|
1
|
Liu X, Hu B, Wang F, Song Y, Fan Z, Wei H, Qiu R, Xu W. Molecular cloning of the rabbit interleukin 6 promoter: Functional characterization of rabbit hemorrhagic disease virus response elements in RK-13 cells. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2016; 65:280-288. [PMID: 27492646 DOI: 10.1016/j.dci.2016.07.017] [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: 07/05/2016] [Revised: 07/27/2016] [Accepted: 07/27/2016] [Indexed: 06/06/2023]
Abstract
Infection with rabbit hemorrhagic disease virus (RHDV) can cause acute liver failure (ALF), leading to severe mortality in rabbits. Inflammatory response, especially the expression of inflammatory cytokines such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6, may play major roles in mediating and amplifying the ALF. Among these cytokines, IL-6 is a multifunctional cytokine with a central role in various physiological inflammatory and immunological processes. In this study, we found that RHDV infection significantly upregulated IL-6 gene expression in vivo. Next, the rabbit IL-6 promoter was cloned and analyzed. Transfection of full-length RHDV cDNA in RK-13 cells upregulated the activity of the IL-6 promoter. A series of 5' deletion constructs demonstrated that AP-1 (activator protein 1), NF-IL6 (nuclear factor interleukin-6), and NF-κB (nuclear factor kappa B) elements were critical for RHDV-induced IL-6 transcription. Besides, the CREB (cAMP-response element binding protein) element may also play an accessory effect on RHDV-induced IL-6 transcription. Collectively, the results elucidate the mechanism of IL-6 induction, and enrich the RHDV pathogenesis in rabbit.
Collapse
Affiliation(s)
- Xing Liu
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biologicals Engineering and Technology, Ministry of Agriculture, National Center for Engineering Research of Veterinary Bio-products, Nanjing 210014, China
| | - Bo Hu
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biologicals Engineering and Technology, Ministry of Agriculture, National Center for Engineering Research of Veterinary Bio-products, Nanjing 210014, China
| | - Fang Wang
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biologicals Engineering and Technology, Ministry of Agriculture, National Center for Engineering Research of Veterinary Bio-products, Nanjing 210014, China.
| | - Yanhua Song
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biologicals Engineering and Technology, Ministry of Agriculture, National Center for Engineering Research of Veterinary Bio-products, Nanjing 210014, China
| | - Zhiyu Fan
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biologicals Engineering and Technology, Ministry of Agriculture, National Center for Engineering Research of Veterinary Bio-products, Nanjing 210014, China
| | - Houjun Wei
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biologicals Engineering and Technology, Ministry of Agriculture, National Center for Engineering Research of Veterinary Bio-products, Nanjing 210014, China
| | - Rulong Qiu
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biologicals Engineering and Technology, Ministry of Agriculture, National Center for Engineering Research of Veterinary Bio-products, Nanjing 210014, China
| | - Weizhong Xu
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biologicals Engineering and Technology, Ministry of Agriculture, National Center for Engineering Research of Veterinary Bio-products, Nanjing 210014, China
| |
Collapse
|
|
2
|
Crespo I, San-Miguel B, Sánchez DI, González-Fernández B, Álvarez M, González-Gallego J, Tuñón MJ. Melatonin inhibits the sphingosine kinase 1/sphingosine-1-phosphate signaling pathway in rabbits with fulminant hepatitis of viral origin. J Pineal Res 2016; 61:168-76. [PMID: 27101794 DOI: 10.1111/jpi.12335] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 04/19/2016] [Indexed: 01/08/2023]
Abstract
The sphingosine kinase (SphK)1/sphingosine-1-phosphate (S1P) pathway is involved in multiple biological processes, including liver diseases. This study investigate whether modulation of the SphK1/S1P system associates to the beneficial effects of melatonin in an animal model of acute liver failure (ALF) induced by the rabbit hemorrhagic disease virus (RHDV). Rabbits were experimentally infected with 2 × 10(4) hemagglutination units of a RHDV isolate and received 20 mg/kg of melatonin at 0, 12, and 24 hr postinfection. Liver mRNA levels, protein concentration, and immunohistochemical labeling for SphK1 increased in RHDV-infected rabbits. S1P production and protein expression of the S1PR1 receptor were significantly elevated following RHDV infection. These effects were significantly reduced by melatonin. Rabbits also exhibited increased expression of toll-like receptor (TLR)4, tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, nuclear factor-kappa B (NF-κB) p50 and p65 subunits, and phosphorylated inhibitor of kappa B (IκB)α. Melatonin administration significantly inhibited those changes and induced a decreased immunoreactivity for RHDV viral VP60 antigen in the liver. Results obtained indicate that the SphK1/S1P system activates in parallel to viral replication and the inflammatory process induced by the virus. Inhibition of the lipid signaling pathway by the indole reveals novel molecular pathways that may account for the protective effect of melatonin in this animal model of ALF, and supports the potential of melatonin as an antiviral agent.
Collapse
Affiliation(s)
- Irene Crespo
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | - Beatriz San-Miguel
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | - Diana I Sánchez
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
| | | | | | - Javier González-Gallego
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | - María J Tuñón
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| |
Collapse
|
|
3
|
Sang JF, Shi XL, Han B, Huang X, Huang T, Ren HZ, Ding YT. Combined mesenchymal stem cell transplantation and interleukin-1 receptor antagonism after partial hepatectomy. World J Gastroenterol 2016; 22:4120-4135. [PMID: 27122663 PMCID: PMC4837430 DOI: 10.3748/wjg.v22.i16.4120] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Revised: 09/24/2015] [Accepted: 12/12/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To study the therapeutic effects of mesenchymal stem cells (MSCs) and an interleukin-1 receptor antagonist (IL-1Ra) in acute liver failure. METHODS Chinese experimental miniature swine (15 ± 3 kg, 5-8 mo) were obtained from the Laboratory Animal Centre of the Affiliated Drum Tower Hospital of Nanjing University Medical School. Acute liver failure was induced via 85% hepatectomy, and animals were treated by MSC transplantation combined with IL-1Ra injection. Blood samples were collected for hepatic function analysis, and the living conditions and survival time were recorded. Liver injury was histologically analyzed. Hepatic cell regeneration and apoptosis were studied by Ki67 immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling, respectively. The levels of protein kinase B and nuclear factor-κB expression were analyzed by Western blotting. RESULTS MSCs were infected with a lentivirus for expression of green fluorescent protein (GFP) for subsequent identification; 97.3% of the MSCs were positive for GFP as assessed by flow cytometry. Additional flow cytometric analysis of cell surface marker expression demonstrated that > 90% of GFP-expressing MSCs were also positive for CD29, CD44, and CD90, indicating that most of these cells expressed typical markers of MSCs, and the population of MSCs was almost pure. Transplantation of MSCs in combination with 2 mg/kg IL-1Ra therapy significantly improved survival time compared to the acute liver failure model group (35.3 ± 6.7 d vs 17.3 ± 5.5 d, P < 0.05). Combined therapy also promoted improvement in serum inflammatory cytokines and biochemical conditions. The observed hepatic histopathologic score was significantly lower in the group with combined therapy than in the model group (3.50 ± 0.87 vs 8.17 ± 1.26, P < 0.01). In addition, liver cell apoptosis in the combined therapy group was significantly inhibited (18.1 ± 2.1% vs 70.8 ± 3.7%, P < 0.01), and hepatic cell regeneration increased. A significant increase in protein kinase B expression and decrease in nuclear factor-κB expression were observed (P < 0.01), which supports their important roles in liver regeneration. CONCLUSION MSCs and IL-1Ra had a synergistic effect in liver regeneration via regulation of inflammation and apoptotic signaling.
Collapse
|
|
4
|
Abstract
OBJECTIVE Autoimmune hepatitis (AIH) is considered an underdiagnosed cause of fulminant hepatic failure (FHF). Autoimmune FHF (AI-FHF) is believed to lead invariably to liver transplantation (LTX) or death. We aimed to describe the autoimmune features of children diagnosed as having AI-FHF and indeterminate FHF (ID-FHF), and describe the outcome of patients with AI-FHF treated with immunosuppressive drugs. METHODS In this case-control study, the files of patients with AI-FHF and ID-FHF were reviewed and compared. AIH was diagnosed based on positive autoantibodies, raised immunoglobulin G, and histology when available. FHF was defined by raised transaminases, international normalised ratio ≥ 2.0, presence of encephalopathy, and no previously recognised liver disease. RESULTS A total of 46 children with FHF were managed in the last 15 years: 10/46 (22%) had AI-FHF, 20/46 (43%) ID-FHF, and 16 had other diagnosis. The mean follow-up time was 4.6 years. AI-FHF and ID-FHF differed for the presence of autoantibodies (10/10, 6/10 liver/kidney microsome [LKM]-type, vs 3/20, none LKM, P < 0.0001), immunoglobulin G level (1845 vs 880 mg/dL, P < 0.001), median age at diagnosis (6.4 vs 1.8 years, P = 0.017), and alanine aminotransferase level (1020 vs 2386 IU/L, P = 0.029). Liver histology did not allow to differentiate the 2 conditions. Among the patients with AI-FHF, 4/9 who received steroids recovered; 5/9 required LTX and 1 died awaiting treatment. CONCLUSIONS AIH is a much more common cause of FHF than previously suggested, and a complete autoantibody testing including LKM-type is essential in this setting. Autoantibodies are uncommon in ID-FHF, and histology cannot distinguish it from AI-FHF. A cautious steroid trial may avoid LTX in some of the patients with AI-FHF.
Collapse
|
|
5
|
Licata A, Mazzola A, Ingrassia D, Calvaruso V, Cammà C, Craxì A. Clinical implications of the hyperdynamic syndrome in cirrhosis. Eur J Intern Med 2014; 25:795-802. [PMID: 25245607 DOI: 10.1016/j.ejim.2014.09.004] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Revised: 09/02/2014] [Accepted: 09/04/2014] [Indexed: 12/24/2022]
Abstract
The hyperdynamic syndrome is a late consequence of portal hypertension in cirrhosis. The principal hemodynamic manifestations of the hyperdynamic syndrome are high cardiac output, and increased heart rate and total blood volume, accompanied by reduced total systemic vascular resistance. Pathophysiology involves a complex of humoral and neural mechanisms that can determine hemodynamic changes, and lead to hyperdynamic circulation. In this review we focus our attention on the manifestations of the hyperdynamic syndrome. Some of these are well described and directly related to portal hypertension (varices, ascites, hepatic encephalopathy, and hepatorenal syndrome), while others, such as hepatopulmonary syndrome, portopulmonary hypertension, and cirrhotic cardiomyopathy, are less known as clinical manifestations related to cirrhosis and, therefore, merit further investigation.
Collapse
Affiliation(s)
- Anna Licata
- Sezione di Gastroenterologia & Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, DIBIMIS, Università di Palermo, Palermo, Italy
| | - Alessandra Mazzola
- Sezione di Gastroenterologia & Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, DIBIMIS, Università di Palermo, Palermo, Italy
| | - Daniela Ingrassia
- Sezione di Gastroenterologia & Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, DIBIMIS, Università di Palermo, Palermo, Italy
| | - Vincenza Calvaruso
- Sezione di Gastroenterologia & Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, DIBIMIS, Università di Palermo, Palermo, Italy
| | - Calogero Cammà
- Sezione di Gastroenterologia & Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, DIBIMIS, Università di Palermo, Palermo, Italy
| | - Antonio Craxì
- Sezione di Gastroenterologia & Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, DIBIMIS, Università di Palermo, Palermo, Italy
| |
Collapse
|
|
6
|
López ML, Kieling CO, Uribe Cruz C, Osvaldt A, Ochs de Muñoz G, Meurer L, Silla L, Matte U. Platelet increases survival in a model of 90% hepatectomy in rats. Liver Int 2014; 34:1049-56. [PMID: 24119092 DOI: 10.1111/liv.12326] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Accepted: 08/29/2013] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Ninety per cent hepatectomy in rodents is a model for acute liver failure. It has been reported that platelets have a strong effect enhancing liver regeneration, because of the production of several growth factors such as serotonin. The aim of this study was to investigate the role of microencapsulated platelets on 90% hepatectomy in rats. METHODS Platelets (PLT) were microencapsulated in sodium alginate and implanted in the peritoneum of rats after 90% partial hepatectomy (PH). Control group received empty capsules (EC). Animals were euthanized at 6, 12, 24, 48 and 72 h post PH (n=9-12/group/time) to evaluate liver regeneration rate, mitotic index, liver content, serum and tissue levels of Interleukin 6 (IL-6) and serotonin and its receptor 5-hydroxytryptamine type 2B (5Ht2b). Survival rate in 10 days was evaluated in a different set of animals (n=20/group). RESULTS Platelets group showed the highest survival rate despite the lowest liver regeneration rate at any time point. Mitotic and BrdU index showed no difference between groups. However, the number of hepatocytes was higher and the internuclear distance was shorter for PLT group. Liver dry weight was similar in both groups indicating that water was the main responsible factor for the weight difference. Gene expression of IL-6 in the liver was significantly higher in EC group 6 h after PH, whereas 5Ht2b was up-regulated at 72 h in PLT group. CONCLUSIONS Platelets enhance survival of animals with 90% PH, probably by an early protective effect on hepatocytes and the increase in growth factor receptors.
Collapse
Affiliation(s)
- Mónica L López
- Gene Therapy Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, do Rio Grande do Sul, Brazil; Post-Graduation Program on Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, do Rio Grande do Sul, Brazil
| | | | | | | | | | | | | | | |
Collapse
|
|
7
|
|
|
8
|
Intraoperative predictors of short-term mortality in living donor liver transplantation due to acute liver failure. Transplant Proc 2013; 45:236-40. [PMID: 23375307 DOI: 10.1016/j.transproceed.2012.06.077] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2012] [Revised: 05/23/2012] [Accepted: 06/19/2012] [Indexed: 12/28/2022]
Abstract
BACKGROUND Acute liver failure (ALF) is a rare and fatal disease with rapidly deteriorating clinical features. Many predictive models for ALF outcomes have been tested, but none have been adopted as definitive guidelines for prognosis because of inconsistencies in accuracy. Most prognostic models for ALF are based on preoperative patient conditions, thus ignoring various specific intraoperative features relevant to postoperative outcomes. We investigated whether intraoperative factors predicted short-term mortality due to ALF in living donor liver transplantations (LDLT). METHODS We retrospectively collected intraoperative data, including surgical time, fluctuations in mean blood pressure (MBP) and heart rate, mean pulmonary arterial pressure (PAP), central venous pressure (CVP), urine output, laboratory data, oxygen indices (PaO(2)/FiO(2)), administered drugs, and transfusion of packed red blood cells (PRBCs) from 101 patients with ALF who underwent LDLT. After simple relationships of individual intraoperative variables with 1-month posttransplant mortality were analyzed, we examined potentially significant intraoperative variables (P < .10) by a multivariate adjustment process with preoperative indicators of ALF prognosis. RESULTS Intraoperative MBP fluctuations, first mean PAP and CVP, last oxygen index, administered calcium chloride, and PRBC transfusion showed individual associations with posttransplant mortality of ALF patients (P < .05). After multivariate adjustment, PRBC transfusion of ≥ 10 pints (odds ratio 4.73; 95% confidence interval [CI] 1.06-21.16) and MBP fluctuations (odds ratio 1.26; 95% CI 1.00-1.58) were identified to be independent predictors of 1-month posttransplant mortality, together with preoperative factors, including severe hepatic encephalopathy, and a Model for End-stage Liver Disease score ≥ 30 points (area under the curve 0.82, P < .001). CONCLUSION MBP fluctuations and large blood transfusions were intraoperative predictors of short-term mortality after LDLT due to ALF. Increased attention to intraoperative manifestations should provide valuable prognostic information for ALF.
Collapse
|
|
9
|
Lynge ME, Laursen MB, Hosta-Rigau L, Jensen BEB, Ogaki R, Smith AAA, Zelikin AN, Städler B. Liposomes as drug deposits in multilayered polymer films. ACS APPLIED MATERIALS & INTERFACES 2013; 5:2967-75. [PMID: 23514370 DOI: 10.1021/am4006868] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
The ex vivo growth of implantable hepatic or cardiac tissue remains a challenge and novel approaches are highly sought after. We report an approach to use liposomes embedded within multilayered films as drug deposits to deliver active cargo to adherent cells. We verify and characterize the assembly of poly(l-lysine) (PLL)/alginate, PLL/poly(l-glutamic acid), PLL/poly(methacrylic acid) (PMA), and PLL/cholesterol-modified PMA (PMAc) films, and assess the myoblast and hepatocyte adhesion to these coatings using different numbers of polyelectrolyte layers. The assembly of liposome-containing multilayered coatings is monitored by QCM-D, and the films are visualized using microscopy. The myoblast and hepatocyte adhesion to these films using PLL/PMAc or poly(styrenesulfonate) (PSS)/poly(allyl amine hydrochloride) (PAH) as capping layers is evaluated. Finally, the uptake of fluorescent lipids from the surface by these cells is demonstrated and compared. The activity of this liposome-containing coating is confirmed for both cell lines by trapping the small cytotoxic compound thiocoraline within the liposomes. It is shown that the biological response depends on the number of capping layers, and is different for the two cell lines when the compound is delivered from the surface, while it is similar when administered from solution. Taken together, we demonstrate the potential of liposomes as drug deposits in multilayered films for surface-mediated drug delivery.
Collapse
Affiliation(s)
- Martin E Lynge
- iNANO Interdisciplinary Nanoscience Centre, Aarhus University, Aarhus 8000, Denmark
| | | | | | | | | | | | | | | |
Collapse
|
|
10
|
Serum sodium based modification of the MELD does not improve prediction of outcome in acute liver failure. BMC Gastroenterol 2013; 13:58. [PMID: 23551795 PMCID: PMC3637827 DOI: 10.1186/1471-230x-13-58] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Accepted: 03/21/2013] [Indexed: 12/25/2022] Open
Abstract
Background Acute liver failure (ALF) is a devastating clinical syndrome with a high mortality rate. The MELD score has been implied as a prognostic tool in ALF. Hyponatremia is associated with lethal outcome in ALF. Inclusion of serum sodium (Na) into the MELD score was found to improve its predictive value in cirrhotic patients. Therefore the aim of this study was to determine whether inclusion of serum Na improves the predictive value of MELD in ALF compared to established criteria. Methods In a prospective single center study (11/2006–12/2010), we recruited 108 consecutive ALF patients (64% females / 36% males), who met the criteria defined by the “Acute Liver Failure Study Group Germany”. Upon admission, clinical and laboratory data were collected, King’s College Criteria (KCC), Model of End Stage Liver Disease score (MELD), and serum sodium based modifications like the MELD-Na score and the United Kingdom Model of End Stage Liver Disease score (UKELD) were calculated and area under the receiver operating characteristic curve analyses were performed regarding the prediction of spontaneous recovery (SR) or non-spontaneous recovery (NSR; death or transplantation). Results Serum bilirubin was of no prognostic value in ALF, and Na also failed to predict NSR in ALF. The classical MELD score was superior to sodium-based modifications and KCC. Conclusions We validated the prognostic value of MELD-Na and UKELD in ALF. Classic MELD score calculations performed superior to KCC in the prediction of NSR. Serum Na and Na-based modifications of MELD did not further improve its prognostic value.
Collapse
|
|
11
|
Shi XL, Zhu W, Tan JJ, Xiao JQ, Zhang L, Xu Q, Ma ZL, Ding YT. Effect evaluation of interleukin-1 receptor antagonist nanoparticles for mesenchymal stem cell transplantation. World J Gastroenterol 2013; 19:1984-1991. [PMID: 23569345 PMCID: PMC3613115 DOI: 10.3748/wjg.v19.i12.1984] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Revised: 12/12/2012] [Accepted: 02/06/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the efficacy of marrow mesenchymal stem cells (MSCs) transplantation combined with interleukin-1 receptor antagonist (IL-1Ra) for acute liver failure (ALF).
METHODS: Chinese experimental miniature swine were randomly divided into four groups (n = 7), and all animals were given D-galactosamine (D-gal) to induce ALF. Group A animals were then injected with 40 mL saline via the portal vein 24 h after D-gal induction; Group B animals were injected with 2 mg/kg IL-1Ra via the ear vein 18 h, 2 d and 4 d after D-gal induction; Group C received approximately 1 × 108 green fluorescence protein (GFP)-labeled MSCs (GFP-MSCs) suspended in 40 mL normal saline via the portal vein 24 h after D-gal induction; Group D animals were injected with 2 mg/kg IL-1Ra via the ear vein 18 h after D-gal induction, MSCs transplantation was then carried out at 24 h after D-gal induction, and finally 2 mg/kg IL-1Ra was injected via the ear vein 1 d and 3 d after surgery as before. Liver function, serum inflammatory parameters and pathological changes were measured and the fate of MSCs was determined.
RESULTS: The optimal efficiency of transfection (97%) was achieved at an multiplicity of infection of 80, as observed by fluorescence microscopy and flow cytometry (FCM). Over 90% of GFP-MSCs were identified as CD44+ CD90+ CD45- MSCs by FCM, which indicated that most GFP-MSCs retained MSCs characteristics. Biochemical assays, the levels of serum inflammatory parameters and histological results in Group D all showed a significant improvement in liver injury compared with the other groups (P < 0.05). The number of GFP-MSCs in Group D was also greater than that in Group B, and the long-term cell proliferation rate was also better in Group D than in the other groups.
CONCLUSION: MSCs transplantation is useful in ALF, IL-1Ra plays an important role in alleviating the inflammatory condition, and combination therapy with MSCs transplantation and IL-1Ra is a promising treatment for ALF.
Collapse
|
|
12
|
Laliena A, San Miguel B, Crespo I, Alvarez M, González-Gallego J, Tuñón MJ. Melatonin attenuates inflammation and promotes regeneration in rabbits with fulminant hepatitis of viral origin. J Pineal Res 2012; 53:270-8. [PMID: 22506987 DOI: 10.1111/j.1600-079x.2012.00995.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
The objective of the present study was to investigate the effect of melatonin on the liver inflammatory and regenerative response in an animal model of fulminant hepatic failure (FHF) of viral origin. Rabbits were experimentally infected with 2×10(4) hemagglutination units of a rabbit hemorrhagic disease virus (RHDV) isolate and received melatonin at two concentrations of 10 or 20mg/kg at 0, 12 and 24hr postinfection. RHDV infection induced an inflammatory response, with increased expression of toll-like receptor 4, high-mobility group box (HMGB)1, interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and C-reactive protein, and decreased expression of decay accelerating factor (DAF/CD55). These effects were significantly reduced by melatonin. Matrix metalloproteinase-9 expression was also lowered in melatonin-treated rabbits. RHDV infection inhibited the hepatic regenerative/proliferative response, with a reduced expression of hepatocyte growth factor (HGF), epidermal growth factor, platelet-derived growth factor (PDGF)-B and vascular endothelial growth factor and their receptors; these responses were prevented by melatonin administration. Melatonin treatment also resulted in reduced expression of phosphorylated Janus kinase and enhanced expression of extracellular mitogen-activated protein kinase (ERK) and signal transducer and activator of transcription (STAT) 3. Our findings show that anti-inflammatory effects and stimulation of regenerative mechanisms contribute to the beneficial effects of melatonin in rabbits with experimental infection by RHDV and support a potential hepatoprotective role of melatonin in FHF.
Collapse
|
|
13
|
Ekser B, Burlak C, Waldman JP, Lutz AJ, Paris LL, Veroux M, Robson SC, Rees MA, Ayares D, Gridelli B, Tector AJ, Cooper DKC. Immunobiology of liver xenotransplantation. Expert Rev Clin Immunol 2012; 8:621-34. [PMID: 23078060 PMCID: PMC3774271 DOI: 10.1586/eci.12.56] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Pigs are currently the preferred species for future organ xenotransplantation. With advances in the development of genetically modified pigs, clinical xenotransplantation is becoming closer to reality. In preclinical studies (pig-to-nonhuman primate), the xenotransplantation of livers from pigs transgenic for human CD55 or from α1,3-galactosyltransferase gene-knockout pigs+/- transgenic for human CD46, is associated with survival of approximately 7-9 days. Although hepatic function, including coagulation, has proved to be satisfactory, the immediate development of thrombocytopenia is very limiting for pig liver xenotransplantation even as a 'bridge' to allotransplantation. Current studies are directed to understand the immunobiology of platelet activation, aggregation and phagocytosis, in particular the interaction between platelets and liver sinusoidal endothelial cells, hepatocytes and Kupffer cells, toward identifying interventions that may enable clinical application.
Collapse
Affiliation(s)
- Burcin Ekser
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- Department of Surgery, Transplant Institute, Indiana University School of Medicine, Indiana University Health, Indianapolis, IN, USA
- Department of Surgery, Transplantation and Advanced Technologies, Vascular Surgery and Organ Transplant Unit, University Hospital of Catania, Catania, Italy
| | - Christopher Burlak
- Department of Surgery, Transplant Institute, Indiana University School of Medicine, Indiana University Health, Indianapolis, IN, USA
| | - Joshua P Waldman
- Department of Urology, University of Toledo Health Sciences Campus, Toledo, OH, USA
| | - Andrew J Lutz
- Department of Surgery, Transplant Institute, Indiana University School of Medicine, Indiana University Health, Indianapolis, IN, USA
| | - Leela L Paris
- Department of Surgery, Transplant Institute, Indiana University School of Medicine, Indiana University Health, Indianapolis, IN, USA
| | - Massimiliano Veroux
- Department of Surgery, Transplantation and Advanced Technologies, Vascular Surgery and Organ Transplant Unit, University Hospital of Catania, Catania, Italy
| | - Simon C Robson
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Michael A Rees
- Department of Urology, University of Toledo Health Sciences Campus, Toledo, OH, USA
| | | | - Bruno Gridelli
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Palermo, Italy
| | - A Joseph Tector
- Department of Surgery, Transplant Institute, Indiana University School of Medicine, Indiana University Health, Indianapolis, IN, USA
| | - David KC Cooper
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| |
Collapse
|
|
14
|
Chávez-Tapia NC, Barrientos-Gutiérrez T, Guerrero-López CM, Santiago-Hernández JJ, Méndez-Sánchez N, Uribe M. Increased mortality from acute liver failure in Mexico. Ann Hepatol 2012; 11:257-262. [PMID: 22345344 DOI: 10.1016/s1665-2681(19)31032-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
INTRODUCTION There is significant geographic variation in the etiology and prognosis of acute liver failure (ALF). Since, little information is available for Latin America. We analyzed ALF mortality trends in Mexico. MATERIAL AND METHODS The rates of mortality attributable to ALF were obtained for 1998 to 2009 from the National System of Health Information in Mexico and analyzed according to date, etiology, sex, age and geographic characteristics through graphical assessment and joinpoint regression. RESULTS From 1998 to 2009, 2,193 ALF-related deaths were reported. A threefold increase in ALF mortality was observed during the period from 1998 to 2009 (the global mortality rate increased from 13.1 to 40.2 deaths per 10,000,000 inhabitants). The most significant increase was observed for viral etiologies after 2006, affecting people 45 years old and over. CONCLUSION ALF-related deaths have increased since 2006. Although we cannot speculate on the specific causes of this increase, it may reflect improvements in the access of vulnerable populations to health care.
Collapse
|
|
15
|
Han S, Bourdon A, Hamou W, Dziedzic N, Goldman O, Gouon-Evans V. Generation of functional hepatic cells from pluripotent stem cells. ACTA ACUST UNITED AC 2012; Suppl 10:1-7. [PMID: 25364624 DOI: 10.4172/2157-7633.s10-008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Liver diseases affect millions of people worldwide, especially in developing country. According to the American Liver Foundation, nearly 1 in every 10 Americans suffers from some form of liver disease. Even though, the liver has great ability to self-repair, in end-stage liver diseases including fibrosis, cirrhosis, and liver cancer induced by viral hepatitis and drugs, the liver regenerative capacity is exhausted. The only successful treatment for chronic liver failure is the whole liver transplantation. More recently, some clinical trials using hepatocyte transplantation have shown some clinical improvement for metabolic liver diseases and acute liver failure. However, the shortage of donor livers remains a life-threatening challenge in liver disease patients. To overcome the scarcity of donor livers, hepatocytes generated from embryonic stem cell or induced pluripotent stem cell differentiation cultures could provide an unlimited supply of such cells for transplantation. This review provides an updated summary of hepatic differentiation protocols published so far, with a characterization of the hepatic cells generated in vitro and their ability to regenerate damaged livers in vivo following transplantation in pre-clinical liver deficient mouse models.
Collapse
Affiliation(s)
- Songyan Han
- Department of Developmental and Regenerative Biology, Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York, USA
| | - Alice Bourdon
- Department of Developmental and Regenerative Biology, Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York, USA
| | - Wissam Hamou
- Department of Developmental and Regenerative Biology, Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York, USA
| | - Noelle Dziedzic
- Department of Developmental and Regenerative Biology, Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York, USA
| | - Orit Goldman
- Department of Developmental and Regenerative Biology, Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York, USA
| | - Valerie Gouon-Evans
- Department of Developmental and Regenerative Biology, Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York, USA
| |
Collapse
|
|
16
|
Cardiotrophin-1 promotes a high survival rate in rabbits with lethal fulminant hepatitis of viral origin. J Virol 2011; 85:13124-32. [PMID: 21976657 DOI: 10.1128/jvi.05725-11] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Rabbit hemorrhagic disease virus (RHDV) causes lethal fulminant hepatitis closely resembling acute liver failure (ALF) in humans. In this study, we investigated whether cardiotrophin-1 (CT-1), a cytokine with hepatoprotective properties, could attenuate liver damage and prolong survival in virus-induced ALF. Twenty-four rabbits were infected with 2 × 10(4) hemagglutination units of RHDV. Twelve received five doses of CT-1 (100 μg/kg) starting at 12 h postinfection (hpi) (the first three doses every 6 h and then two additional doses at 48 and 72 hpi), while the rest received saline. The animals were analyzed for survival, serum biochemistry, and viral load. Another cohort (n = 22) was infected and treated similarly, but animals were sacrificed at 30 and 36 hpi to analyze liver histology, viral load, and the expression of factors implicated in liver damage and repair. All infected rabbits that received saline died by 60 hpi, while 67% of the CT-1-treated animals survived until the end of the study. Treated animals showed improved liver function and histology, while the viral loads were similar. In the livers of CT-1-treated rabbits we observed reduction of oxidative stress, diminished PARP1/2 and JNK activation, and decreased inflammatory reaction, as reflected by reduced expression of tumor necrosis factor alpha, interleukin-1β, Toll-like receptor 4, VCAM-1, and MMP-9. In addition, CT-1-treated rabbits exhibited marked upregulation of TIMP-1 and increased expression of cytoprotective and proregenerative growth factors, including platelet-derived growth factor B, epidermal growth factor, platelet-derived growth factor receptor β, and c-Met. In conclusion, in a lethal form of acute viral hepatitis, CT-1 increases animal survival by attenuating inflammation and activating cytoprotective mechanisms, thus representing a promising therapy for ALF of viral origin.
Collapse
|
|
17
|
Abstract
Bone marrow mesenchymal stem cells (BM-MSCs) are a kind of multipotent stem cells that have the capacity to undergo self-renewal and multi-lineage differentiation. In an appropriate microenvironment, BM-MSCs can differentiate into bone, cartilage, fat, nerve, liver or other cells. Based on this characteristic, BM-MSCs might be used as new seed cells for orthotopic liver transplantation and bioartificial liver support system. This paper reviews the recent advances in research on the use of BM-MSCs as a treatment for acute liver failure.
Collapse
|