemia, and weight gain was similar between groups. CONCLUSION CS avoidance with basiliximab, calcineurin inhibitor, and EC-MPS is safe and effective as CS- containing immunosuppression in adult OLT.
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Affiliation(s)
- Carlo B Ramirez
- Division of Transplantation, Department of Surgery, Thomas Jefferson University, Philadelphia, PA19107, USA.
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11
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Taki-Eldin A, Zhou L, Xie HY, Zheng SS. Liver regeneration after liver transplantation. ACTA ACUST UNITED AC 2012; 48:139-53. [PMID: 22572792 DOI: 10.1159/000337865] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Accepted: 02/07/2012] [Indexed: 12/14/2022]
Abstract
BACKGROUND/PURPOSE The liver has a remarkable capacity to regenerate after injury or resection. The aim of this review is to outline the mechanisms and factors affecting liver regeneration after liver transplantation. METHODS Relevant studies were reviewed using Medline, PubMed and Springer databases. RESULTS A variety of cytokines (such as interleukin-6 and tumor necrosis factor-α), growth factors (like hepatocyte growth factor and transforming growth factor-α) and cells are involved in liver regeneration. Several factors affect liver regeneration after transplantation such as ischemic injury, graft size, immunosuppression, steatosis, donor age and viral hepatitis. CONCLUSION Liver regeneration has been studied for many years. However, further research is essential to reveal the complex processes affecting liver regeneration, which may provide novel strategies in the management of liver transplantation recipients and donors.
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Affiliation(s)
- A Taki-Eldin
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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12
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Shibata T, Mizuguchi T, Nakamura Y, Kawamoto M, Meguro M, Ota S, Hirata K, Ooe H, Mitaka T. Low-dose steroid pretreatment ameliorates the transient impairment of liver regeneration. World J Gastroenterol 2012; 18:905-914. [PMID: 22408349 PMCID: PMC3297049 DOI: 10.3748/wjg.v18.i9.905] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2011] [Revised: 09/16/2011] [Accepted: 01/18/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To determine if liver regeneration (LR) could be disturbed following radiofrequency (RF) ablation and whether modification of LR by steroid administration occurs. METHODS Sham operation, partial hepatectomy (PH), and partial hepatectomy with radiofrequency ablation (PHA) were performed on adult Fisher 344 rats. We investigated the recovery of liver volume, DNA synthetic activities, serum cytokine/chemokine levels and signal transducers and activators of transcription 3 DNA-binding activities in the nucleus after the operations. Additionally, the effects of steroid (dexamethasone) pretreatment in the PH group (S-PH) and the PHA group (S-PHA) were compared. RESULTS The LR after PHA was impaired, with high serum cytokine/chemokine induction compared to PH, although the ratio of the residual liver weight to body weight was not significantly different. Steroid pretreatment disturbed LR in the S-PH group. On the other hand, low-dose steroid pretreatment improved LR and suppressed tumor necrosis factor (TNF)-α elevation in the S-PHA group, with recovery of STAT3 DNA-binding activity. On the other hand, low-dose steroid pretreatment improved LR and suppressed TNF-α elevation in the S-PHA group, with recovery of STAT3 DNA-binding activity. CONCLUSION LR is disturbed after RF ablation, with high serum cytokine/chemokine induction. Low-dose steroid administration can improve LR after RF ablation with TNF-α suppression.
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13
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Kimura M, Moteki H, Ogihara M. Inhibitory effects of dexamethasone on hepatocyte growth factor-induced DNA synthesis and proliferation in primary cultures of adult rat hepatocytes. J Pharmacol Sci 2011; 115:390-8. [PMID: 21350311 DOI: 10.1254/jphs.10302fp] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
We investigated the effects of dexamethasone on hepatocyte growth factor (HGF)-induced DNA synthesis and proliferation in serum-free primary cultures of adult rat hepatocytes. Isolated hepatocytes were cultured at a density of 3.3 × 10(4) cells/cm(2) in Williams' medium E containing 5% newborn bovine serum and various concentrations of dexamethasone for 1, 2, and 3 h. After a 3-h attachment period, the medium was then changed, and cells were cultured in serum-free dexamethasone (10(-10) M)-containing Williams' medium E with or without glucocorticoid receptor antagonists. After addition of dexamethasone to the culture medium, the growth-stimulating effects of HGF (5 ng/mL) on the primary cultured hepatocytes were time- and dose-dependently inhibited. The mineralcorticoid aldosterone (10(-7) M) did not produce the same growth-inhibitory effects as dexamethasone (10(-8) M). The inhibitory effects of dexamethasone were reversed by treatment with the glucocorticoid-receptor antagonist mifepristone (RU486, 10(-6) M) or a monoclonal antibody against glucocorticoid receptor (100 ng/mL). In addition, the growth-inhibitory dose of dexamethasone did not affect HGF-induced receptor tyrosine kinase and extracellular signal-regulated kinase 2 phosphorylation. These results indicate that dexamethasone dose-dependently delays and inhibits HGF-induced DNA synthesis and proliferation through its own intracellular receptor in primary cultures of adult rat hepatocytes.
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Affiliation(s)
- Mitsutoshi Kimura
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, Sakado, Japan.
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14
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Kimura M, Moteki H, Ogihara M. Inhibitory Effects of Dexamethasone on Epidermal Growth Factor-Induced DNA Synthesis and Proliferation in Primary Cultures of Adult Rat Hepatocytes. Biol Pharm Bull 2011; 34:682-7. [DOI: 10.1248/bpb.34.682] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Mitsutoshi Kimura
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Josai University
| | - Hajime Moteki
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Josai University
| | - Masahiko Ogihara
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Josai University
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15
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Strey CW, Marquez-Pinilla RM, Markiewski MM, Siegmund B, Oppermann E, Lambris JD, Bechstein WO. Early post-operative measurement of cytokine plasma levels combined with pre-operative bilirubin levels identify high-risk patients after liver resection. Int J Mol Med 2010; 27:447-54. [PMID: 21206966 DOI: 10.3892/ijmm.2010.592] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2010] [Accepted: 11/02/2010] [Indexed: 01/16/2023] Open
Abstract
Identification of patients at risk of a complicated course after liver resection is crucial for adapting post-operative care. In the present study, we investigated the diagnostic value of the plasma levels of various cytokines obtained immediately after surgery. IL-6, IL-10, IL-8, monokine induced by interferon-γ (MIG), monocyte chemotactic protein-1 (MCP-1) and interferon-inducible protein-10 (IP-10) concentrations were measured in 26 patients after liver resection using a cytometric bead assay and were correlated with liver function, resectate weight, surgery duration, ischemia/reperfusion, hospitalization time and occurrence of complications. Patients with post-surgical complications showed distinctive patterns of IL-6 and IL-8 as early as minutes to hours after surgery. In addition, although pre-operative bilirubin in most patients remained within the normal range, a cut-off of 1 mg/dl separated the patients into groups with different profiles of IL-6, IL-8, and MCP-1 secretion and different likelihoods of experiencing post-operative complications (bilirubin levels ≥1.0 vs. <1.0 mg/dl; IL-6 (4 h): 701 vs. 265; IL-8 (6 h): 262 vs. 97 pg/ml; p<0.05 for both). Extended hospitalization, related to delayed recovery, was correlated with increased IL-8 and MCP-1 immediately after surgery. In conclusion, on the basis of these observations, we suggest that early measurement of post-operative levels of MCP-1, IL-6, and IL-8 can be used to identify individuals at risk of post-operative complications immediately after liver surgery.
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Affiliation(s)
- Christoph W Strey
- Department of General and Vascular Surgery, Johann Wolfgang Goethe-University Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
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16
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Schwer CI, Stoll P, Pietsch U, Stein P, Laqua J, Goebel U, Hoetzel A, Schmidt R. Up-regulation of heme oxygenase-1 by sevoflurane is not dependent on Kupffer cells and associates with ERK1/2 and AP-1 activation in the rat liver. Int J Biochem Cell Biol 2010; 42:1876-83. [PMID: 20727416 DOI: 10.1016/j.biocel.2010.08.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2010] [Revised: 07/19/2010] [Accepted: 08/10/2010] [Indexed: 11/18/2022]
Abstract
Sevoflurane is a potent non-toxic inducer of the hepatoprotective enzyme heme oxygenase-1 (HO-1). So far, little is known about the underlying molecular mechanism. Therefore the aim of this study was to characterize the respective signal transduction pathway and in particular to elucidate the role of Kupffer cells in this context. Rats were treated with or without sevoflurane. The effects on hepatic HO-1 gene expression, mitogen-activated protein kinases and transcription factors were studied by Northern and Western blot analyses, immunostaining, electrophoretic mobility shift assays, and enzymatic activity assays. Kupffer cells were depleted by administration of clodronate liposomes in vivo to characterize their role in HO-1 signal transduction. In additional in vitro experiments, HO-1 mRNA expression in primary rat hepatocytes and HepG2 cells was assessed. Sevoflurane up-regulated HO-1 gene expression in pericentral hepatocytes and increased HO enzyme activity in vivo. This was associated with activation of ERK1/2 and activator protein-1. We identified c-jun/AP-1, JunD, c-fos, and Fra-1 as active subunits of the activator protein-1 complex. Administration of clodronate liposomes to rats led to depletion of Kupffer cells without affecting sevoflurane induced HO-1 expression. Moreover, sevoflurane up-regulated HO-1 mRNA in primary rat hepatocytes but not in HepG2 cells. Our results suggest that sevoflurane induced HO-1 gene expression in pericentral hepatocytes does not depend on Kupffer cells and is associated with activation of ERK1/2 and activator protein-1. Since we could recently demonstrate significant hepatoprotective effects of HO-1 induced by isoflurane, the present results may help to establish new concepts in hepatic organ protection.
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Affiliation(s)
- Christian Ingo Schwer
- Department of Anesthesiology and Critical Care Medicine, University Medical Center Freiburg, Freiburg, Germany
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17
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Sliwa E, Dobrowolski P, Tatara MR, Piersiak T, Siwicki A, Rokita E, Pierzynowski SG. Alpha-ketoglutarate protects the liver of piglets exposed during prenatal life to chronic excess of dexamethasone from metabolic and structural changes. J Anim Physiol Anim Nutr (Berl) 2009; 93:192-202. [PMID: 19320932 DOI: 10.1111/j.1439-0396.2007.00805.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Glucocorticoids play a role in the origin of the features of the metabolic diseases. Alpha-ketoglutarate (AKG) is defined as glutamine homologue and derivative, conditionally an essential amino acid. In the liver, glutamine serves as a precursor for ureagenesis, gluconeogenesis and acute phase protein synthesis The aim of the study was to determine the effect of AKG administered to piglets prenatally exposed to dexamethasone, on the structure of the liver and its metabolic function. Sows were administered with dexamethasone (3 mg/sow/48 h) from day 70 of pregnancy to the parturition, and then after the birth, the piglets were divided into the group administered with AKG (0.4 g/kg body weight) or physiological saline. Biochemical markers, lysozyme and ceruloplasmin serum activities, concentrations of selected free amino acids, macro- and microelements and histomorphometry of the liver tissue were determined. The total cholesterol concentrations in the sows and their newborns from the Dex groups were higher by 72% and 64%, respectively, compared with the control groups. Triacylglycerol concentration was higher by 50% in sows from the Dex group and 55% in the new-born piglets. Alpha-ketoglutarate administered to the piglets after prenatal influence of dexamethasone lowered the total cholesterol concentration by 40%, and enhanced aspartate by 41%, serine by 76%, glutamate by 105%, glutamine by 36%, glycine by 53% and arginine by 105%, as well as methionine and cystathionine, but increased the sulphur concentration compared with the control (p < 0.01). Intracellular space D decreased after AKG administration in comparison with the piglets from Dex/Control group not treated with AKG. Postnatal administration of AKG had a protective effect on liver structure, and lowered the total cholesterol concentration in piglets prenatally exposed to dexamethasone, and also influenced selected macro- and microelement serum concentrations and amino acids plasma concentration.
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Affiliation(s)
- E Sliwa
- Department of Animal Physiology, Agricultural University, Lublin, Poland.
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18
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Shaked A, Ghobrial RM, Merion RM, Shearon TH, Emond JC, Fair JH, Fisher RA, Kulik LM, Pruett TL, Terrault NA, the A2ALL Study Group. Incidence and severity of acute cellular rejection in recipients undergoing adult living donor or deceased donor liver transplantation. Am J Transplant 2009; 9:301-8. [PMID: 19120082 PMCID: PMC3732169 DOI: 10.1111/j.1600-6143.2008.02487.x] [Citation(s) in RCA: 127] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Living donor liver transplantation (LDLT) may have better immunological outcomes compared to deceased donor liver transplantation (DDLT). The aim of this study was to analyze the incidence of acute cellular rejection (ACR) after LDLT and DDLT. Data from the adult-to-adult living donor liver transplantation (A2ALL) retrospective cohort study on 593 liver transplants done between May 1998 and March 2004 were studied (380 LDLT; 213 DDLT). Median LDLT and DDLT follow-up was 778 and 713 days, respectively. Rates of clinically treated and biopsy-proven ACR were compared. There were 174 (46%) LDLT and 80 (38%) DDLT recipients with >/=1 clinically treated episodes of ACR, whereas 103 (27%) LDLT and 58 (27%) DDLT recipients had >/=1 biopsy-proven ACR episode. A higher proportion of LDLT recipients had clinically treated ACR (p = 0.052), but this difference was largely attributable to one center. There were similar proportions of biopsy-proven rejection (p = 0.97) and graft loss due to rejection (p = 0.16). Longer cold ischemia time was associated with a higher rate of ACR in both groups despite much shorter median cold ischemia time in LDLT. These data do not show an immunological advantage for LDLT, and therefore do not support the application of unique posttransplant immunosuppression protocols for LDLT recipients.
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Affiliation(s)
- Abraham Shaked
- Department of Surgery, University of Pennsylvania, Philadelphia, PA
| | - R. Mark Ghobrial
- Department of Surgery, University of California, Los Angeles, Los Angeles, CA
| | | | | | - Jean C. Emond
- Department of Medicine and Surgery, Columbia University College of Physicians & Surgeons, New York, NY
| | - Jeffrey H. Fair
- Department of Surgery, University of North Carolina, Chapel Hill, NC
| | - Robert A. Fisher
- Department of Surgery, Medical College of Virginia Hospitals, Virginia Commonwealth University, Richmond, VA
| | - Laura M. Kulik
- Department of Medicine, Northwestern University, Chicago, IL
| | | | - Norah A. Terrault
- Department of Medicine, University of California, San Francisco, San Francisco, CA
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19
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Effects of Immunosuppressants on Hepatocyte Cell Mitosis During Liver Regeneration in Growing Animal Models of Partial Hepatectomy. Transplant Proc 2008; 40:1641-4. [PMID: 18589165 DOI: 10.1016/j.transproceed.2008.01.077] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2007] [Revised: 10/21/2007] [Accepted: 01/16/2008] [Indexed: 11/17/2022]
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20
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Tannuri ACA, Tannuri U, Wakamatsu A, Mello ES, Coelho MCM, Dos Santos NASR. Effect of the immunosuppressants on hepatocyte proliferation and apoptosis in a young animal model of liver regeneration: an immunohistochemical study using tissue microarrays. Pediatr Transplant 2008; 12:40-6. [PMID: 18186887 DOI: 10.1111/j.1399-3046.2007.00766.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Hepatocyte proliferation and apoptosis (programmed cell death) occur during the liver parenchyma regeneration and the liver size modeling is mainly controlled by hepatocyte apoptosis. The purpose of the present study was to verify the influence of immunosuppressant drugs on these phenomena by utilizing tissue microarray techniques. Thirty-six weaning rats (age 21-23 days, weight 30-50 g) were divided into six groups: control, sham, hepatectomy, hepatectomy plus solumedrol, hepatectomy plus CsA, and hepatectomy plus Tac. The animals were killed one day after hepatectomy, and the remnant livers were weighed and harvested for tissue microarray sections. Liver cell proliferation was evaluated by staining for PCNA and apoptosis was detected by the TUNEL method. It was verified that CsA promoted a decrease in the liver weight, Tac and CsA decreased the proliferation index of hepatocytes, and glucocorticoid had no significant effects. The apoptosis index was not altered by hepatectomy or immunosuppressants. Our data indicate that, in the growing rat, CsA and Tac have negative effects on hepatocyte proliferation and have no effect on the hepatocyte apoptosis.
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Pulitanò C, Guzzetti E, Arru M, Ferla G, Aldrighetti L. In defense of the administration of perioperative steroids in liver transplantation. Liver Transpl 2008; 14:124-5. [PMID: 18161769 DOI: 10.1002/lt.21371] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Scheving LA, Buchanan R, Krause MA, Zhang X, Stevenson MC, Russell WE. Dexamethasone modulates ErbB tyrosine kinase expression and signaling through multiple and redundant mechanisms in cultured rat hepatocytes. Am J Physiol Gastrointest Liver Physiol 2007; 293:G552-9. [PMID: 17585012 DOI: 10.1152/ajpgi.00140.2007] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Glucocorticoids paradoxically exert both stimulatory and inhibitory effects on the proliferation of cultured rat hepatocytes. We studied the effects of dexamethasone, a synthetic glucocorticoid, on the proliferation of cultured rat hepatocytes. The timing of growth factor addition modified the action of high-dose dexamethasone (10(-6) M) on DNA synthesis. When we added transforming growth factor-alpha at the time of plating, 10(-6) M dexamethasone weakly stimulated DNA synthesis by 26% relative to cells cultured in dexamethasone-free media. When we delayed growth factor addition until 24-48 h after plating, 10(-6) M dexamethasone inhibited DNA synthesis by 50%. Using immunological methods, we analyzed the expression and signaling patterns of the ErbB kinases in dexamethasone-treated cells. High-dose dexamethasone stabilized the expression of epidermal growth factor receptor (EGFr) and ErbB3, and it suppressed the de novo expression of ErbB2 that occurs during the third and fourth day of culture in 10(-8) M dexamethasone. High-dose dexamethasone by 72 h suppressed basal and EGF-associated phosphorylation of ERK and Akt. The reduction in ERK1/2 phosphorylation correlated with suppression of a culture-dependent increase in Son-of sevenless 1 (Sos1) and ERK1/2 expression. High-dose dexamethasone in hepatocytes stabilized or upregulated several inhibitory effectors of EGFr/ErbB2 and ERK, including receptor-associated late transducer (RALT) and MKP-1, respectively. Thus 10(-6) M dexamethasone exerts a time-dependent and redundant inhibitory effect on EGFr-mediated proliferative signaling in hepatocytes, targeting not only the ErbB proteins but also their various positive and negative effectors.
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Affiliation(s)
- Lawrence A Scheving
- Division of Pediatric Endocrinology, 1055 Medical Research Bldg. 4, Vanderbilt University Medical Center, Nashville, TN 37232-0710, USA.
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Akamatsu N, Sugawara Y, Tamura S, Imamura H, Kokudo N, Makuuchi M. Regeneration and function of hemiliver graft: right versus left. Surgery 2006; 139:765-772. [PMID: 16782431 DOI: 10.1016/j.surg.2005.12.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2005] [Revised: 12/08/2005] [Accepted: 12/16/2005] [Indexed: 10/24/2022]
Abstract
BACKGROUND A right liver graft used almost routinely for adult living donor liver transplantation (LDLT), is associated with a higher incidence of morbidity and mortality in the donor. We compared volume regeneration and graft function between left and right liver grafts to examine the feasibility of using left liver grafts. METHODS The left liver was considered acceptable as a graft when it was estimated to be over 40% of the recipient standard liver volume. Otherwise, right liver harvesting was used, provided the estimated right liver volume was less than 70% of the donor's standard liver volume. Graft volume on computed tomography and the results of liver function tests 1, 3, and 12 months after LDLT were compared between recipients with left (n = 76) and right (n = 83) grafts. Possible factors influencing graft regeneration were evaluated by multivariate analysis. RESULTS A higher regeneration rate in the left liver graft group resulted in the same ratio of graft to standard liver volume as in the right liver graft group (88% vs 87%) 1 year after LDLT. Liver function tests and 5-year survival rates were comparable between the 2 groups. An episode of acute rejection was a predictive factor for impaired graft regeneration 1 month after LDLT. The initial ratio of graft volume to standard liver volume was an independent factor for regeneration 1 year after LDLT. CONCLUSIONS A properly evaluated left liver graft can be used as safely as a right liver graft in adult-to-adult LDLT. The findings of the present study justify LDLT with a left liver graft under specific selection criteria and may be preferred to a right liver graft.
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Affiliation(s)
- Nobuhisa Akamatsu
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Japan
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Tsung A, Kaizu T, Nakao A, Shao L, Bucher B, Fink MP, Murase N, Geller DA. Ethyl pyruvate ameliorates liver ischemia-reperfusion injury by decreasing hepatic necrosis and apoptosis. Transplantation 2005; 79:196-204. [PMID: 15665768 DOI: 10.1097/01.tp.0000151681.07474.2e] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Hepatic ischemia-reperfusion injury (I/R) occurs in the settings of transplantation, trauma, and elective liver resections. Reactive oxygen species (ROS) have been shown to play a major role in organ I/R injury. Pyruvate, a key intermediate in cellular metabolism, is an effective scavenger of ROS. The purpose of this study was to test the hypothesis that ethyl pyruvate (EP), a soluble pyruvate derivative, is effective in preventing hepatic I/R injury. METHODS Lewis rats underwent 60 minutes of partial warm hepatic ischemia. Three doses of EP dissolved in lactated Ringer's solution or lactated Ringer's solution (LR) alone were given by intravenous injection. Serum and tissue samples were obtained at 1 to 24 hours postreperfusion. RESULTS Serum transaminases, degree of hepatic necrosis, and neutrophil infiltration were all significantly decreased in the EP-treated rats compared with control animals. The amount of hepatic lipid peroxidation was also significantly decreased in EP-treated animals. Both circulating levels and hepatic expression of inflammatory cytokines were significantly decreased in the EP-treated animals. Furthermore, EP inhibited activation of extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase mitogen-activated protein kinases, as well as nuclear factor-kappaB, signaling pathways involved in cytokine release. Treatment with EP also inhibited hepatic apoptosis. CONCLUSION EP has a protective effect on hepatic I/R injury, mediated in part by decreasing lipid peroxidation, down-regulation of inflammatory mediators, and inhibition of apoptosis. Strategies using this additive to LR solution should be considered in clinical settings of ischemic liver injury to decrease organ damage.
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Affiliation(s)
- Allan Tsung
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
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25
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Zhao X, Koshiba T, Fujimoto Y, Pirenne J, Yoshizawa A, Ito T, Kamei H, Jobara K, Ogawa K, Uryuhara K, Takada Y, Tanaka K. Proinflammatory and antiinflammatory cytokine production during ischemia-reperfusion injury in a case of identical twin living donor liver transplantation using no immunosuppression. Transplant Proc 2005; 37:392-4. [PMID: 15808656 DOI: 10.1016/j.transproceed.2004.12.272] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Bolus steroids are usually administered prior to graft reperfusion in an attempt to provide protection against ischemia reperfusion injury (IRI). However, the anti-IRI properties of steroids have not been established. Living donor liver transplantation (LDLT) between identical twins provides a unique opportunity to study the natural production of cytokines during transplantation without the confounding influences of the alloimmune response or of immunosuppression in particular steroids. METHODS A 38-year-old male with hepatitis C virus-related cirrhosis and multiple hepatocellular carcinomas received a hepatic right lobe graft from his identical twin. No immunosuppression was administered, not even intraoperative bolus steroids. IRI was assessed by serum transaminases as well as by proinflammatory interleukin (IL) IL-1beta, tumor necrosis factor (TNF)-alpha, IL-8 cytokines and for potent regenerative/anti-inflammatory (IL-6, IL-10) mediators. RESULTS Despite no administration of steroids, low peak levels of serum transaminases were observed. Serum IL-6 and IL-10 dramatically and rapidly increased during liver transplantation, namely, 160 and 20 times higher than baseline, respectively. In contrast, IL-1beta and TNF-alpha remained low during and after transplantation and an increase in IL-8 was less obvious. CONCLUSION Syngeneic LDLT without intraoperative bolus steroids is feasible, yielding no penalty in terms of IRI. A predominance of protective cytokines was observed in the absence of steroids. Thus, the concept that intraoperative administration of steroids is necessary to protect liver transplants from IRI must be revisited.
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Affiliation(s)
- X Zhao
- Department of Transplantation and Immunology, Transplant Tolerance Unit, Kyoto University, Faculty of Medicine, Kyoto, Japan
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Rajaraman G, Burczynski FJ. Effect of dexamethasone, 2-bromopalmitate and clofibrate on L-FABP mediated hepatoma proliferation. J Pharm Pharmacol 2004; 56:1155-61. [PMID: 15324484 DOI: 10.1211/0022357044111] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Cytosolic liver fatty acid binding protein (L-FABP) is involved in many intracellular functions including cellular mitogenesis. We investigated the role of L-FABP and the plasma membrane liver fatty acid binding proteins (L-FABP(pm)) in the modulation of hepatoma growth and proliferation, hypothesizing that agents that affect either the content of, or ligand binding to, L-FABP would affect hepatocellular mitogenesis. L-FABP expressing 1548-rat hepatoma cells were treated with 0.5 microM dexamethasone or 500 microM clofibrate for 4 days to downregulate and upregulate L-FABP expression, respectively. The competitive inhibitor 2-bromopalmitate (BrPA, 600 microM) was used to inhibit ligand binding to L-FABP. The peripherally present plasma membrane fatty acid transporter was inactivated by treating cells with 1:50 rabbit antisera (FABP-Ab) raised against L-FABP. Western blot analysis was used to monitor L-FABP levels while [(3)H]-thymidine incorporation and growth curves were used to monitor hepatocellular proliferation. [(3)H]-Palmitate clearance studies were performed using monolayer cultures. Palmitate clearance in dexamethasone-, BrPA- and FABP-Ab-treated cells was significantly reduced when compared with control (P < 0.05), while clofibrate treatment moderately increased the rate. [(3)H]-Thymidine incorporation by dexamethasone- and BrPA-treated cells was significantly lower than control (P < 0.05), suggesting that hepatocellular proliferation was inhibited. Clofibrate treatment did not statistically affect growth rate. Lowering L-FABP using dexamethasone or interfering with its activity using BrPA significantly affected hepatocellular proliferation. This may be due to the non-availability of long-chain fatty acids or other intracellular mediators that are transported by L-FABP to the nucleus.
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Affiliation(s)
- G Rajaraman
- Faculty of Pharmacy, University of Manitoba, 50 Sifton Road, Winnipeg, Manitoba R3T 2N2, Canada
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Xu CS, Han HP, Yuan JY, Chang CF, Li WQ, Yang KJ, Zhao LF, Li YC, Zhang HY, Salman R, Zhang JB. Gene expression difference in regenerating rat liver after 0-36-40-44h short interval successive partial hepatectomy. Shijie Huaren Xiaohua Zazhi 2004; 12:654-663. [DOI: 10.11569/wcjd.v12.i3.654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To identify genes related to rat liver regeneration (LR) after 0-36-40-44h short interval successive partial hepatectomy (SISPH) and to analyze their action and expression profile in LR.
METHODS: A cDNA microarray containing 551 elements (liver chip) was made to analyze extensively expression changes of them in 0-36-40-44h SISPH, which were selected from subtractive cDNA libraries of the LR. Cluster analysis of these gene expression profile was performed by Genemath.
RESULTS: Among the selected 551 cDNA, 157 were up- ordown-regulated more than twofold at one or more time points. Of the 157 elements, 86 were up-regulated and 71 down-regulated, and 70 were not reported and 87 were reported, which had not been previously reported to be involved in LR. By cluster analysis and generalization analysis, 6 distinct temporal induction or suppression patterns showed that immediate induction, intermediate induction, late induction, immediate suppression, intermediate suppression, and late suppression. Comparison of the gene expression in SISPH with after PH found that 38 genes were specially altered in SISPH, and the expression trends for other 119 genes were similar between SISPH and PH, except of the various abundance at the different time points.
CONCLUSION: In 0-36-40-44h SISPH, the numbers of the up-regulated and down-regulated genes show no apparent difference. The genes expressed lately are more than that immediately, and much more than that intermediately. The genes expressed abundantly are much less than that increased 2-5 folds.
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