|
1
|
Pretzsch E, Nieß H, Khaled NB, Bösch F, Guba M, Werner J, Angele M, Chaudry IH. Molecular Mechanisms of Ischaemia-Reperfusion Injury and Regeneration in the Liver-Shock and Surgery-Associated Changes. Int J Mol Sci 2022; 23:12942. [PMID: 36361725 PMCID: PMC9657004 DOI: 10.3390/ijms232112942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/16/2022] [Accepted: 10/20/2022] [Indexed: 09/01/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (IRI) represents a major challenge during liver surgery, liver preservation for transplantation, and can cause hemorrhagic shock with severe hypoxemia and trauma. The reduction of blood supply with a concomitant deficit in oxygen delivery initiates various molecular mechanisms involving the innate and adaptive immune response, alterations in gene transcription, induction of cell death programs, and changes in metabolic state and vascular function. Hepatic IRI is a major cause of morbidity and mortality, and is associated with an increased risk for tumor growth and recurrence after oncologic surgery for primary and secondary hepatobiliary malignancies. Therapeutic strategies to prevent or treat hepatic IRI have been investigated in animal models but, for the most part, have failed to provide a protective effect in a clinical setting. This review focuses on the molecular mechanisms underlying hepatic IRI and regeneration, as well as its clinical implications. A better understanding of this complex and highly dynamic process may allow for the development of innovative therapeutic approaches and optimize patient outcomes.
Collapse
Affiliation(s)
- Elise Pretzsch
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Hanno Nieß
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Florian Bösch
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany
| | - Markus Guba
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Martin Angele
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Irshad H. Chaudry
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| |
Collapse
|
|
2
|
Vachher M, Bansal S, Kumar B, Yadav S, Arora T, Wali NM, Burman A. Contribution of organokines in the development of NAFLD/NASH associated hepatocellular carcinoma. J Cell Biochem 2022; 123:1553-1584. [PMID: 35818831 DOI: 10.1002/jcb.30252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/17/2022] [Accepted: 03/29/2022] [Indexed: 12/16/2022]
Abstract
Globally the incidence of hepatocellular carcinoma (HCC) is on an upsurge. Evidence is accumulating that liver disorders like nonalcoholic fatty liver disease (NAFLD) and its more progressive form nonalcoholic steatohepatitis (NASH) are associated with increased risk of developing HCC. NAFLD has a prevalence of about 25% and 50%-90% in obese population. With the growing burden of obesity epidemic worldwide, HCC presents a major healthcare burden. While cirrhosis is one of the major risk factors of HCC, available literature suggests that NAFLD/NASH associated HCC also develops in minimum or noncirrhotic livers. Therefore, there is an urgent need to understand the pathogenesis and risk factors associated with NAFLD and NASH related HCC that would help in early diagnosis and favorable prognosis of HCC secondary to NAFLD. Adipokines, hepatokines and myokines are factors secreted by adipocytes, hepatocytes and myocytes, respectively, playing essential roles in cellular homeostasis, energy balance and metabolism with autocrine, paracrine and endocrine effects. In this review, we endeavor to focus on the role of these organokines in the pathogenesis of NAFLD/NASH and its progression to HCC to augment the understanding of the factors stimulating hepatocytes to acquire a malignant phenotype. This shall aid in the development of novel therapeutic strategies and tools for early diagnosis of NAFLD/NASH and HCC.
Collapse
Affiliation(s)
- Meenakshi Vachher
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Savita Bansal
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Bhupender Kumar
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Sandeep Yadav
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Taruna Arora
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Nalini Moza Wali
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Archana Burman
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| |
Collapse
|
|
3
|
González-Candia A, Candia AA, Paz A, Mobarec F, Urbina-Varela R, del Campo A, Herrera EA, Castillo RL. Cardioprotective Antioxidant and Anti-Inflammatory Mechanisms Induced by Intermittent Hypobaric Hypoxia. Antioxidants (Basel) 2022; 11:antiox11061043. [PMID: 35739940 PMCID: PMC9220055 DOI: 10.3390/antiox11061043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 05/05/2022] [Accepted: 05/06/2022] [Indexed: 11/25/2022] Open
Abstract
More than 80 million people live and work (in a chronic or intermittent form) above 2500 masl, and 35 million live in the Andean Mountains. Furthermore, in Chile, it is estimated that 100,000 people work in high-altitude shifts, where stays in the lowlands are interspersed with working visits in the highlands. Acute exposure to high altitude has been shown to induce oxidative stress in healthy human lowlanders due to increased free radical formation and decreased antioxidant capacity. However, intermittent hypoxia (IH) induces preconditioning in animal models, generating cardioprotection. Here, we aim to describe the responses of a cardiac function to four cycles of intermittent hypobaric hypoxia (IHH) in a rat model. The twelve adult Wistar rats were randomly divided into two equal groups, a four-cycle of IHH and a normobaric hypoxic control. Intermittent hypoxia was induced in a hypobaric chamber in four continuous cycles (1 cycle = 4 days of hypoxia + 4 days of normoxia), reaching a barometric pressure equivalent to 4600 m of altitude (428 Torr). At the end of the fourth cycle, cardiac structural and functional variables were also determined by echocardiography; furthermore, cardiac oxidative stress biomarkers (4-Hydroxynonenal, HNE; nitrotyrosine, NT), antioxidant enzymes, and NLRP3 inflammasome panel expression are also determined. Our results show a higher ejection and a shortening fraction of the left ventricle function by the end of the fourth cycle. Furthermore, cardiac tissue presented a decreased expression of antioxidant proteins. However, a decrease in IL-1β, TNF-αn, and oxidative stress markers is observed in IHH compared to normobaric hypoxic controls. Non-significant differences were found in protein levels of NLRP3 and caspase-1. IHH exposure determines structural and functional heart changes. These findings suggest that initial states of IHH are beneficial for cardiovascular function and protection.
Collapse
Affiliation(s)
| | - Alejandro A. Candia
- Laboratory of Vascular Function & Reactivity, Pathophysiology Program, ICBM, Faculty of Medicine, Universidad de Chile, Santiago 7500922, Chile; (A.A.C.); (A.P.); (F.M.)
- Department for the Woman and Newborn Health Promotion, Universidad de Chile, Santiago 7500922, Chile
| | - Adolfo Paz
- Laboratory of Vascular Function & Reactivity, Pathophysiology Program, ICBM, Faculty of Medicine, Universidad de Chile, Santiago 7500922, Chile; (A.A.C.); (A.P.); (F.M.)
| | - Fuad Mobarec
- Laboratory of Vascular Function & Reactivity, Pathophysiology Program, ICBM, Faculty of Medicine, Universidad de Chile, Santiago 7500922, Chile; (A.A.C.); (A.P.); (F.M.)
| | - Rodrigo Urbina-Varela
- Laboratorio de Fisiología y Bioenergética Celular, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile; (R.U.-V.); (A.d.C.)
| | - Andrea del Campo
- Laboratorio de Fisiología y Bioenergética Celular, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile; (R.U.-V.); (A.d.C.)
| | - Emilio A. Herrera
- Laboratory of Vascular Function & Reactivity, Pathophysiology Program, ICBM, Faculty of Medicine, Universidad de Chile, Santiago 7500922, Chile; (A.A.C.); (A.P.); (F.M.)
- International Center for Andean Studies (INCAS), University of Chile, Putre 1070000, Chile
- Correspondence: (E.A.H.); or (R.L.C.); Tel.: +56-982-337-566 (R.L.C.)
| | - Rodrigo L. Castillo
- Departamento de Medicina Interna Oriente, Facultad de Medicina, Universidad de Chile, Santiago 7500922, Chile
- Unidad de Paciente Crítico, Hospital del Salvador, Santiago 7500922, Chile
- Correspondence: (E.A.H.); or (R.L.C.); Tel.: +56-982-337-566 (R.L.C.)
| |
Collapse
|
|
4
|
Zhang S, Cao Y, Xu B, Zhang H, Zhang S, Sun J, Tang Y, Wang Y. An antioxidant nanodrug protects against hepatic ischemia-reperfusion injury by attenuating oxidative stress and inflammation. J Mater Chem B 2022; 10:7563-7569. [PMID: 35389415 DOI: 10.1039/d1tb02689e] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Liver transplantation is currently recognized as the only effective therapeutic option for end-stage liver disease. Hepatic ischemia-reperfusion injury (IRI) remains a major cause of graft damage or dysfunction, and is mediated by the abundant production of reactive oxygen species (ROS) and a complex cascade of inflammation during the reperfusion period. However, no universal antioxidant has been applied in clinical practice due to its low bioavailability and non-specific targeting. Herein, cerium oxide and manganese oxide nanocomposites (CM NCs), with the advantages of high biocompatibility, passive liver-targeting and short-term metabolic excretion, were synthesized as a nanodrug for hepatic IRI therapy. The CM NCs exhibited excellent superoxide dismutase (SOD) and catalase (CAT) mimetic activity to scavenge ROS and generate oxygen (O2). Therefore, CM NCs could alleviate oxidative stress, subsequently suppress the activation of Kupffer cells (KCs) and neutrophils, and reduce the secretion of inflammatory factors due to the synergistic effect of ROS scavenging and O2 production. By exploring the underlying mechanisms of the CM NCs in the treatment of hepatic IRI, we suggest that the CM NCs with ROS scavenging and inflammation regulation capacity show clinical potential for hepatic IRI management and provide new perspectives in the treatment of other oxidative-stress-related diseases.
Collapse
Affiliation(s)
- Shuai Zhang
- Department of Cardiovascular Center, The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, Jilin, China.
| | - Yue Cao
- The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, Jilin, China
| | - Bo Xu
- The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, Jilin, China
| | - Hao Zhang
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry (CIAC), Chinese Academy of Sciences, Changchun, Jilin, 130022, China.
| | - Songtao Zhang
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry (CIAC), Chinese Academy of Sciences, Changchun, Jilin, 130022, China.
| | - Jian Sun
- Department of Cardiovascular Center, The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, Jilin, China.
| | - Ying Tang
- Department of Gastroenterol, The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, Jilin, China.
| | - Yinghui Wang
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry (CIAC), Chinese Academy of Sciences, Changchun, Jilin, 130022, China.
| |
Collapse
|
|
5
|
Srivastava A, Sharma H, Khanna S, Sadhu Balasundaram T, Chowdhury S, Chowdhury R, Mukherjee S. Interleukin-6 Induced Proliferation Is Attenuated by Transforming Growth Factor-β-Induced Signaling in Human Hepatocellular Carcinoma Cells. Front Oncol 2022; 11:811941. [PMID: 35127527 PMCID: PMC8810489 DOI: 10.3389/fonc.2021.811941] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 12/13/2021] [Indexed: 11/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is often associated with an inflammatory setting. A plethora of cytokines are secreted in this milieu, actively contributing to the progression of the disease; however, the extent of cytokine interaction and how it contributes to HCC development remains an enigma. In this regard, our analysis of available patient-derived data suggests that cytokines like interleukin-6 (IL-6) and transforming growth factor-beta (TGF-β) are enriched in HCC. We further analyzed the effect of these cytokines independently or in combination on HCC cells. Importantly, IL-6 was found to induce a STAT-3-dependent proliferation and mediate its pro-proliferative effects through activation and direct interaction with the p65 subunit of NFkB. Alternatively, TGF-β was found to induce a SMAD-dependent induction of epithelial to mesenchymal transition (EMT) coupled to growth arrest in these cells. Interestingly, the simultaneous addition of IL-6 and TGF-β failed to profoundly impact EMT markers but resulted in attenuation of IL-6-induced pro-proliferative effects. Analysis of the putative molecular mechanism revealed a decrease in IL-6 receptor (IL-6R) transcript levels, reduced expression of IL-6-induced STAT-3, and its nuclear localization upon addition of TGF-β along with IL-6. Consequently, a reduced p65 activation was also observed in combination treatment. Importantly, SMAD levels were unperturbed and the cells showed more TGF-β-like features under combination treatment. Finally, we observed that TGF-β resulted in enrichment of repressive chromatin mark (H3K27me3) coupled to growth arrest, while IL-6 induced an open chromatin signature (H3K4me3) associated with an enhanced expression of EZH2. Overall, for the first time, we show that TGF-β attenuates IL-6-induced effects by regulating the receptor level, downstream signaling, and the epigenome. Understanding the complex interactions between these cytokines can be imperative to a better understanding of the disease, and manipulation of cytokine balance can act as a prospective future therapeutic strategy.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Sudeshna Mukherjee
- Department of Biological Sciences, Birla Institute of Technology and Science (BITS) Pilani, Rajasthan, India
| |
Collapse
|
|
6
|
Risk factors of early liver dysfunction after liver transplantation using grafts from donation after citizen death donors. Transpl Immunol 2022; 71:101525. [PMID: 34990790 DOI: 10.1016/j.trim.2021.101525] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 12/29/2021] [Indexed: 11/23/2022]
Abstract
BACKGROUND As an early complication after liver transplantation, early allograft dysfunction (EAD) indicates a poor prognosis. This study analyzes the risk factors related to early allograft dysfunction (EAD) after liver transplantation using grafts from donation after citizen death (DCD) to provide a reference for the prevention of EAD after DCD liver transplantation. METHODS A total of 32 patients who underwent DCD liver transplantation in the organ transplantation center of our hospital from September 2013 to January 2021 were enrolled in this study. The patients were divided into the EAD group and non-EAD group according to whether they developed EAD after transplantation. The general data of the donors and recipients before transplantation, intraoperative conditions, and clinical data within one week after transplantation were compared between the two groups, and related complications were statistically analyzed. The follow-up time was one week postoperatively or, if they died within the first week postoperatively, until the patient died. RESULTS The subjects included 10 females and 22 males, and the incidence of postoperative EAD was 25% (8/32). Four patients (12%) had primary malignant tumors (primary liver cancer and cholangiocarcinoma), and five donors (15%) had fatty liver. The univariate analysis revealed that the donor BMI (P = 0.005), degree of fatty liver (P = 0.025), aspartate aminotransferase (P = 0.001), alanine aminotransferase (P < 0.001), and total bilirubin (P = 0.009) were related to the occurrence of EAD after DCD liver transplantation. By analyzing the correlation between the incidence EAD and postoperative complications after liver transplantation using grafts from DCD donors, it was shown that the incidence of primary nonfunction (PNF) is related to EAD (P = 0.024). CONCLUSION Donor BMI, the degree of fatty liver, and preoperative liver function are risk factors for EAD after DCD liver transplantation, and the occurrence of EAD after DCD liver transplantation significantly increases the probability of PNF.
Collapse
|
|
7
|
Quantitative Proteomic Analysis of Plasma after Remote Ischemic Conditioning in a Rhesus Monkey Ischemic Stroke Model. Biomolecules 2021; 11:biom11081164. [PMID: 34439830 PMCID: PMC8393806 DOI: 10.3390/biom11081164] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/02/2021] [Accepted: 08/04/2021] [Indexed: 11/28/2022] Open
Abstract
Background: Animal and clinical studies have shown that remote ischemic conditioning (RIC) has protective effects for cerebral vascular diseases, with induced humoral factor changes in the peripheral blood. However, many findings are heterogeneous, perhaps due to differences in the RIC intervention schemes, enrolled populations, and sample times. This study aimed to examine the RIC-induced changes in the plasma proteome using rhesus monkey models of strokes. Methods: Two adult rhesus monkeys with autologous blood clot-induced middle cerebral artery (MCA) occlusion underwent RIC interventions twice a week for five consecutive weeks. Each RIC treatment included five cycles of five minutes of ischemia alternating with five minutes of reperfusion of the forearm. The blood samples were taken from the median cubital vein of the monkeys at baseline and immediately after each week’s RIC stimulus. The plasma samples were isolated for a proteomic analysis using mass spectrometry (MS). Results: Several proteins related to lipid metabolism (Apolipoprotein A-II and Apolipoprotein C-II), coagulation (Fibrinogen alpha chain and serpin), immunoinflammatory responses (complement C3 and C1), and endovascular hemostasis (basement membrane-specific heparan sulfate proteoglycan) were significantly modulated after the RIC intervention. Many of these induced changes, such as in the lipid metabolism regulation and anticoagulation responses, starting as early as two weeks following the RIC intervention. The complementary activation and protection of the endovascular cells occurred more than three weeks postintervention. Conclusions: Multiple protective effects were induced by RIC and involved lipid metabolism regulation (anti-atherogenesis), anticoagulation (antithrombosis), complement activation, and endovascular homeostasis (anti-inflammation). In conclusion, this study indicates that RIC results in significant modulations of the plasma proteome. It also provides ideas for future research and screening targets.
Collapse
|
|
8
|
Duan Y, Meng Y, Gao Z, Wang X, Zhang H. microRNA-9-5p protects liver sinusoidal endothelial cell against oxygen glucose deprivation/reperfusion injury. Open Life Sci 2021; 16:375-383. [PMID: 33977146 PMCID: PMC8060979 DOI: 10.1515/biol-2021-0042] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 01/15/2021] [Accepted: 02/10/2021] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Maintenance of the function and survival of liver sinusoidal endothelial cells (LSECs) play a crucial role in hepatic ischemia/reperfusion (I/R) injury, a major cause of liver impairment during the surgical treatment. Emerging evidence indicates a critical role of microRNAs in I/R injury. This study aims to investigate whether miR-9-5p exerts a protective effect on LSECs. METHODS We transfected LSECs with miR-9-5p mimic or mimic NC. LSECs were treated with oxygen and glucose deprivation (OGD, 5% CO2, and 95% N2), followed by glucose-free Dulbecco's modified Eagle's medium (DMEM) medium for 6 h and high glucose (HG, 30 mmol/L glucose) DMEM medium for 12 h. The biological role of miR-9-5p in I/R-induced LSEC injury was determined. RESULTS In the in vitro model of OGD/HG injury in LSECs, the expression levels of miR-9-5p were significantly downregulated, and those of CXC chemokine receptor-4 (CXCR4) upregulated. LSEC I/R injury led to deteriorated cell death, enhanced oxidative stress, and excessive inflammatory response. Mechanistically, we showed that miR-9-5p overexpression significantly downregulated both mRNA and protein levels of CXCR4, followed by the rescue of LSECs, ameliorated inflammatory response, and deactivation of pro-apoptotic signaling pathways. CONCLUSIONS miR-9-5p promotes LSEC survival and inhibits apoptosis and inflammatory response in LSECs following OGD/HG injury via downregulation of CXCR4.
Collapse
Affiliation(s)
- Yi Duan
- Department of Anesthesiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Beijing 102218, China
| | - Yuanyuan Meng
- Department of Anesthesiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Beijing 102218, China
| | - Zhifeng Gao
- Department of Anesthesiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Beijing 102218, China
| | - Xiaoyu Wang
- Department of Anesthesiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Beijing 102218, China
| | - Huan Zhang
- Department of Anesthesiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Beijing 102218, China
| |
Collapse
|
|
9
|
Inhaled Argon Impedes Hepatic Regeneration after Ischemia/Reperfusion Injury in Rats. Int J Mol Sci 2020; 21:ijms21155457. [PMID: 32751707 PMCID: PMC7432339 DOI: 10.3390/ijms21155457] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 07/20/2020] [Accepted: 07/28/2020] [Indexed: 11/16/2022] Open
Abstract
Organoprotective effects of noble gases are subject of current research. One important field of interest is the effect of noble gases on hepatic regenerative capacity. For the noble gas argon, promising studies demonstrated remarkable experimental effects in neuronal and renal cells. The aim of this study was to investigate the effects of argon on the regenerative capacity of the liver after ischemia/reperfusion injury (IRI). Male, Sprague-Dawley rats underwent hepatic IRI by clamping of the hepatic artery. Expression of hepatoproliferative genes (HGF, IL-1β, IL-6, TNF), cell cycle markers (BrdU, TUNEL, Ki-67), and liver enzymes (ALT, AST, Bilirubin, LDH) were assessed 3, 36, and 96 h after IRI. Expression of IL-1β and IL-6 was significantly higher after argon inhalation after 36 h (IL-1β 5.0 vs. 8.7 fold, p = 0.001; IL-6 9.6 vs. 19.1 fold, p = 0.05). Ki-67 was higher in the control group compared to the argon group after 36 h (214.0 vs. 38.7 positive cells/1000 hepatocytes, p = 0.045). Serum levels of AST and ALT did not differ significantly between groups. Our data indicate that argon inhalation has detrimental effects on liver regeneration after IRI as measured by elevated levels of the proinflammatory cytokines IL-1β and IL-6 after 36 h. In line with these results, Ki-67 is decreased in the argon group, indicating a negative effect on liver regeneration in argon inhalation.
Collapse
|
|
10
|
Abstract
The NLRP3 inflammasome may contribute to infarct development during acute cardiac ischemia-reperfusion (IR). Because infarct size strongly correlates with the degree of heart failure in the long term, therapies that reduce reperfusion injury are still needed as first primary care against heart failure development. Inhibition of the NLRP3 inflammasome is currently viewed as such a potential therapy. However, previous research studies directed at inhibition of various inflammatory pathways in acute cardiac IR injury were often disappointing. This is because inflammation is a double-edged sword, detrimental when hyperactive, but beneficial at lower activity, with activity critically dependent on time of reperfusion and cellular location. Moreover, several inflammatory mediators can also mediate cardioprotective signaling. It is reasonable that this also applies to the NLRP3 inflammasome, although current literature has mainly focused on its detrimental effects in the context of acute cardiac IR. Therefore, in this review, we focus on beneficial, cardioprotective properties of the NLRP3 inflammasome and its components NLRP3, ASC, and caspase-1. The results show that (1) NLRP3 deficiency prevents cardioprotection in isolated heart by ischemic preconditioning and in vivo heart by TLR2 activation, associated with impaired STAT3 or Akt signaling, respectively; (2) ASC deficiency also prevents in vivo TLR2-mediated protection; and (3) caspase-1 inhibition results in decreased infarction but impaired protection through the Akt pathway during mild ischemic insults. In conclusion, the NLRP3 inflammasome is not only detrimental, it can also be involved in cardioprotective signaling, thus fueling the future challenge to acquire a full understanding of NLRP3 inflammasome role in cardiac IR before embarking on clinical trials using NLRP3 inhibitors.
Collapse
|
|
11
|
Saito H, Tanaka T, Sugahara M, Tanaka S, Fukui K, Wakashima T, Nangaku M. Inhibition of prolyl hydroxylase domain (PHD) by JTZ-951 reduces obesity-related diseases in the liver, white adipose tissue, and kidney in mice with a high-fat diet. J Transl Med 2019; 99:1217-1232. [PMID: 30952940 DOI: 10.1038/s41374-019-0239-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 01/16/2019] [Accepted: 01/28/2019] [Indexed: 12/11/2022] Open
Abstract
The epidemic of obesity and its complications is rapidly increasing worldwide. Recent drug discoveries established the utility of prolyl hydroxylase domain (PHD) inhibitors as stabilizers of hypoxia-inducible factors (HIFs) in vivo, which are currently in human clinical studies for the treatment of anemia in chronic kidney disease (CKD). These studies suggest a role for PHD inhibitors in ameliorating obesity and hyperlipidemia. We hypothesized that HIF activation using a PHD inhibitor, JTZ-951, protects from obesity-related diseases in the white adipose tissue (WAT), liver, and kidney in mice fed with high-fat diet (HFD). Eight-week-old, C57BL/6J mice were fed with HFD for 20 weeks with or without JTZ-951(0.005%; mixed in chow). Body weight and plasma non-high-density lipoprotein (HDL) cholesterol levels were significantly lower in the JTZ-951 group as compared with the vehicle group. PHD inhibition improved liver steatosis, macrophage infiltration into WAT and adipocyte fibrosis. In the kidney, PHD inhibition reduced albuminuria. Histologically, the number of F4/80- positive infiltrating macrophages and mesangial expansion were milder in the JTZ-951 group. Relative mRNA expression of adiponectin in WAT was higher in the JTZ-951-treated group and inversely correlated with hepatic steatosis score, adipocyte macrophage aggregation, and albuminuria. Activation of HIF ameliorates multiple obesity-related consequences in mice with HFD. The results of the present study offer the promising view that pharmacological PHD inhibition may be beneficial for the treatment of obesity-related diseases that can be ameliorated by weight loss.
Collapse
Affiliation(s)
- Hisako Saito
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Tetsuhiro Tanaka
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
| | - Mai Sugahara
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Shinji Tanaka
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Kenji Fukui
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.,Biological and Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc, Osaka, Japan
| | - Takeshi Wakashima
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.,Biological and Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc, Osaka, Japan
| | - Masaomi Nangaku
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
| |
Collapse
|
|
12
|
Zhao J, Wang Y, Wu X, Tong P, Yue Y, Gao S, Huang D, Huang J. Inhibition of CCL19 benefits non‑alcoholic fatty liver disease by inhibiting TLR4/NF‑κB‑p65 signaling. Mol Med Rep 2018; 18:4635-4642. [PMID: 30221732 DOI: 10.3892/mmr.2018.9490] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 08/21/2018] [Indexed: 11/06/2022] Open
Abstract
Non‑alcoholic fatty liver disease (NAFLD), which affects approximately one‑third of the general population, has become a global health problem. Thus, more effective treatments for NAFLD are urgently required. In the present study, high levels of C‑C motif ligand 19 (CCL19), signaling pathways such as Toll‑like receptor 4 (TLR4)/nuclear factor‑κB (NF‑κB), and proinflammatory factors including interleukin‑6 (IL‑6) and tumor necrosis factor‑α (TNF‑α) were detected in NAFLD patients, thereby indicating that there may be an association between CCL19 and these factors in NAFLD progression. Using a high‑fat diet (HFD), the present study generated a Sprague‑Dawley rat model of NAFLD, which displayed dyslipidemia with increased levels of plasma aspartate aminotransferase, alanine aminotransferase, total cholesterol and triglyceride. Dyslipidemia, liver histopathology and gene expression analyses indicated that the NAFLD model was successfully induced by HFD, and metformin and berberine (BBR) were effective treatments for NAFLD. HFD‑induced CCL19 levels and associated factors were markedly reduced by the two drug treatments. In addition, metformin or BBR alone significantly promoted adenosine monophosphate‑activated protein kinase (AMPK) phosphorylation, which was inhibited by HFD. These results demonstrated that metformin and BBR could improve NAFLD, which may be via the activation of AMPK signaling, and the high expression of CCL19 in NAFLD was significantly reduced by metformin and BBR. It could be inferred that inhibition of CCL19 may be an effective treatment for NAFLD.
Collapse
Affiliation(s)
- Jiajing Zhao
- Department of Traditional Chinese Medicine, Putuo District People's Hospital of Shanghai City, Shanghai 200060, P.R. China
| | - Yingjue Wang
- Department of Traditional Chinese Medicine, Putuo District People's Hospital of Shanghai City, Shanghai 200060, P.R. China
| | - Xi Wu
- Department of Endocrinology, Huashan Hospital, Fu Dan University, Shanghai 200040, P.R. China
| | - Ping Tong
- Department of Endocrinology, Putuo District People's Hospital of Shanghai City, Shanghai 200060, P.R. China
| | - Yaohan Yue
- Department of Traditional Chinese Medicine, Putuo District People's Hospital of Shanghai City, Shanghai 200060, P.R. China
| | - Shurong Gao
- Department of Traditional Chinese Medicine, Putuo District People's Hospital of Shanghai City, Shanghai 200060, P.R. China
| | - Dongping Huang
- Department of General Surgery, Putuo District People's Hospital of Shanghai City, Shanghai 200060, P.R. China
| | - Jianwei Huang
- Department of General Surgery, Putuo District People's Hospital of Shanghai City, Shanghai 200060, P.R. China
| |
Collapse
|
|
13
|
Zhou D, Ding J, Ya J, Pan L, Wang Y, Ji X, Meng R. Remote ischemic conditioning: a promising therapeutic intervention for multi-organ protection. Aging (Albany NY) 2018; 10:1825-1855. [PMID: 30115811 PMCID: PMC6128414 DOI: 10.18632/aging.101527] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Accepted: 08/10/2018] [Indexed: 12/21/2022]
Abstract
Despite decades of formidable exploration, multi-organ ischemia-reperfusion injury (IRI) encountered, particularly amongst elderly patients with clinical scenarios, such as age-related arteriosclerotic vascular disease, heart surgery and organ transplantation, is still an unsettled conundrum that besets clinicians. Remote ischemic conditioning (RIC), delivered via transient, repetitive noninvasive IR interventions to distant organs or tissues, is regarded as an innovative approach against IRI. Based on the available evidence, RIC holds the potential of affording protection to multiple organs or tissues, which include not only the heart and brain, but also others that are likely susceptible to IRI, such as the kidney, lung, liver and skin. Neuronal and humoral signaling pathways appear to play requisite roles in the mechanisms of RIC-related beneficial effects, and these pathways also display inseparable interactions with each other. So far, several hurdles lying ahead of clinical translation that remain to be settled, such as establishment of biomarkers, modification of RIC regimen, and deep understanding of underlying minutiae through which RIC exerts its powerful function. As this approach has garnered an increasing interest, herein, we aim to encapsulate an overview of the basic concept and postulated protective mechanisms of RIC, highlight the main findings from proof-of-concept clinical studies in various clinical scenarios, and also to discuss potential obstacles that remain to be conquered. More well designed and comprehensive experimental work or clinical trials are warranted in future research to confirm whether RIC could be utilized as a non-invasive, inexpensive and efficient adjunct therapeutic intervention method for multi-organ protection.
Collapse
Affiliation(s)
- Da Zhou
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Department of China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Geriatric Disorders, Beijing, China
- Equal contribution
| | - Jiayue Ding
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Department of China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Geriatric Disorders, Beijing, China
- Equal contribution
| | - Jingyuan Ya
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Department of China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Geriatric Disorders, Beijing, China
| | - Liqun Pan
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Department of China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Geriatric Disorders, Beijing, China
| | - Yuan Wang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Department of China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Geriatric Disorders, Beijing, China
| | - Xunming Ji
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Department of China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Geriatric Disorders, Beijing, China
| | - Ran Meng
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Department of China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Geriatric Disorders, Beijing, China
| |
Collapse
|
|
14
|
Brisson H, Arbelot C, Monsel A, Parisot C, Girard M, Savier E, Vezinet C, Lu Q, Vaillant JC, Golmard JL, Gorochov G, Langeron O, Rouby JJ. Impact of graft preservation solutions for liver transplantation on early cytokine release and postoperative organ dysfunctions. A pilot study. Clin Res Hepatol Gastroenterol 2017; 41:564-574. [PMID: 28330599 DOI: 10.1016/j.clinre.2016.12.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 12/23/2016] [Accepted: 12/28/2016] [Indexed: 02/06/2023]
Abstract
INTRODUCTION During liver transplantation, graft ischemia-reperfusion injury leads to a systemic inflammatory response producing postoperative organ dysfunctions. The aim of this observational and prospective study was to compare the impact of Solution de conservation des organes et tissus (SCOT) 15 and University of Wisconsin (UW) preservation solutions on early cytokine release, postreperfusion syndrome and postoperative organ dysfunctions. METHODS Thirty-seven liver transplantations were included: 21 in UW Group and 16 in SCOT 15 group. Five cytokines were measured in systemic blood after anesthetic induction, 30minutes after unclamping portal vein and on postoperative day 1. RESULTS Following unclamping portal vein, cytokines were released in systemic circulation. Systemic cytokine concentrations were higher in UW than in SCOT 15 group: Interleukin-10, Interleukine-6. In SCOT 15 group, significant reduction of postreperfusion syndrome incidence and acute kidney injury were observed. Alanine and aspartate aminotransferase peak concentrations were higher in SCOT 15 group than in UW group. However, from postoperative day 1 to day 10, aminotransferase returned to normal values and did not differ between groups. CONCLUSIONS Compared to UW, SCOT 15 decreases systemic cytokine release resulting from graft ischemia-reperfusion injury and reduces incidence of postreperfusion syndrome and postoperative renal failure.
Collapse
Affiliation(s)
- H Brisson
- Department of Anesthesiology and Critical Care Medicine, Multidisciplinary Intensive Care Unit, AP-HP, La Pitié-Salpêtrière Hospital, université Paris 06, université Pierre-et-Marie-Curie, 75013 Paris, France(1); UMR-S 945, La Pitié-Salpêtrière Hospital, Institut national de la santé et de la recherche médicale, AP-HP, université Paris 06, université Pierre-et-Marie-Curie, 75013 Paris, France.
| | - C Arbelot
- Department of Anesthesiology and Critical Care Medicine, Multidisciplinary Intensive Care Unit, AP-HP, La Pitié-Salpêtrière Hospital, université Paris 06, université Pierre-et-Marie-Curie, 75013 Paris, France(1)
| | - A Monsel
- Department of Anesthesiology and Critical Care Medicine, Multidisciplinary Intensive Care Unit, AP-HP, La Pitié-Salpêtrière Hospital, université Paris 06, université Pierre-et-Marie-Curie, 75013 Paris, France(1)
| | - C Parisot
- UMR-S 945, La Pitié-Salpêtrière Hospital, Institut national de la santé et de la recherche médicale, AP-HP, université Paris 06, université Pierre-et-Marie-Curie, 75013 Paris, France
| | - M Girard
- Department of Anesthesiology and Critical Care Medicine, Multidisciplinary Intensive Care Unit, AP-HP, La Pitié-Salpêtrière Hospital, université Paris 06, université Pierre-et-Marie-Curie, 75013 Paris, France(1)
| | - E Savier
- Department of Digestive and Hepato-Pancreato-Biliary Surgery, AP-HP, La Pitié-Salpêtrière Hospital, université Paris 06, université Pierre-et-Marie-Curie, 75013 Paris, France; Inserm, U1082, plateform IBISA, université de Poitiers, faculté de médecine et de pharmacie, 86021 Poitiers, France
| | - C Vezinet
- Department of Anesthesiology and Critical Care Medicine, Multidisciplinary Intensive Care Unit, AP-HP, La Pitié-Salpêtrière Hospital, université Paris 06, université Pierre-et-Marie-Curie, 75013 Paris, France(1)
| | - Q Lu
- Department of Anesthesiology and Critical Care Medicine, Multidisciplinary Intensive Care Unit, AP-HP, La Pitié-Salpêtrière Hospital, université Paris 06, université Pierre-et-Marie-Curie, 75013 Paris, France(1)
| | - J-C Vaillant
- Department of Digestive and Hepato-Pancreato-Biliary Surgery, AP-HP, La Pitié-Salpêtrière Hospital, université Paris 06, université Pierre-et-Marie-Curie, 75013 Paris, France
| | - J-L Golmard
- ER4 "Modélisation en recherche clinique", université Paris 06, université Pierre-et-Marie-Curie et UF de biostatistique, La Pitié-Salpêtrière Hospital, 75013 Paris, France
| | - G Gorochov
- UMR-S 945, La Pitié-Salpêtrière Hospital, Institut national de la santé et de la recherche médicale, AP-HP, université Paris 06, université Pierre-et-Marie-Curie, 75013 Paris, France
| | - O Langeron
- Department of Anesthesiology and Critical Care Medicine, Multidisciplinary Intensive Care Unit, AP-HP, La Pitié-Salpêtrière Hospital, université Paris 06, université Pierre-et-Marie-Curie, 75013 Paris, France(1)
| | - J-J Rouby
- Department of Anesthesiology and Critical Care Medicine, Multidisciplinary Intensive Care Unit, AP-HP, La Pitié-Salpêtrière Hospital, université Paris 06, université Pierre-et-Marie-Curie, 75013 Paris, France(1)
| | | |
Collapse
|
|
15
|
Potential Hepatoprotective Role of Galectin-3 during HCV Infection in End-Stage Renal Disease Patients. DISEASE MARKERS 2017; 2017:6275987. [PMID: 28487598 PMCID: PMC5405569 DOI: 10.1155/2017/6275987] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 02/24/2017] [Accepted: 02/26/2017] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus infection (HCV), one of the greatest causes of liver disease, is a frequent complication in patients with end-stage renal disease (ESRD) on dialysis. ESRD is defined as decreased glomerular filtration and also accompanied by impaired function of the immune system. Galectin-3 is a β-galactoside-binding lectin, involved in various biological processes including pathogenesis of chronic renal disease. The aim of our study was to estimate disease severity in ESRD HCV+ patients and analyze the serum concentrations of IL-1β, IL-4, IL-23, and IL-6; anti-HCV antibodies; and galectin-3. Also, we attempted to determine potential correlation between galectin-3 level and parameters of disease severity ALT and AST. Our results showed decreased levels of ALT and AST (p = 0.00), demonstrating less liver destruction in ESRD HCV+ patients in comparison to HCV+ patients. Increased levels of IL-6 (p = 0.03) implicate a hepatoprotective role of IL-6 in these patients. Also, level of galectin-3 (p = 0.00) in the serum of ESRD HCV+ patients was higher than that of HCV+ patients. This alteration was accompanied with negative correlation between galectin-3 and AST and ALT, respectively (p = 0.029; p = 0.033). The presence of increased systemic levels of IL-6 and Gal-3 in ESRD HCV+ patients may be an attempt to counteract or limit ongoing proinflammatory processes and to downregulate chronic inflammation, suggesting the new aspects of HCV infection in ESRD patients.
Collapse
|
|
16
|
Sosa RA, Zarrinpar A, Rossetti M, Lassman CR, Naini BV, Datta N, Rao P, Harre N, Zheng Y, Spreafico R, Hoffmann A, Busuttil RW, Gjertson DW, Zhai Y, Kupiec-Weglinski JW, Reed EF. Early cytokine signatures of ischemia/reperfusion injury in human orthotopic liver transplantation. JCI Insight 2016; 1:e89679. [PMID: 27942590 DOI: 10.1172/jci.insight.89679] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND. Orthotopic liver transplant (OLT) is the primary therapy for end-stage liver disease and acute liver failure. However, ischemia/reperfusion injury (IRI) can severely compromise allograft survival. To understand the evolution of immune responses underlying OLT-IRI, we evaluated longitudinal cytokine expression profiles from adult OLT recipients before transplant through 1 month after transplant. METHODS. We measured the expression of 38 cytokines, chemokines, and growth factors in preoperative and postoperative recipient circulating systemic blood (before transplant and 1 day, 1 week, and 1 month after transplant) and intraoperative portal blood (before and after reperfusion) of 53 OLT patients and analyzed this expression in relation to biopsy-proven IRI (n = 26 IRI+; 27 IRI-), clinical liver function tests early (days 1-7) after transplant, and expression of genes encoding cytokine receptors in biopsies of donor allograft taken before and after reperfusion. RESULTS. Bilirubin and arginine transaminase levels early after transplant correlated with IRI. Fourteen cytokines were significantly increased in the systemic and/or portal blood of IRI+ recipients that shifted from innate to adaptive-immune responses over time. Additionally, expression of cognate receptors for 10 of these cytokines was detected in donor organ biopsies by RNAseq. CONCLUSION. These results provide a mechanistic roadmap of the early immunological events both before and after IRI and suggest several candidates for patient stratification, monitoring, and treatment. FUNDING. Ruth L. Kirschstein National Research Service Award T32CA009120, Keck Foundation award 986722, and a Quantitative & Computational Biosciences Collaboratory Postdoctoral Fellowship.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Ping Rao
- Department of Pathology and Laboratory Medicine
| | | | - Ying Zheng
- Department of Pathology and Laboratory Medicine
| | - Roberto Spreafico
- Department of Microbiology, Immunology, and Molecular Genetics, and.,Institute for Quantitative and Computational Biosciences, UCLA, California, USA
| | - Alexander Hoffmann
- Department of Microbiology, Immunology, and Molecular Genetics, and.,Institute for Quantitative and Computational Biosciences, UCLA, California, USA
| | | | | | | | | | | |
Collapse
|
|
17
|
Li C, Li J, Chen Y, Zhong X, Kang M. Effect of curcumin on visfatin and zinc-α2-glycoprotein in a rat model of non-alcoholic fatty liver disease. Acta Cir Bras 2016; 31:706-713. [DOI: 10.1590/s0102-865020160110000001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 10/16/2016] [Indexed: 12/19/2022] Open
Affiliation(s)
| | | | - Yun Chen
- Southwest Medical University, China
| | | | - Min Kang
- Southwest Medical University, China
| |
Collapse
|
|
18
|
Detection of piRNAs in whitespotted bamboo shark liver. Gene 2016; 590:51-6. [PMID: 27267405 DOI: 10.1016/j.gene.2016.06.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Revised: 05/20/2016] [Accepted: 06/03/2016] [Indexed: 01/12/2023]
Abstract
Piwi-interacting RNAs (piRNAs) are 26 to 31-nt small non-coding RNAs that have been reported mostly in germ-line cells and cancer cells. However, the presence of piRNAs in the whitespotted bamboo shark liver has not yet been reported. In a previous study of microRNAs in shark liver, some piRNAs were detected from small RNAs sequenced by Solexa technology. A total of 4857 piRNAs were predicted and found in shark liver. We further selected 17 piRNAs with high and significantly differential expression between normal and regenerative liver tissues for subsequent verification by Northern blotting. Ten piRNAs were further identified, and six of these were matched to known piRNAs in piRNABank. The actual expression of six known and four novel piRNAs was validated by qRT-PCR. In addition, a total of 401 target genes of the 10 piRNAs were predicted by miRanda. Through GO and pathway function analyses, only five piRNAs could be annotated with eighteen GO annotations. The results indicated that the identified piRNAs are involved in many important biological responses, including immune inflammation, cell-specific differentiation and development, and angiogenesis. This manuscript provides the first identification of piRNAs in the liver of whitespotted bamboo shark using Solexa technology as well as further elucidation of the regulatory role of piRNAs in whitespotted bamboo shark liver. These findings may provide a useful resource and may facilitate the development of therapeutic strategies against liver damage.
Collapse
|
|
19
|
Cannistrà M, Ruggiero M, Zullo A, Gallelli G, Serafini S, Maria M, Naso A, Grande R, Serra R, Nardo B. Hepatic ischemia reperfusion injury: A systematic review of literature and the role of current drugs and biomarkers. Int J Surg 2016; 33 Suppl 1:S57-70. [PMID: 27255130 DOI: 10.1016/j.ijsu.2016.05.050] [Citation(s) in RCA: 243] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatic ischemia reperfusion injury (IRI) is not only a pathophysiological process involving the liver, but also a complex systemic process affecting multiple tissues and organs. Hepatic IRI can seriously impair liver function, even producing irreversible damage, which causes a cascade of multiple organ dysfunction. Many factors, including anaerobic metabolism, mitochondrial damage, oxidative stress and secretion of ROS, intracellular Ca(2+) overload, cytokines and chemokines produced by KCs and neutrophils, and NO, are involved in the regulation of hepatic IRI processes. Matrix Metalloproteinases (MMPs) can be an important mediator of early leukocyte recruitment and target in acute and chronic liver injury associated to ischemia. MMPs and neutrophil gelatinase-associated lipocalin (NGAL) could be used as markers of I-R injury severity stages. This review explores the relationship between factors and inflammatory pathways that characterize hepatic IRI, MMPs and current pharmacological approaches to this disease.
Collapse
Affiliation(s)
- Marco Cannistrà
- Department of Surgery, Annunziata Hospital of Cosenza, Cosenza, Italy.
| | - Michele Ruggiero
- Department of Surgery, Annunziata Hospital of Cosenza, Cosenza, Italy.
| | - Alessandra Zullo
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | - Giuseppe Gallelli
- Department of Emergency, Pugliese-Ciaccio Hospital, Catanzaro, Italy.
| | - Simone Serafini
- Department of Surgery, Annunziata Hospital of Cosenza, Cosenza, Italy.
| | - Mazzitelli Maria
- Department of Primary Care, Provincial Health Authority of Vibo Valentia, 89900 Vibo Valentia, Italy.
| | - Agostino Naso
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | - Raffaele Grande
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | - Raffaele Serra
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | - Bruno Nardo
- Department of Surgery, Annunziata Hospital of Cosenza, Cosenza, Italy; Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, University of Bologna, Italy.
| |
Collapse
|
|
20
|
Interleukin-6 concentration in the transgenic pig's liver preserved for 24 hours in Biolasol solution. Transplant Proc 2015; 46:2552-4. [PMID: 25380863 DOI: 10.1016/j.transproceed.2014.09.047] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
INTRODUCTION Increasing the human lifespan contributes to a higher number of patients with end-stage organ failure, which in turn stimulates the search for alternative sources. Xenotransplantation seems to be a promising approach in this respect. OBJECTIVE Analysis of changes in interleukin (IL)-6 concentration during 24-hour preservation of transgenic swine livers, depending on the kind of transgenesis and preservation solution used. MATERIALS AND METHODS The experiment was carried out in swine livers with transferred human genes that were divided into 5 groups. The following human genes were transferred: α1,2-fucosyltransferase (group I and II), α-galactosidase (III), combined α1,2-fucosyltransferase/α-galactosidase transgene (IV), and livers without modification (V). The livers were perfused and subsequently stored for 24 hours in Ringer's (group I) or Biolasol solutions (II-V). Reflush was then performed. IL-6 concentration was analyzed in the solution samples collected at the beginning and end of perfusion, and after 24 hours of preservation. ELISA was used to evaluate IL-6 concentration. RESULTS In liver homogenates from group I, IL-6 concentration after 24 hours of preservation increased by 8.24% compared to the levels observed after perfusion, whereas in the other groups IL-6 concentration decreased. The most significant decrease, 49.51%, was observed in group II; the least significant in group IV, 10.72%. In case of supernatants, a statistically significant increase of AUC0-30min level in relation to perfusion was observed in every group after 24-hour preservation and reperfusion. The highest values of AUC0-30min were observed in group I (α1,2-fucosyltransferase, Ringer's solution). CONCLUSION The study indicates the hepatoprotective action of Biolasol solution.
Collapse
|
|
21
|
Athanasopoulos P, Mastoraki A, Papalois A, Nastos C, Kondi-Pafiti A, Kostopanagiotou G, Smyrniotis V, Arkadopoulos N. Expression of Inflammatory and Regenerative Genes in a Model of Liver Ischemia/Reperfusion and Partial Hepatectomy. J INVEST SURG 2015; 29:67-73. [DOI: 10.3109/08941939.2015.1060280] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
|
|
22
|
Iyer S, Upadhyay PK, Majumdar SS, Nagarajan P. Animal Models Correlating Immune Cells for the Development of NAFLD/NASH. J Clin Exp Hepatol 2015; 5:239-45. [PMID: 26628841 PMCID: PMC4632099 DOI: 10.1016/j.jceh.2015.06.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Accepted: 06/08/2015] [Indexed: 02/08/2023] Open
Abstract
This review mainly elaborates on the animal models available for understanding the pathogenesis of the second hit of non-alcoholic fatty liver disease (NAFLD) involving immune system. This is known to be a step forward from simple steatosis caused during the first hit, which leads to the stage of inflammation followed by more serious liver conditions like non-alcoholic steatohepatitis (NASH) and cirrhosis. Immune-deficient animal models serve as an important tool for understanding the role of a specific cell type or a cytokine in the progression of NAFLD. These animal models can be used in combination with the already available animal models of NAFLD, including dietary models, as well as genetically modified mouse models. Advancements in molecular biological techniques enabled researchers to produce several new animal models for the study of NAFLD, including knockin, generalized knockout, and tissue-specific knockout mice. Development of NASH/NAFLD in various animal models having compromised immune system is discussed in this review.
Collapse
Key Words
- APPs, acute-phase proteins
- BAFF, B cell activating factor
- Btk, Bruton's tyrosine kinase gene
- DAMPs, damage-associated molecular patterns
- HCC, hepatocellular carcinoma
- IRFs, Interferon regulatory factors
- JNK, c-Jun N-terminal kinase
- MCD, methionine choline-deficient
- NAFLD
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- NLRs, Nod-like receptors
- PAMPs, pathogen-associated molecular patterns
- immune cells
- mouse models
Collapse
Affiliation(s)
| | | | | | - Perumal Nagarajan
- Address for correspondence: Perumal Nagarajan, National Institute of Immunology, Experimental Animal Facility, JNU Campus, New Delhi 110067, India. Tel.: +91 11 26703709; fax: +91 11 26742125.
| |
Collapse
|
|
23
|
Gravante G, Ong SL, Metcalfe MS, Sorge R, Sconocchia G, Orlando G, Lloyd DM, Dennison AR. Cytokine response to ischemia/reperfusion injury in an ex vivo perfused porcine liver model. Transplant Proc 2015; 41:1107-12. [PMID: 19460492 DOI: 10.1016/j.transproceed.2009.02.054] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND We evaluated the degree of inflammatory response after ischemia/reperfusion injury by an extracorporeal normothermic autologous hemoperfusion of porcine livers. MATERIALS AND METHODS Livers explanted from 7 pigs were perfused extracorporeally at 39 degrees C with autologous blood. Serum samples were obtained hourly until 6 hours from the beginning of reperfusion and assayed for 9 different cytokines. RESULTS Significant elevations in interleukin 6 (IL-6) and IL-8 were noted following reperfusion (P < .001), with both demonstrating an increase which followed a sigmoid curve; other cytokines that were assessed showed no significant change. CONCLUSIONS The ex vivo model excludes the liver from the influence of external systemic factors such as hormones, the autonomic nervous system, and other regulatory molecules produced elsewhere in the body, allowing the response to the ischemia/reperfusion injury to be studied in isolation and in considerable detail. Although this study examined a relatively short period, the increases in only IL-6 and IL-8 suggested that these are important molecules in the early phase after reperfusion.
Collapse
Affiliation(s)
- G Gravante
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, United Kingdom.
| | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Giri S, Acikgöz A, Bader A. Isolation and Expansion of Hepatic Stem-like Cells from a Healthy Rat Liver and their Efficient Hepatic Differentiation of under Well-defined Vivo Hepatic like Microenvironment in a Multiwell Bioreactor. J Clin Exp Hepatol 2015; 5:107-22. [PMID: 26155038 PMCID: PMC4491607 DOI: 10.1016/j.jceh.2015.03.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 03/20/2015] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Currently, undifferentiated cells are found in all tissue and term as local stem cells which are quiescent in nature and less in number under normal healthy conditions but activate upon injury and repair the tissue or organs via automated activating mechanism. Due to very scanty presence of local resident somatic local stem cells in healthy organs, isolation and expansion of these adult stems is an immense challenge for medical research and cell based therapy. Particularly organ like liver, there is an ongoing controversy about existence of liver stem cells. METHODS Herein, Hepatic stem cells population was identified during culture of primary hepatocyte cells upon immediate isolation of primary hepatocyte cells. These liver stem cells has been expanded extensively and differentiated into primary hepatocytes under defined culture conditions in a nanostructured self assembling peptides modular bioreactor that mimic the state of art of liver microenvironment and compared with Matrigel as a positive control. Nanostructured self assembling peptides were used a defined extracellular matrix and Matrigel was used for undefined extracellular matrix. Proliferation of hepatic stem cells was investigated by two strategies. First strategy is to provide high concentration of hepatocyte growth factor (HGF) and second strategy is to evaluate the role of recombinant human erythropoietin (rHuEPO) in presence of trauma/ischemia cytokines (IL-6, TNF-α). Expansion to hepatic differentiation is observed by morphological analysis and was evaluated for the expression of hepatocyte-specific genes using RT-PCR and biochemical methods. RESULTS Hepatocyte-specific genes are well expressed at final stage (day 21) of differentiation period. The differentiated hepatocytes exhibited functional hepatic characteristics such as albumin secretion, urea secretion and cytochrome P450 expression. Additionally, immunofluorescence analysis revealed that hepatic stem cells derived hepatocytes exhibited mature hepatocyte markers (albumin, CK-19, CPY3A1, alpha 1-antitrypsin). Expansion and hepatic differentiation was efficiently in nanostructured self assembling peptides without such batch to batch variation while there was much variation in Matrigel coated bioreactor. In conclusion, the results of the study suggest that the nanostructured self assembling peptides coated bioreactor supports expansion as well as hepatic differentiation of liver stem cells which is superior than Matrigel. CONCLUSION This defined microenvironment conditions in bioreactor module can be useful for research involving bioartificial liver system, stem cell research and engineered liver tissue which could contribute to regenerative cell therapies or drug discovery and development.
Collapse
Key Words
- A1AT, Alpha 1-antitrypsin
- AFP, α-fetoprotein
- CK 7, Cytokeratin 7
- CK-19, Cytokeratin 19
- CPY3A1, Cytochrome P450 3A 1
- EROD, Ethoxyresorufin O-deethylase
- GaIN, D-galactosamine
- HGF, Hepatocyte growth factor
- IL-6, Interleukin 6
- MROD, Methoxyresorufin O-demethylase
- Matrigel
- PROD, Pentoxyresorufin O-depentylase
- TNF-α, Tumor necrosis factor alpha
- Thy1, Thy-1 cell surface antigen
- bioreactor
- defined culture conditions
- hepatic stem cells
- nanostructured self assembling peptides
- rHuEPO, Recombinant human erythropoietin
Collapse
Affiliation(s)
- Shibashish Giri
- Department of Cell Techniques and Applied Stem Cell Biology, Center for Biotechnology and Biomedicine (BBZ), University of Leipzig, Deutscher Platz 5, 04103 Leipzig, Germany,Address for correspondence: Shibashish Giri, Department of Cell Techniques and Applied Stem Cell Biology, Center for Biotechnology and Biomedicine, Medical faculty, University of Leipzig, Deutscher Platz 5, D-04103 Leipzig, Germany.
| | - Ali Acikgöz
- Department of Cell Techniques and Applied Stem Cell Biology, Center for Biotechnology and Biomedicine (BBZ), University of Leipzig, Deutscher Platz 5, 04103 Leipzig, Germany,Department of Gastroenterology and Hepatology, Klinikum St Georg, Delitzscher Straße, Leipzig, Germany
| | - Augustinus Bader
- Department of Cell Techniques and Applied Stem Cell Biology, Center for Biotechnology and Biomedicine (BBZ), University of Leipzig, Deutscher Platz 5, 04103 Leipzig, Germany
| |
Collapse
|
|
25
|
Stojsavljević S, Gomerčić Palčić M, Virović Jukić L, Smirčić Duvnjak L, Duvnjak M. Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20:18070-18091. [PMID: 25561778 PMCID: PMC4277948 DOI: 10.3748/wjg.v20.i48.18070] [Citation(s) in RCA: 247] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 10/21/2014] [Accepted: 11/18/2014] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient with no history of alcohol abuse or other causes for secondary hepatic steatosis. The pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) has not been fully elucidated. The "two-hit" hypothesis is probably a too simplified model to elaborate complex pathogenetic events occurring in patients with NASH. It should be better regarded as a multiple step process, with accumulation of liver fat being the first step, followed by the development of necroinflammation and fibrosis. Adipose tissue, which has emerged as an endocrine organ with a key role in energy homeostasis, is responsive to both central and peripheral metabolic signals and is itself capable of secreting a number of proteins. These adipocyte-specific or enriched proteins, termed adipokines, have been shown to have a variety of local, peripheral, and central effects. In the current review, we explore the role of adipocytokines and proinflammatory cytokines in the pathogenesis of NAFLD. We particularly focus on adiponectin, leptin and ghrelin, with a brief mention of resistin, visfatin and retinol-binding protein 4 among adipokines, and tumor necrosis factor-α, interleukin (IL)-6, IL-1, and briefly IL-18 among proinflammatory cytokines. We update their role in NAFLD, as elucidated in experimental models and clinical practice.
Collapse
|
|
26
|
Guan LY, Fu PY, Li PD, Li ZN, Liu HY, Xin MG, Li W. Mechanisms of hepatic ischemia-reperfusion injury and protective effects of nitric oxide. World J Gastrointest Surg 2014; 6:122-128. [PMID: 25068009 PMCID: PMC4110529 DOI: 10.4240/wjgs.v6.i7.122] [Citation(s) in RCA: 132] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Revised: 05/26/2014] [Accepted: 06/20/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (IRI) is a pathophysiological event post liver surgery or transplantation and significantly influences the prognosis of liver function. The mechanisms of IRI remain unclear, and effective methods are lacking for the prevention and therapy of IRI. Several factors/pathways have been implicated in the hepatic IRI process, including anaerobic metabolism, mitochondria, oxidative stress, intracellular calcium overload, liver Kupffer cells and neutrophils, and cytokines and chemokines. The role of nitric oxide (NO) in protecting against liver IRI has recently been reported. NO has been found to attenuate liver IRI through various mechanisms including reducing hepatocellular apoptosis, decreasing oxidative stress and leukocyte adhesion, increasing microcirculatory flow, and enhancing mitochondrial function. The purpose of this review is to provide insights into the mechanisms of liver IRI, indicating the potential protective factors/pathways that may help to improve therapeutic regimens for controlling hepatic IRI during liver surgery, and the potential therapeutic role of NO in liver IRI.
Collapse
|
|
27
|
Han J, Yu C, Souza RF, Theiss AL. Prohibitin 1 modulates mitochondrial function of Stat3. Cell Signal 2014; 26:2086-95. [PMID: 24975845 DOI: 10.1016/j.cellsig.2014.06.006] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 06/19/2014] [Indexed: 02/08/2023]
Abstract
Mitochondrial dysfunction in intestinal epithelial cells (IEC) is thought to precede the onset of inflammatory bowel diseases (IBD). Expression of Prohibitin 1 (PHB), a mitochondrial protein required for optimal electron transport chain (ETC) activity, is decreased in mucosal biopsies during active and inactive IBD. In addition to its activities as a transcription factor, Signal Transducer and Activator of Transcription 3 (Stat3) resides in the mitochondria of cells where phosphorylation at S727 is required for optimal ETC activity and protects against stress-induced mitochondrial dysfunction. Here, we show that PHB overexpression protects against mitochondrial stress and apoptosis of cultured IECs induced by TNFα, which is a pro-inflammatory cytokine involved in IBD pathogenesis. Expression of pS727-Stat3 dominant negative eliminates protection by PHB against TNFα-induced mitochondrial stress and apoptosis. PHB interacts with pS727-Stat3 in the mitochondria of cultured IECs and in colonic epithelium from wild-type mice. Our data suggest a protective role of PHB that is dependent on pS727-Stat3 to prevent mitochondrial dysfunction in IECs. Reduced levels of PHB during IBD may be an underlying factor promoting mitochondrial dysfunction of the intestinal epithelium.
Collapse
Affiliation(s)
- Jie Han
- Department of Internal Medicine, Division of Gastroenterology, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, United States
| | - Chunhua Yu
- Department of Medicine, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Rhonda F Souza
- Department of Medicine, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Arianne L Theiss
- Department of Internal Medicine, Division of Gastroenterology, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, United States.
| |
Collapse
|
|
28
|
Qi Q, Bie P. Different roles of hepatic hypothermic ischemia and ischemic preconditioning in chemically induced hepatocarcinogenesis in rats. J Surg Res 2014; 189:213-21. [PMID: 24725680 DOI: 10.1016/j.jss.2014.03.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 02/28/2014] [Accepted: 03/05/2014] [Indexed: 12/22/2022]
Abstract
BACKGROUND Hepatic ischemia-reperfusion (IR) injury, an unfavorable complication of hepatectomy, could be prevented by hypothermic ischemia and ischemic preconditioning (IPC). However, the effects of these two approaches on hepatocarcinogenesis have not been examined. The aim of the study was to investigate roles of hypothermic ischemia and IPC in a chemically induced rat liver tumor model. METHODS Twenty-four Sprague-Dawley rats were treated with diethylnitrosamine and phenobarbital to induce hepatocellular carcinoma. Rats underwent hepatic ischemic injury, hypothermic ischemia, and IPC. Twenty-eight-wk-old rats were sacrificed to evaluate the morbidity and growth of liver tumor. Cytokines were measured at the protein and messenger RNA level. RESULTS IR injury significantly promoted liver tumor development. Intriguingly, hypothermic ischemia, but not IPC, delayed liver carcinogenesis, although both of them suppressed the hepatic IR injury. IPC-treated rats showed elevated interleukin (IL)-6 concentration in the serum and messenger RNA expression in liver. In addition, higher levels of IL-6 activated signal transducer and activator of transcription 3 in the liver of IPC-treated rats. The hepatic expression of target genes of signal transducer and activator of transcription 3 signaling, cyclin D1, c-myc, c-fos, and c-jun, all of which might participate in tumor progression, increased in IPC group, compared with that of IR group. CONCLUSIONS These data indicated hypothermic ischemia could ameliorate both IR injury and liver tumor development. However, IPC, another effective method to prevent hepatic IR injury, might exacerbate liver tumor growth. The elevated level of IL-6 was one of the reasons for the different effects of hypothermic ischemia and IPC on hepatocarcinogenesis in rats.
Collapse
Affiliation(s)
- Qingan Qi
- Southwest Hospital and Institute of Hepatobilitary Surgery, Third Military Medical University, Chongqing, China
| | - Ping Bie
- Southwest Hospital and Institute of Hepatobilitary Surgery, Third Military Medical University, Chongqing, China.
| |
Collapse
|
|
29
|
Ischemic preconditioning improves liver tolerance to congestion-reperfusion injury in mice. J Surg Res 2014; 189:152-8. [PMID: 24589179 DOI: 10.1016/j.jss.2014.01.061] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 01/13/2014] [Accepted: 01/31/2014] [Indexed: 12/15/2022]
Abstract
BACKGROUND Congestion-reperfusion injury (CRI) is a common complication after living donor liver transplantation, which has not been fully understood. It causes more severe inflammatory response as compared with ischemia-reperfusion injury (IRI). Ischemic preconditioning (IPC) has been endowed with powerful protective properties toward IRI. This study aimed to investigate whether IPC also has a protective effect against CRI and potential underlying mechanisms. MATERIALS AND METHODS Mice were randomly divided into sham operation, CRI, IPC-CRI, and congestion precondition (CPC-CRI) group. The hepatic vein of the left anterior hepatic lobe was occluded for 75 min followed by reperfusion in the CRI group. The blood inflow was previously clamped for 10 min followed by 10 min of reperfusion just before occluding the hepatic vein in the IPC-CRI group. To imitating IPC in the CPC-CRI group, 10 min of congestion followed by 10 min of reperfusion just before CRI was performed. The animals were sacrificed at 2, 6, 24, 48 h, and 7 d after reperfusion. The blood and liver samples were collected for hepatic function assay, histology, terminal deoxynucleotidyl transferase dUTP nick end labeling, myeloperoxidase, and real-time polymerase chain reaction analysis. RESULTS Mice in the CRI, IPC-CRI, and CPC-CRI group demonstrated elevated liver enzymes, histologic damage, cellular apoptosis, and inflammatory response compared with those in the sham operation group. Compared with the CRI group, mice in the IPC-CRI group expressed lower alanine transaminase activities (2 h: 839.2 ± 132.5 versus 384.2 ± 94.8, P < 0.01; and 6 h: 680 ± 142.4 versus 342.3 ± 99.7, P < 0.01) and lower myeloperoxidase levels (2 h: 7.1 ± 4.0 U/g versus 3.8 ± 1.6 U/g, P < 0.05; and 6 h: 8.1 ± 1.3 U/g versus 5.2 ± 3.0 U/g, P < 0.05). However, the alanine transaminase level in the CPC-CRI group was notably higher at 2 h (839.2 ± 132.5 versus 1087.5 ± 192.5, P < 0.05). Livers from mice in the IPC-CRI group showed better tissue integrity, diminished hepatocellular injury, and apoptosis at 2 and 6 h. The messenger RNA transcriptions of interleukin 1 and interleukin 6 were significantly lower after 2-24 h of reperfusion, whereas tumor necrosis factor α and monocyte chemoattractant protein 1 were significantly lower after 24 h of reperfusion in the IPC-CRI group. CONCLUSIONS IPC can significantly improve liver tolerance to CRI by attenuating neutrophil infiltration, proinflammatory cytokine formation, and hepatocytes apoptosis. This pretreatment strategy holds greater prospect of being translated into clinical use in living donor liver transplantation.
Collapse
|
|
30
|
Krenz M, Baines C, Kalogeris T, Korthuis R. Cell Survival Programs and Ischemia/Reperfusion: Hormesis, Preconditioning, and Cardioprotection. ACTA ACUST UNITED AC 2013. [DOI: 10.4199/c00090ed1v01y201309isp044] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
|
|
31
|
Heeringa M, Hastings A, Yamazaki S, de Koning P. Serum biomarkers in nonalcoholic steatohepatitis: value for assessing drug effects? Biomark Med 2013; 6:743-57. [PMID: 23227839 DOI: 10.2217/bmm.12.87] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease throughout the world. In the USA, approximately 3-5% of the population are affected, and the prevalence of this condition is increasing. NASH is associated with an increased risk of liver-related morbidity, such as cirrhosis and fibrosis, as well as cardiovascular disease, and in spite of several clinical studies investigating putative new drugs, no approved treatment is currently available. This is partly due to the nature of the disease. NASH is a complex, slowly progressing disease, and confirmatory clinical trials have long treatment durations and require invasive end points (a liver biopsy). Such invasive assessments are only accepted in confirmatory trials; clinical studies in the exploratory clinical development phase must rely on noninvasive biomarkers as the primary end point. Experimental and clinical research continues to achieve validation and qualification of biomarkers in NASH, which will hopefully assist the development of new treatments for NASH patients.
Collapse
Affiliation(s)
- Marten Heeringa
- Global Clinical Pharmacology & Exploratory Development, Astellas Pharma Global Development-Europe, Elisabethhof 1, 2353 EW Leiderdorp, The Netherlands.
| | | | | | | |
Collapse
|
|
32
|
Chiu CC, Huang YT, Wang YC, Chang YC, Ching YH, Chen HHC, Chuang HL. Pretreatment with lipopolysaccharide ameliorates Pseudomonas exotoxin A-induced hepatotoxicity in rats. Immunopharmacol Immunotoxicol 2013; 35:296-303. [PMID: 23384342 DOI: 10.3109/08923973.2013.764503] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
CONTEXT Liver injury can be induced by various hepatotoxicants, including Pseudomonas aeruginosa exotoxin A (PEA). Our previous study indicated that PEA-induced rat hepatotoxicity was T cells and Kupffer cells dependent. Several reports have demonstrated that non-toxic doses of bacterial lipopolysaccharide (LPS) can protect liver against the chemicals-induced toxicity such as acetaminophen and concanavalin-A. OBJECTIVE This study aimed to investigate the protecting mechanisms of LPS on PEA-induced hepatotoxicity. RESULTS Rats pretreated with LPS (40 μg/kg, 12 h before PEA admission) significantly decreased animal mortality, serum enzyme (ALT, AST and T-bil) activities, histopathological changes and hepatocytes apoptosis following challenge with PEA. The concentrations of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and interleukin-2 (IL-2) were reduced, but IL-6 and IL-10 were increased in the serum. In addition, prior treatment of these LPS-pretreated rats with gadolinium chloride (GdCl3), a selective Kupffer cell depletion agent, markedly enhanced liver injury after PEA administration. In contrast, the pretreatment of LPS to T-cell deficient athymic nude rats still display significant attenuation of PEA-induced liver injury. This observation further confirmed our hypothesis that LPS ameliorate PEA-hepatotoxicity was through Kupffer cells but not T cells. Moreover, LPS-induced hepatoprotection ability was neutralized by co-treatment with anti-TNF-α antibodies, but not with anti-IFN-γ antibodies. Finally, replacement of LPS with RS-LPS (Rhodobacter sphaeroides LPS), a Toll like receptor-4 (TLR-4) antagonist, resulted in severe hepatotoxicity. CONCLUSION These results suggested that Kupffer cells, TNF-α and TLR-4 play central mediator roles during the hepatoprotection against PEA-induced hepatotoxicity conferred by LPS.
Collapse
|
|
33
|
Gultekin FA, Cakmak GK, Turkcu UO, Yurdakan G, Demir FEO, Comert M. Effects of Ozone Oxidative Preconditioning on Liver Regeneration after Partial Hepatectomy in Rats. J INVEST SURG 2013; 26:242-52. [DOI: 10.3109/08941939.2012.750698] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Fatma Ayca Gultekin
- Department of General Surgery, School of Medicine, Bulent Ecevit University, Kozlu, Zonguldak, Turkey
| | - Guldeniz Karadeniz Cakmak
- Department of General Surgery, School of Medicine, Bulent Ecevit University, Kozlu, Zonguldak, Turkey
| | | | - Gamze Yurdakan
- Department of Pathology, School of Medicine, Bulent Ecevit University, Kozlu, Zonguldak, Turkey
| | - F. Ebru Ofluoglu Demir
- Ahmet Erdogan Vocational School of Health Services, Bulent Ecevit University, Kozlu, Zonguldak, Turkey
| | - Mustafa Comert
- Department of General Surgery, School of Medicine, Bulent Ecevit University, Kozlu, Zonguldak, Turkey
| |
Collapse
|
|
34
|
Jin LM, Jin SF, Liu YX, Zhou L, Xie HY, Yan S, Xu X, Zheng SS. Ischemic preconditioning enhances hepatocyte proliferation in the early phase after ischemia under hemi-hepatectomy in rats. Hepatobiliary Pancreat Dis Int 2012; 11:521-6. [PMID: 23060398 DOI: 10.1016/s1499-3872(12)60217-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Ischemia/reperfusion (I/R) injury is an important barrier to liver surgery and transplantation because it impairs remnant liver/reduced-size-graft regeneration. Ischemic preconditioning (IPC), as an effective measure to overcome I/R injury, has been shown to enhance the regenerative capacity of hepatocytes. However, investigations have always focused on regeneration in the late phase after reperfusion. This study aimed to investigate whether IPC enhances hepatocyte proliferation in the early phase after reperfusion and possible underlying mechanisms. METHODS A total of 90 rats were divided into three groups: hemi-hepatectomy alone (PHx group), 60 minutes of ischemia plus hemi-hepatectomy (I/R group), and a cycle of 10 minutes of alternating I/R prior to 60 minutes of ischemia plus hemi-hepatectomy (IPC group). Each group was divided into five subgroups sacrificed after 0.5, 2, 6, 12 or 24 hours (n=6/subgroup). Subsequently, serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) were measured; caspase-3 and proliferating cell nuclear antigen (PCNA) proteins were also determined by Western blotting. Furthermore, PCNA was detected by immunohistochemistry to identify the expression site. RESULTS Serum ALT and AST levels after 2-24 hours of reperfusion in the PHx and IPC groups were remarkably decreased compared to the I/R group, and the serum TNF-alpha was relatively lower. A significant increase of serum IL-6 levels was found in the PHx and IPC groups compared with the I/R group at each time point. Furthermore, PCNA expression was remarkably increased in the IPC group after 6-12 hours of reperfusion, and in the earlier 0.5 and 6 hours time points after reperfusion have shown the massive PCNA-positive hepatocytes. At the same time, the expression of liver p-JNK was higher in the IPC group in the early phase after reperfusion than that of the I/R group and its expression was consistent with the PCNA. CONCLUSION IPC can initiate hepatocyte proliferation in the early phase after ischemia under hemi-hepatectomy, and may be associated with p-JNK expression and triggered by TNF-alpha/IL-6 signals.
Collapse
Affiliation(s)
- Li-Ming Jin
- Department of General Surgery, First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou 310003, China
| | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Ajamieh H, Farrell G, Wong HJ, Yu J, Chu E, Chen J, Teoh N. Atorvastatin protects obese mice against hepatic ischemia-reperfusion injury by Toll-like receptor-4 suppression and endothelial nitric oxide synthase activation. J Gastroenterol Hepatol 2012; 27:1353-61. [PMID: 22432744 DOI: 10.1111/j.1440-1746.2012.07123.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Steatosis accentuates the severity of hepatic ischemia-reperfusion injury (IRI). 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ("statins") protect the heart and brain against post-ischemic injury, without necessarily lowering serum cholesterol. We tested whether 10-day or 1-day atorvastatin administration protects livers with fatty change or non-alcoholic steatohepatitis (NASH) against IRI. METHODS Mice with dietary or genetic simple steatosis (SS) or NASH were subjected to 60 min of partial hepatic ischemia/24-h reperfusion, with/without atorvastatin administered with food (5 mg/kg body weight) for 10 days, or injected intravenously (5 mg/kg) 24 h before ischemia. Liver injury, Toll-like receptor-4 (TLR4), cytokines/chemokines, endothelial nitric oxide synthase (eNOS), activation and thromboxane B2 production were determined. RESULTS Atorvastatin conferred 70-90% hepatic protection against IRI in obese animals with SS or NASH, in which IRI was accentuated twofold to fivefold. IRI markedly upregulated TLR4 and activated nuclear factor-κB (NF-κB); atorvastatin abrogated these effects, as well as activating eNOS. Atorvastatin dampened the post-ischemic induction of thromboxane B2, macrophage inflammatory protein-1a, monocyte chemotactic protein-1, tumor necrosis factor-α, interleukin (IL)-12 p40, γ-interferon, IL-6, and adhesion molecules (vascular cell adhesion molecule-1, E-selectin, vascular endothelial-cadherin), and reduced macrophage and neutrophil recruitment. There was no reduction in serum cholesterol that could explain these effects, and hepatic cholesterol was normal in these mice. A single 24-h injection of atorvastatin conferred equivalent hepatoprotection. CONCLUSION Statins exert major hepatoprotection against IRI in lean, fatty, and NASH livers that is not due to cholesterol removal. Rather, statins downregulate TLR4 to prevent NF-κB activation, with resultant suppression of adhesion molecules, chemokines/cytokines, and thromboxane B2 production. Short-term statin treatment is an effective, readily-available preventive agent against hepatic IRI, irrespective of obesity and fatty liver disease.
Collapse
Affiliation(s)
- Hussam Ajamieh
- Gastroenterology and Hepatology Unit, Australian National University Medical School, the Canberra Hospital, Australian Capital Territory, Canberra, Australia
| | | | | | | | | | | | | |
Collapse
|
|
36
|
Zuurbier CJ, Jong WMC, Eerbeek O, Koeman A, Pulskens WP, Butter LM, Leemans JC, Hollmann MW. Deletion of the innate immune NLRP3 receptor abolishes cardiac ischemic preconditioning and is associated with decreased Il-6/STAT3 signaling. PLoS One 2012; 7:e40643. [PMID: 22848390 PMCID: PMC3407219 DOI: 10.1371/journal.pone.0040643] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Accepted: 06/13/2012] [Indexed: 01/04/2023] Open
Abstract
Objective Recent studies indicate that the innate immune system is not only triggered by exogenous pathogens and pollutants, but also by endogenous danger signals released during ischemia and necrosis. As triggers for the innate immune NLRP3 inflammasome protein complex appear to overlap with those for cardiac ischemia-reperfusion (I/R) and ischemic preconditioning (IPC), we explored the possibility that the NLRP3 inflammasome is involved in IPC and acute I/R injury of the heart. Principal Findings Baseline cardiac performance and acute I/R injury were investigated in isolated, Langendorff-perfused hearts from wild-type (WT), ASC−/− and NLRP3−/− mice. Deletion of NLRP3 inflammasome components ASC−/− or NLRP3−/− did not affect baseline performance. The deletions exacerbated I/R-induced mechanical dysfunction, but were without effect on I/R-induced cell death. When subjected to IPC, WT and ASC−/− hearts were protected against I/R injury (improved function and less cell death). However, IPC did not protect NLRP3−/− hearts against I/R injury. NLRP3−/− hearts had significantly decreased cardiac IL-6 levels with a trend towards lower IL-1β levels at end reperfusion, suggesting abrogation of IPC through diminished IL-6 and/or IL-1β signaling. Subsequent experiments showed that neutralising IL-6 using an antibody against IL-6 abrogated IPC in WT hearts. However, inhibition of the IL-1r receptor with the IL-1 receptor inhibitor Anakinra (100 mg/L) did not abrogate IPC in WT hearts. Analysis of survival kinases after IPC demonstrated decreased STAT3 expression in NLRP3−/− hearts when compared to WT hearts. Conclusions The data suggest that the innate immune NLRP3 protein, in an NLRP3-inflammasome-independent fashion, is an integral component of IPC in the isolated heart, possibly through an IL-6/STAT3 dependent mechanism.
Collapse
Affiliation(s)
- Coert J Zuurbier
- Laboratory of Experimental Intensive Care and Anesthesiology, Department of Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
| | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Xia YX, Lu L, Wu ZS, Pu LY, Sun BC, Wang XH. Inhibition of GSK-3beta ameliorates hepatic ischemia-reperfusion injury through GSK-3beta/beta-catenin signaling pathway in mice. Hepatobiliary Pancreat Dis Int 2012; 11:278-84. [PMID: 22672822 DOI: 10.1016/s1499-3872(12)60161-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Glycogen synthase kinase (GSK)-3beta/beta-catenin signaling regulates ischemia-reperfusion (I/R)-induced apoptosis and proliferation, and inhibition of GSK-3beta has beneficial effects on I/R injury in the heart and the central nervous system. However, the role of this signaling in hepatic I/R injury remains unclear. The present study aimed to investigate the effects and mechanism of GSK-3beta/beta-catenin signaling in hepatic I/R injury. METHODS Male C57BL/6 mice (weighing 22-25 g) were pretreated with either SB216763, an inhibitor of GSK-3beta, or vehicle. These mice were subjected to partial hepatic I/R. Blood was collected for test of alanine aminotransferase (ALT), and liver specimen for assays of phosphorylation at the Ser9 residue of GSK-3beta, GSK-3beta activity, axin 2 and the anti-apoptotic factors Bcl-2 and survivin, as well as the proliferative factors cyclin D1 and proliferating cell nuclear antigen, and apoptotic index (TUNEL). Real-time PCR, Western blotting and immunohistochemical staining were used. RESULTS SB216763 increased phospho-GSK-3beta levels and suppressed GSK-3beta activity (1880+/-229 vs 3280+/-272 cpm, P<0.01). ALT peaked at 6 hours after reperfusion. Compared with control, SB216763 decreased ALT after 6 hours of reperfusion (4451+/-424 vs 7868+/-845 IU/L, P<0.01), and alleviated hepatocyte necrosis and vacuolization. GSK-3beta inhibition led to the accumulation of beta-catenin in the cytosol (0.40+/-0.05 vs 1.31+/-0.11, P<0.05) and nucleus (0.62+/-0.14 vs 1.73+/-0.12, P<0.05), beta-catenin further upregulated the expression of axin 2. Upregulation of GSK-3beta/beta-catenin signaling increased Bcl-2, survivin and cyclin D1. Serological and histological analyses showed that SB216763 alleviated hepatic I/R-induced injury by reducing apoptosis (1.4+/-0.2% vs 3.6+/-0.4%, P<0.05) and enhanced liver proliferation (56+/-8% vs 19+/-4%, P<0.05). CONCLUSION Inhibition of GSK-3beta ameliorates hepatic I/R injury through the GSK-3beta/beta-catenin signaling pathway.
Collapse
Affiliation(s)
- Yong-Xiang Xia
- Liver Transplantation Center, Nanjing Medical University, Nanjing, China
| | | | | | | | | | | |
Collapse
|
|
38
|
Jia Y, Zhou F, Deng P, Fan Q, Li C, Liu Y, Fu X, Zhou Y, Xu X, Sun X. Interleukin 6 protects H(2)O(2)-induced cardiomyocytes injury through upregulation of prohibitin via STAT3 phosphorylation. Cell Biochem Funct 2012; 30:426-31. [PMID: 22431190 DOI: 10.1002/cbf.2820] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2011] [Accepted: 02/15/2012] [Indexed: 12/26/2022]
Abstract
OBJECTIVE Hydrogen peroxide (H(2)O(2)) is a potent reactive oxygen species that causes cardiomyocytes injury. As an important cytokine, interleukin 6 (IL-6) has cardioprotective effects as it plays an essential role in the late phase of preconditioning. Our work is to investigate if IL-6 preconditioning has protective effects on neonatal rat ventricular cardiomyocytes in response to H(2)O(2) and its underlying mechanism. METHODS Gel-based comparative proteomic approach along with small interfering RNA (siRNA) and Western blot analysis was used to analyse mechanisms of IL-6 preconditioning on H(2)O(2)-induced neonatal rat ventricular cardiomyocytes injury. RESULTS IL-6 preconditioning protected cardiomyocytes against H(2)O(2)-induced cell death. Proteomic analysis showed that IL-6 pretreatment further increased the expression of prohibitin and improved the viability of cardiomyocytes exposed to H(2)O(2). Knocking down of prohibitin with siRNA abrogated this protection by increasing apoptosis rate. Tyrosine kinase inhibitor AG490 decreased signal transducers and activators of transcription 3 (STAT3) phosphorylation and down-regulated prohibitin expression in cardiomyocytes pretreated with IL-6 and exposed to H(2)O(2), which further dampened the protective effects of IL-6 preconditioning. CONCLUSION Our results provide direct evidence that prohibitin is a protective factor of IL-6 preconditioning in H(2)O(2)-induced neonatal rat ventricular cardiomyocytes death. The upregulation of prohibitin by IL-6 is, at least, partially regulated through STAT3 phosphorylation.
Collapse
Affiliation(s)
- Yuhua Jia
- Nanfang hospital, Southern Medical University, Guangzhou, China
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Braunersreuther V, Viviani GL, Mach F, Montecucco F. Role of cytokines and chemokines in non-alcoholic fatty liver disease. World J Gastroenterol 2012; 18:727-35. [PMID: 22371632 PMCID: PMC3286135 DOI: 10.3748/wjg.v18.i8.727] [Citation(s) in RCA: 260] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Revised: 07/27/2011] [Accepted: 08/04/2011] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) includes a variety of histological conditions (ranging from liver steatosis and steatohepatitis, to fibrosis and hepatocarcinoma) that are characterized by an increased fat content within the liver. The accumulation/deposition of fat within the liver is essential for diagnosis of NAFLD and might be associated with alterations in the hepatic and systemic inflammatory state. Although it is still unclear if each histological entity represents a different disease or rather steps of the same disease, inflammatory processes in NAFLD might influence its pathophysiology and prognosis. In particular, non-alcoholic steatohepatitis (the most inflamed condition in NAFLDs, which more frequently evolves towards chronic and serious liver diseases) is characterized by a marked activation of inflammatory cells and the upregulation of several soluble inflammatory mediators. Among several mediators, cytokines and chemokines might play a pivotal active role in NAFLD and are considered as potential therapeutic targets. In this review, we will update evidence from both basic research and clinical studies on the potential role of cytokines and chemokines in the pathophysiology of NAFLD.
Collapse
|
|
40
|
Friedman BH, Wolf JH, Wang L, Putt ME, Shaked A, Christie JD, Hancock WW, Olthoff KM. Serum cytokine profiles associated with early allograft dysfunction in patients undergoing liver transplantation. Liver Transpl 2012; 18:166-76. [PMID: 22006860 PMCID: PMC3266982 DOI: 10.1002/lt.22451] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Early allograft dysfunction (EAD) occurring in the first week post-liver transplantation is associated with increased graft failure and mortality and is believed to be largely due to ischemia/reperfusion injury. We anticipated that the presence of EAD would be reflected by alterations in expression of serum proteins associated with an inflammatory response in the peri-operative period, and hypothesized that a specific pattern of expression might correlate with the development of EAD. The serum levels of 25 cytokines, chemokines, and immunoreceptors were measured by Luminex multiplex assays pre- and post-liver transplantation. Levels of each cytokine biomarker were compared in adult recipients with or without EAD at serial time points using samples collected pre-operatively and at 1, 7, 14, and 30 days post-transplant. EAD was defined according to standard criteria as maximum alanine transferase (ALT) or aspartate transferase (AST) levels on days 1-7 of >2000 U/ml, day 7 bilirubin level ≥10 mg/dl, or a day 7 international normalized ratio (INR) ≥1.7. Multivariable analyses showed that patients experiencing EAD had lower pre-operative IL-6 and higher IL-2R levels. Patients with EAD also showed higher MCP-1 (CCL2), IL-8 (CXCL8), and RANTES (CCL5) chemokine levels in the early post-operative period, suggesting up-regulation of the NF-kB pathway, in addition to higher levels of chemokines and cytokines associated with T cell immunity, including MIG (CXCL9), IP-10 (CXCL10) and IL-2R. These findings identify several possible biomarkers and pathways associated with EAD, that may guide future validation studies and investigation of specific cellular and molecular mechanisms of graft dysfunction. Furthermore, if validated, our findings may contribute to perioperative prediction of the occurrence of EAD and ultimately lead to identification of potential interventional therapies.
Collapse
Affiliation(s)
- Benjamin H. Friedman
- Department of Surgery, Penn Transplant Institute, University of Pennsylvania School of Medicine, Philadelphia, PA,Division of Transplantation Immunology, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA
| | - Joshua H. Wolf
- Department of Surgery, Penn Transplant Institute, University of Pennsylvania School of Medicine, Philadelphia, PA,Division of Transplantation Immunology, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA
| | - Liqing Wang
- Division of Transplantation Immunology, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA
| | - Mary E. Putt
- Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA
| | - Abraham Shaked
- Department of Surgery, Penn Transplant Institute, University of Pennsylvania School of Medicine, Philadelphia, PA
| | - Jason D. Christie
- Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA,Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA
| | - Wayne W. Hancock
- Division of Transplantation Immunology, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA
| | - Kim M. Olthoff
- Department of Surgery, Penn Transplant Institute, University of Pennsylvania School of Medicine, Philadelphia, PA,Correspondence and proofs: Kim M. Olthoff, M.D., Department of Surgery, Liver Transplant Program, University of Pennsylvania, 3400 Spruce Street, 2 Dulles Building, Philadelphia, PA 19104, Phone: 215-662-6136; Fax: 215-662-2244;
| |
Collapse
|
|
41
|
Fung CP, Chang FY, Lin JC, Ho DMT, Chen CT, Chen JH, Yeh KM, Chen TL, Lin YT, Siu LK. Immune response and pathophysiological features of Klebsiella pneumoniae liver abscesses in an animal model. J Transl Med 2011; 91:1029-39. [PMID: 21464821 DOI: 10.1038/labinvest.2011.52] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Capsular serotypes K1 and K2, the rmpA gene (a regulator of the mucoid phenotype) and aerobactin from Klebsiella pneumoniae have been identified as the major virulence factors for pyogenic liver abscesses with high morbidity, mortality and severe complications. The pathological mechanisms remain unclear. In this study, we compared liver immune responses and pathological changes in response to different serotypes of K. pneumoniae infections. A mouse model was used to investigate cytokine and chemokine production, histopathology findings, phagocytic uptake and mortality induced by serotypes K1 (magA(+), rmpA(+), aerobactin(+)), K2 (magA(-), rmpA(+), aerobactin(+)), K62 (magA(-), rmpA(-), aerobactin(-)) and an acapsulated isogenic K1 mutant (ΔK1, magA(+), rmpA(+), aerobactin(+)). K. pneumoniae serotypes K1 and K2 showed lower 50% lethal dose values and more phagocytic resistance to neutrophils than K62 and the ΔK1 mutant. In sequential liver samples, viable bacteria counts increased 3 h to 3 days after low-dose inoculation (<10(1) colony-forming unit (cfu)) with K1 and K2, while K62 and ΔK1 cleared rapidly and became undetectable even with high-dose inoculation (∼2.9 × 10(5) cfu). Time-dependent increases in cytokines and chemokines, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-10, keratinocyte-derived chemokines and macrophage inflammatory protein-2, were observed in the serum and liver tissue of K1- and K2-infected mice, and severe disease progression manifesting as microabscesses was also identified. K62 and ΔK1 inoculation did not result in similar immune responses and histological changes. These findings illustrate the critical role of phagocytic resistance against innate immunological defense mechanisms as well as its contribution to the development of liver abscesses.
Collapse
Affiliation(s)
- Chang-Phone Fung
- Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University, Taiwan, ROC.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Diannexin decreases inflammatory cell infiltration into the islet graft, reduces β-cell apoptosis, and improves early graft function. Transplantation 2010; 90:709-16. [PMID: 20634785 DOI: 10.1097/tp.0b013e3181ed55d8] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND A major unmet challenge is to reduce the islet mass needed for insulin independence in type 1 diabetic recipients after islet transplantation. The recombinant homodimer of human annexin V, diannexin, has completed a Phase II Clinical Trial in Kidney Transplantation (NCT00615966). METHODS We developed a marginal islet mass transplantation model (10-12 islets per gram of recipient body weight) and investigated whether diannexin prevents β-cell apoptosis and improves islet graft function. Diannexin was administered to islet cell donors shortly before pancreas harvest, added to isolation reagents, and infused into recipients at the time of transplantation and repeated daily until day 4. RESULTS In the syngeneic marginal islet mass transplantation model, the median time needed to achieve normoglycemia was reduced from 17.0 days among untreated controls to 3.5 days among diannexin-treated recipients (P=0.004). Histologic analysis of islet grafts harvested on day 3 posttransplantation revealed decreased macrophage (44.7%±9.8% vs. 19.2%±3.2%, P=0.007) and T-cell infiltration (25.9%±5.5% vs. 9.1%±1.1%, P=0.004), and a lower rate of islet cell apoptosis (20.5%±2.8% vs. 7.6%±2.3%, P=0.01) with diannexin treatment. Expression profiling of the islet grafts showed significantly lower levels of mRNA for the proapoptotic molecule Bid, but higher levels of interleukin-6, interferon-γ, and immunosuppressive cytokine interleukin-10. CONCLUSIONS Our findings demonstrate that diannexin improves the early function of marginal mass islet grafts, and its effects are associated with reductions in inflammatory cell infiltration and β-cell death by apoptosis after islet transplantation.
Collapse
|
|
43
|
Abu-Amara M, Yang SY, Tapuria N, Fuller B, Davidson B, Seifalian A. Liver ischemia/reperfusion injury: processes in inflammatory networks--a review. Liver Transpl 2010; 16:1016-32. [PMID: 20818739 DOI: 10.1002/lt.22117] [Citation(s) in RCA: 261] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Liver ischemia/reperfusion (IR) injury is typified by an inflammatory response. Understanding the cellular and molecular events underpinning this inflammation is fundamental to developing therapeutic strategies. Great strides have been made in this respect recently. Liver IR involves a complex web of interactions between the various cellular and humoral contributors to the inflammatory response. Kupffer cells, CD4+ lymphocytes, neutrophils, and hepatocytes are central cellular players. Various cytokines, chemokines, and complement proteins form the communication system between the cellular components. The contribution of the danger-associated molecular patterns and pattern recognition receptors to the pathophysiology of liver IR injury are slowly being elucidated. Our knowledge on the role of mitochondria in generating reactive oxygen and nitrogen species, in contributing to ionic disturbances, and in initiating the mitochondrial permeability transition with subsequent cellular death in liver IR injury is continuously being expanded. Here, we discuss recent findings pertaining to the aforementioned factors of liver IR, and we highlight areas with gaps in our knowledge, necessitating further research.
Collapse
Affiliation(s)
- Mahmoud Abu-Amara
- Liver Transplantation and Hepatobiliary Unit, Royal Free Hospital, London, United Kingdom
| | | | | | | | | | | |
Collapse
|
|
44
|
Wei H, Wei H, Wang H, Tian Z, Sun R. Activation of natural killer cells inhibits liver regeneration in toxin-induced liver injury model in mice via a tumor necrosis factor-alpha-dependent mechanism. Am J Physiol Gastrointest Liver Physiol 2010; 299:G275-82. [PMID: 20448144 DOI: 10.1152/ajpgi.00026.2010] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Liver lymphocytes are enriched in natural killer (NK) cells, and activation of NK cells by injection of polyinosinic-polycytidylic acid (poly I:C) inhibits liver regeneration in the partial hepatectomy model via production of IFN-gamma. However, the role of NK cells in liver regeneration in a model of carbon tetrachloride (CCl(4))-induced liver injury remains unknown. In this study, we investigated the effect of activation of NK cells induced by poly I:C on liver regeneration in the CCl(4) model. Administration of poly I:C suppressed liver regeneration in CCl(4)-treated mice. Depletion of NK cells but not Kupffer cells or T cells restored liver regeneration in poly I:C/CCl(4)-treated mice. Poly I:C and CCl(4) cotreatment synergistically induced accumulation of NK cells in the liver and NK cell production of IFN-gamma and tumor necrosis factor (TNF)-alpha. Serum levels of these two cytokines were also synergistically induced after poly I:C and CCl(4) treatment. Finally, blockage of TNF-alpha but not IFN-gamma restored liver regeneration in poly I:C/CCl(4)-treated mice. Taken together, these findings suggest that poly I:C treatment inhibits liver regeneration in the CCl(4)-induced liver injury model via induction of NK cell production of TNF-alpha.
Collapse
Affiliation(s)
- Hairong Wei
- Institute of Immunology, Hefei National Laboratory for Physical Sciences at Microscale, School of Life Sciences, University of Science and Technology of China, 443 Huangshan Rd., Hefei City, Anhui 230027, People's Republic of China
| | | | | | | | | |
Collapse
|
|
45
|
Wei Y, Chen P, de Bruyn M, Zhang W, Bremer E, Helfrich W. Carbon monoxide-releasing molecule-2 (CORM-2) attenuates acute hepatic ischemia reperfusion injury in rats. BMC Gastroenterol 2010; 10:42. [PMID: 20444253 PMCID: PMC2873601 DOI: 10.1186/1471-230x-10-42] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2009] [Accepted: 05/05/2010] [Indexed: 02/08/2023] Open
Abstract
Background Hepatic ischemia-reperfusion injury (I/Ri) is a serious complication occurring during liver surgery that may lead to liver failure. Hepatic I/Ri induces formation of reactive oxygen species, hepatocyte apoptosis, and release of pro-inflammatory cytokines, which together causes liver damage and organ dysfunction. A potential strategy to alleviate hepatic I/Ri is to exploit the potent anti-inflammatory and cytoprotective effects of carbon monoxide (CO) by application of so-called CO-releasing molecules (CORMs). Here, we assessed whether CO released from CORM-2 protects against hepatic I/Ri in a rat model. Methods Forty male Wistar rats were randomly assigned into four groups (n = 10). Sham group underwent a sham operation and received saline. I/R group underwent hepatic I/R procedure by partial clamping of portal structures to the left and median lobes with a microvascular clip for 60 minutes, yielding ~70% hepatic ischemia and subsequently received saline. CORM-2 group underwent the same procedure and received 8 mg/kg of CORM-2 at time of reperfusion. iCORM-2 group underwent the same procedure and received iCORM-2 (8 mg/kg), which does not release CO. Therapeutic effects of CORM-2 on hepatic I/Ri was assessed by measuring serum damage markers AST and ALT, liver histology score, TUNEL-scoring of apoptotic cells, NFkB-activity in nuclear liver extracts, serum levels of pro-inflammatory cytokines TNF-α and IL-6, and hepatic neutrophil infiltration. Results A single systemic infusion with CORM-2 protected the liver from I/Ri as evidenced by a reduction in serum AST/ALT levels and an improved liver histology score. Treatment with CORM-2 also up-regulated expression of the anti-apoptotic protein Bcl-2, down-regulated caspase-3 activation, and significantly reduced the levels of apoptosis after I/Ri. Furthermore, treatment with CORM-2 significantly inhibited the activity of the pro-inflammatory transcription factor NF-κB as measured in nuclear extracts of liver homogenates. Moreover, CORM-2 treatment resulted in reduced serum levels of pro-inflammatory cytokines TNF-α and IL-6 and down-regulation of the adhesion molecule ICAM-1 in the endothelial cells of liver. In line with these findings, CORM-2 treatment reduced the accumulation of neutrophils in the liver upon I/Ri. Similar treatment with an inactive variant of CORM-2 (iCORM-2) did not have any beneficial effect on the extent of liver I/Ri. Conclusions CORM-2 treatment at the time of reperfusion had several distinct beneficial effects on severity of hepatic I/Ri that may be of therapeutic value for the prevention of tissue damage as a result of I/Ri during hepatic surgery.
Collapse
Affiliation(s)
- Yunwei Wei
- Third department of General Surgery, First Clinical Hospital Harbin, Harbin Medical University, Harbin 150001, Heilongjiang, China.
| | | | | | | | | | | |
Collapse
|
|
46
|
Teoh NC, Williams J, Hartley J, Yu J, McCuskey RS, Farrell GC. Short-term therapy with peroxisome proliferation-activator receptor-alpha agonist Wy-14,643 protects murine fatty liver against ischemia-reperfusion injury. Hepatology 2010; 51:996-1006. [PMID: 20131406 DOI: 10.1002/hep.23420] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
UNLABELLED Steatosis increases operative morbidity/mortality from ischemia-reperfusion injury (IRI); few pharmacological approaches have been protective. Using novel genetic/dietary models of nonalcoholic steatohepatitis (NASH) and simple steatosis (SS) in Alms1 mutant (foz/foz) mice, we characterized severity of IRI in NASH versus SS and lean liver and tested our hypothesis that the lipid-lowering effects of the peroxisome proliferation-activator receptor (PPAR)-alpha agonist Wy-14,643 would be hepatoprotective. Mice were subjected to 60-minute partial hepatic IRI. Microvascular changes were assessed at 15-minute reperfusion by in vivo microscopy, injury at 24 hours by serum alanine aminotransferase (ALT), and hepatic necrosis area. Injury and inflammation mediators were determined by way of immunoblotting for intercellular cellular adhesion molecule, vascular cellular adhesion molecule, p38, c-jun N-terminal kinase, IkappaB-alpha, interleukin (IL)-1a, IL-12, tumor necrosis factor-alpha (TNF-alpha) and IL-6, cell cycle by cyclin D1 and proliferating cell nuclear antigen immunohistochemistry. In foz/foz mice fed a high-fat diet (HFD) to cause NASH or chow (SS), IRI was exacerbated compared with HFD-fed or chow-fed wild-type littermates by ALT release; corresponding necrotic areas were 60 +/- 22% NASH, 29 +/- 9% SS versus 7 +/- 1% lean. Microvasculature of NASH or SS livers was narrowed by enormous lipid-filled hepatocytes, significantly reducing numbers of perfused sinusoids, all exacerbated by IRI. Wy-14,643 reduced steatosis in NASH and SS livers, whereas PPAR-alpha stimulation conferred substantial hepatoprotection against IRI by ALT release, with reductions in vascular cellular adhesion molecule-1, IL-1a, TNF-alpha, IL-12, activated nuclear factor-kappaB (NF-kappaB), p38, IL-6 production and cell cycle entry. CONCLUSION NASH and SS livers are both more susceptible to IRI. Mechanisms include possible distortion of the microvasculature by swollen fat-laden hepatocytes, and enhanced production of several cytokines. The beneficial effects of Wy-14,643 may be exerted by dampening adhesion molecule and cytokine responses, and activating NF-kappaB, IL-6 production, and p38 kinase to effect cell cycle entry.
Collapse
Affiliation(s)
- Narci C Teoh
- Gastroenterology and Hepatology Unit, and Australian National University Medical School, Level 2, Building 1, The Canberra Hospital, Garran, ACT 2604, Australia.
| | | | | | | | | | | |
Collapse
|
|
47
|
Jassem W, Fuggle S, Thompson R, Arno M, Taylor J, Byrne J, Heaton N, Rela M. Effect of ischemic preconditioning on the genomic response to reperfusion injury in deceased donor liver transplantation. Liver Transpl 2009; 15:1750-65. [PMID: 19938126 DOI: 10.1002/lt.21936] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Ischemic preconditioning (IP) is an effective method for protecting organs from ischemia/reperfusion (IR) injury; however, the molecular basis of this protective effect is poorly understood. This study assessed the gene expression profile in liver allografts during transplantation and evaluated the impact of IP. Prereperfusion and postreperfusion biopsy specimens from livers subjected to IP (n = 19) or no preconditioning (the IR group; n = 16) were obtained. Total RNA was extracted and hybridized to GeneChip microarrays, and the findings were validated with real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR). IP livers showed less of an increase in aspartate aminotransferase after transplantation. A microarray analysis of the IR group showed increased expression of 57 genes mainly involved in cell death, inflammation and immune response, stress, and modulation of the cell cycle. The IP group showed attenuation of the expression of these genes after reperfusion. Additionally, IP led to increased expression of 43 genes involved in growth and maintenance, cell-cycle regulation, proliferation, and development. The expression of the 12 most significant genes was validated in all patients with real-time qRT-PCR, and the fold changes of a number of genes correlated with clinical parameters and graft outcomes. IP protection of liver allografts was associated with a reduction in the expression of immune response genes and promotion of those involved in protection and repair.
Collapse
Affiliation(s)
- Wayel Jassem
- Liver Transplant Unit, Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Vollmar B, Menger MD. The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev 2009; 89:1269-339. [PMID: 19789382 DOI: 10.1152/physrev.00027.2008] [Citation(s) in RCA: 368] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The complex functions of the liver in biosynthesis, metabolism, clearance, and host defense are tightly dependent on an adequate microcirculation. To guarantee hepatic homeostasis, this requires not only a sufficient nutritive perfusion and oxygen supply, but also a balanced vasomotor control and an appropriate cell-cell communication. Deteriorations of the hepatic homeostasis, as observed in ischemia/reperfusion, cold preservation and transplantation, septic organ failure, and hepatic resection-induced hyperperfusion, are associated with a high morbidity and mortality. During the last two decades, experimental studies have demonstrated that microcirculatory disorders are determinants for organ failure in these disease states. Disorders include 1) a dysregulation of the vasomotor control with a deterioration of the endothelin-nitric oxide balance, an arterial and sinusoidal constriction, and a shutdown of the microcirculation as well as 2) an overwhelming inflammatory response with microvascular leukocyte accumulation, platelet adherence, and Kupffer cell activation. Within the sequelae of events, proinflammatory mediators, such as reactive oxygen species and tumor necrosis factor-alpha, are the key players, causing the microvascular dysfunction and perfusion failure. This review covers the morphological and functional characterization of the hepatic microcirculation, the mechanistic contributions in surgical disease states, and the therapeutic targets to attenuate tissue injury and organ dysfunction. It also indicates future directions to translate the knowledge achieved from experimental studies into clinical practice. By this, the use of the recently introduced techniques to monitor the hepatic microcirculation in humans, such as near-infrared spectroscopy or orthogonal polarized spectral imaging, may allow an early initiation of treatment, which should benefit the final outcome of these critically ill patients.
Collapse
Affiliation(s)
- Brigitte Vollmar
- Institute for Experimental Surgery, University of Rostock, Rostock, Germany.
| | | |
Collapse
|
|
49
|
Aller R, de Luis DA, Izaola O, Sagrado MG, Conde R, Velasco MC, Alvarez T, Pacheco D, González JM. Influence of visfatin on histopathological changes of non-alcoholic fatty liver disease. Dig Dis Sci 2009; 54:1772-7. [PMID: 19005759 DOI: 10.1007/s10620-008-0539-9] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2008] [Accepted: 09/11/2008] [Indexed: 12/22/2022]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a common liver disease. The aim of the present study was to explore the relation of visfatin with underlying histopathological changes of NAFLD patients. SUBJECTS A population of 55 NAFLD patients was analyzed in a cross-sectional study. A liver biopsy was realized. Weight, basal glucose, insulin, insulin resistance (HOMA), total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and visfatin levels were measured. A bioimpedance was performed. RESULTS AND CONCLUSIONS The mean age was 42.8 +/- 11.2 years, the mean BMI was 33.1 +/- 10.2 with 37 males (67.3%) and 18 females (32.7%). Probabilities to have; portal inflammation increased 1.11 (CI95%:1.03-1.50) with each increment of 1 ng/ml of visfatin concentration, high grade of steatosis increased 1.25 (CI 95%:1.06-1.61) with each unit of insulin concentrations, fibrosis increased 1.12 (CI 95%:1.02-1.43) with each unit of fat mass and lobulillar inflammation increased 13.4 (CI 95%:1.3-147) with each unit of HOMA-IR. Portal inflammation frequencies were different between groups (low visfatin group 13.07 < ng/ml: 37.5% versus high visfatin group 13.07 > ng/ml: 62.5%; P < 0.05). In conclusion, several histopathological changes in liver biopsies could be explained by insulin concentrations, HOMA-IR, and fat mass amount. Moreover, visfatin plasma concentrations could predict the presence of portal inflammation in NAFLD patients.
Collapse
Affiliation(s)
- R Aller
- Institute of Endocrinology and Nutrition, Medicine School and Unit of Investigation, Hospital Rio Hortega, University of Valladolid, C/Los perales 16, 47130, Simancas, Valladolid, Spain
| | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Tacchini L, Cairo G, De Ponti C, Massip M, Rosellò-Catafau J, Peralta C. Up regulation of IL-6 by ischemic preconditioning in normal and fatty rat livers: Association with reduction of oxidative stress. Free Radic Res 2009; 40:1206-17. [PMID: 17050174 DOI: 10.1080/10715760600885432] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
We analyzed the role of IL-6 in the protection that ischemic preconditioning (IP) exerts against hepatic ischemia reperfusion-mediated (I/R) oxidative damage, particularly in fatty livers. IP-related IL-6 up-regulation during reperfusion in steatotic and non-steatotic livers was correlated with reduced indices of liver damage, as also demonstrated by pharmacological modulation of IL-6. IP activated NF-kB and HSF during ischemia (Isc), whereas AP-1 activity was unaffected. IP blunted the activation of STAT3 and stress-responsive genes, such as NF-kB, AP-1 and heme oxygenase (HO-1) during reperfusion. The role of reduced oxidative stress in hepatoprotection of fatty livers was further demonstrated by the fact that: (i) IP prevented the decrease of glutathione levels and the increase of lipid peroxidation; (ii) the anti-oxidant GSH-ester prevented lipid peroxidation and necrosis. In conclusion, IP modulates the activity of transcription factors and triggers IL-6 production; this may prevent hepatic I/R damage in a oxidative stress-dependent way, particularly in fatty livers.
Collapse
Affiliation(s)
- Lorenza Tacchini
- Institute of General Pathology, University of Milano, via Mangiagalli 31, 20133, Milano, Italy
| | | | | | | | | | | |
Collapse
|