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Xu Y, Tang Y, Lu J, Zhang W, Zhu Y, Zhang S, Ma G, Jiang P, Zhang W. PINK1-mediated mitophagy protects against hepatic ischemia/reperfusion injury by restraining NLRP3 inflammasome activation. Free Radic Biol Med 2020; 160:871-886. [PMID: 32947010 DOI: 10.1016/j.freeradbiomed.2020.09.015] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 08/28/2020] [Accepted: 09/11/2020] [Indexed: 12/21/2022]
Abstract
Activation of nucleotide-binding domain leucine-rich repeat containing family pyrin domain containing 3 (NLRP3) inflammasome in Kupffer cells (KCs) contributes significantly to hepatic ischemia/reperfusion (I/R) injury, while the mechanism of how NLRP3 inflammasome is regulated remains less well defined. Recent evidence has showed that mitophagy acts as a central player for maintaining mitochondrial homeostatis through elimination of damaged mitochondria, leading to the prevention of hyperinflammation triggered by NLRP3 activation. In this study, we aimed at investigating the potential role of PTEN-induced kinase 1 (PINK1)-mediated mitophagy in hepatic I/R injury. C57BL/6 mice subjected to partial warm hepatic I/R or primary KCs exposed to anoxia/reoxygenation (A/R) was used as in vivo or in vitro model, respectively. Mitophagy was measured by protein levels of PINK1, Parkin, LC3B-II, TOMM20 and p62. NLRP3, caspase-1 and IL-1β at mRNA and/or protein levels were used as indicators of inflammasome activation. Our results demonstrated remarkable hepatic inflammation and NLRP3 inflammasome activation during hepatic I/R, along with increased PINK1-mediated mitophagy. Notably, overexpression of PINK1 in vivo attenuated hepatic I/R injury, ROS production, NLRP3 activation and hepatic inflammation. In parallel, A/R challenge in vitro also triggered NLRP3 activation in KCs accompanied by increase in mitophagy. Enhanced mitophagy mediated by PINK1 overexpression further inhibited NLRP3 activation and reversed the KC-mediated inflammatory injury to hepatocytes. Kinase-dead mutation of PINK1 completely abolished the above protective effects by PINK1. Blocking of mitophagy/autophagy by silencing of PINK1/Parkin, ATG5, NDP52 or OPTN showed the totally opposite effects, respectively. Treatment with different autophagic inhibitors also consistently reversed the PINK1-mediated effects, suggesting that an intact PINK1-mediated mitophagy signaling was crucial for ablation of NLRP3 signaling in the presence of A/R. Together, these results support a critical role of PINK1-mediated mitophagy in mitochondrial quality control for KC activation and function in hepatic I/R.
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Affiliation(s)
- Ying Xu
- Department of Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Yinbing Tang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Jiawei Lu
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Weiya Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Yan Zhu
- Department of Respiration, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Shouliang Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Gui Ma
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Pengcheng Jiang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China.
| | - Wenbo Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China.
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Mendes-Braz M, Martins JO. Diabetes Mellitus and Liver Surgery: The Effect of Diabetes on Oxidative Stress and Inflammation. Mediators Inflamm 2018; 2018:2456579. [PMID: 29853784 PMCID: PMC5964489 DOI: 10.1155/2018/2456579] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2017] [Revised: 04/02/2018] [Accepted: 04/11/2018] [Indexed: 12/11/2022] Open
Abstract
Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycaemia and high morbidity worldwide. The detrimental effects of hyperglycaemia include an increase in the oxidative stress (OS) response and an enhanced inflammatory response. DM compromises the ability of the liver to regenerate and is particularly associated with poor prognosis after ischaemia-reperfusion (I/R) injury. Considering the growing need for knowledge of the impact of DM on the liver following a surgical procedure, this review aims to present recent publications addressing the effects of DM (hyperglycaemia) on OS and the inflammatory process, which play an essential role in I/R injury and impaired hepatic regeneration after liver surgery.
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Affiliation(s)
- Mariana Mendes-Braz
- Laboratory of Immunoendocrinology, Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences of University Sao Paulo (FCF/USP), São Paulo, SP, Brazil
| | - Joilson O. Martins
- Laboratory of Immunoendocrinology, Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences of University Sao Paulo (FCF/USP), São Paulo, SP, Brazil
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Xu Y, Yao J, Zou C, Zhang H, Zhang S, Liu J, Ma G, Jiang P, Zhang W. Asiatic acid protects against hepatic ischemia/reperfusion injury by inactivation of Kupffer cells via PPARγ/NLRP3 inflammasome signaling pathway. Oncotarget 2017; 8:86339-86355. [PMID: 29156799 PMCID: PMC5689689 DOI: 10.18632/oncotarget.21151] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 08/21/2017] [Indexed: 01/17/2023] Open
Abstract
Hepatic ischemia/reperfusion (I/R) contributes to major complications in clinical practice affecting perioperative morbidity and mortality. Recent evidence suggests the key role of nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammaosme activation on the pathogenesis of I/R injury. Asiatic acid (AA) is a pentacyclic triterpene derivative presented with versatile activities, including antioxidant, anti-inflammation and hepatoprotective effects. This study was designed to determine whether AA had potential hepatoprotective benefits against hepatic I/R injury, as well as to unveil the underlying mechanisms involved in the putative effects. Mice subjected to warm hepatic I/R, and Kupffer cells (KCs) or RAW264.7 cells challenged with lipopolysaccharide (LPS)/H2O2, were pretreated with AA. Administration of AA significantly attenuated hepatic histopathological damage, global inflammatory level, apoptotic signaling level, as well as NLRP3 inflammasome activation. These effects were correlated with increased expression of peroxisome proliferator-activated receptor gamma (PPARγ). Conversely, pharmacological inhibition of PPARγ by GW9662 abolished the protective effects of AA on hepatic I/R injury and in turn aggravated NLRP3 inflammasome activation. Activation of NLRP3 inflammasome was most significant in nonparenchymal cells (NPCs). Depletion of KCs by gadolinium chloride (GdCl3) further attenuated the detrimental effects of GW9662 on hepatic I/R as well as NLRP3 activation. In vitro, AA concentration-dependently inhibited LPS/H2O2-induced NLRP3 inflammaosome activation in KCs and RAW264.7 cells. Either GW9662 or genetic knockdown of PPARγ abolished the AA-mediated inactivation of NLRP3 inflammasome. Mechanistically, AA attenuated I/R or LPS/H2O2-induced ROS production and phosphorylation level of JNK, p38 MAPK and IκBα but not ERK, a mechanism dependent on PPARγ. Finally, AA blocked the deleterious effects of LPS/H2O2-induced macrophage activation on hepatocyte viability in vitro, and improved survival in a lethal hepatic I/R injury model in vivo. Collectively, these data suggest that AA is effective in mitigating hepatic I/R injury through attenuation of KCs activation via PPARγ/NLRP3 inflammasome signaling pathway.
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Affiliation(s)
- Ying Xu
- Department of Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Jun Yao
- Department of Gastroenterology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Chen Zou
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Heng Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Shouliang Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Jun Liu
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Gui Ma
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Pengcheng Jiang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Wenbo Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
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Tapuria N, Junnarkar S, Abu-amara M, Fuller B, Seifalian AM, Davidson BR. Haemoxygenase modulates cytokine induced neutrophil chemoattractant in hepatic ischemia reperfusion injury. World J Gastroenterol 2016; 22:7518-7535. [PMID: 27672274 PMCID: PMC5011667 DOI: 10.3748/wjg.v22.i33.7518] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2015] [Revised: 02/05/2016] [Accepted: 05/23/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the hepatic microcirculatory changes due to Haemoxygenase (HO), effect of HO inhibition on remote ischemic preconditioning (RIPC) and modulation of CINC.
METHODS Eight groups of animals were studied - Sham, ischemia reperfusion injury (IRI) the animals were subjected to 45 min of hepatic ischemia followed by three hours of reperfusion, RIPC (remote ischemic preconditioning) + IRI group, remote ischemic preconditioning in sham (RIPC + Sham), PDTC + IR (Pyridodithiocarbamate, HO donor), ZnPP + RIPC + IRI (Zinc protoporphyrin prior to preconditioning), IR-24 (45 min of ischemia followed by 24 h of reperfusion), RIPC + IR-24 (preconditioning prior to IR). After 3 and 24 h of reperfusion the animals were killed by exsanguination and samples were taken.
RESULTS Velocity of flow (160.83 ± 12.24 μm/s), sinusoidal flow (8.42 ± 1.19) and sinusoidal perfusion index (42.12 ± 7.28) in hepatic IR were lower (P < 0.05) in comparison to RIPC and PDTC (HO inducer). RIPC increased velocity of flow (328.04 ± 19.13 μm/s), sinusoidal flow (17.75 ± 2.59) and the sinusoidal perfusion index (67.28 ± 1.82) (P < 0.05). PDTC (HO induction) reproduced the effects of RIPC in hepatic IR. PDTC restored RBC velocity (300.88 ± 22.109 μm/s), sinusoidal flow (17.66 ± 3.71) and sinusoidal perfusion (82.33 ± 3.5) to near sham levels. ZnPP (HO inhibition) reduced velocity of flow of RBC in the RIPC group (170.74 ± 13.43 μm/s and sinusoidal flow in the RIPC group (9.46 ± 1.34). ZnPP in RIPC (60.29 ± 1.82) showed a fall in perfusion only at 180 min of reperfusion. Neutrophil adhesion in IR injury is seen in both postsinusoidal venules (769.05 ± 87.48) and sinusoids (97.4 ± 7.49). Neutrophil adhesion in RIPC + IR injury is reduced in both postsinusoidal venules (219.66 ± 93.79) and sinusoids (25.69 ± 9.08) (P < 0.05). PDTC reduced neutrophil adhesion in both postsinusoidal venules (89.58 ± 58.32) and sinusoids (17.98 ± 11.01) (P < 0.05) reproducing the effects of RIPC. ZnPP (HO inhibition) increased venular (589.04 ± 144.36) and sinusoidal neutrophil adhesion in preconditioned animals (121.39 ± 30.65) (P < 0.05). IR after 24 h of reperfusion increased venular and sinusoidal neutrophil adhesion in comparison to the early phase and was significantly reduced by RIPC. Hepatocellular cell death in IRI (80.83 ± 13.03), RIPC + IR (17.35 ± 2.47), and PTDC + IR (11.66 ± 1.17) reduced hepatocellular death. ZnPP + RIPC + IR (41.33 ± 3.07) significantly increased hepatocellular death (P < 0.05 PTDC/RIPC vs ZnPP and IR). The CINC cytokine levels in sham (101.32 ± 6.42). RIPC + sham (412.18 ± 65.24) as compared to sham (P < 0.05). CINC levels in hepatic IR were (644.08 ± 181.24). PDTC and RIPC CINC levels were significantly lower than hepatic IR (P < 0.05). HO inhibition in preconditioned animals with Zinc protoporphyrin increased serum CINC levels (521.81 ± 74.9) (P < 0.05). The serum CINC levels were high in the late phase of hepatic IR (15306 ± 1222.04). RIPC reduced CINC levels in the late phase of IR (467.46 ± 26.06), P < 0.05.
CONCLUSION RIPC protects hepatic microcirculation by induction of HO and modulation of CINC in hepatic IR.
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Cavalieri B, Mosca M, Ramadori P, Perrelli MG, De Simone L, Colotta F, Bertini R, Poli G, Cutrìn JC. Neutrophil Recruitment in the Reperfused-Injured Rat Liver was Effectively Attenuated by Repertaxin, a Novel Allosteric Noncompetitive Inhibitor of Cxcl8 Receptors: A Therapeutic Approach for the Treatment of Post-Ischemic Hepatic Syndromes. Int J Immunopathol Pharmacol 2016; 18:475-86. [PMID: 16164828 DOI: 10.1177/039463200501800307] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Hepatic reperfusion injury represents a crucial problem in several clinical situations including liver transplantation, extensive hepatectomy and hypovolemic shock with resuscitation. Repertaxin is a new non-competive allosteric blocker of interleukin-8 (CXCL8) receptors, which by locking CXCR1/R2 in an inactive conformation, prevents receptor signaling and polymorphonuclear leukocyte (PMN) Chemotaxis. The present study shows that repertaxin dramatically prevents rat post-ischemic hepatocellular necrosis (80% of inhibition) and PMN infiltration (96% of inhibition) at a clinically-relevant time (24 h) of reperfusion. Treatment with repertaxin by continuous infusion is demonstrated to be the optimal route of administration of the compound especially in view of its clinical threrapeutic use. Because repertaxin has proven to be safe and well tolerated in different animal studies and in phase I studies in human volunteers, it is in fact a candidate novel therapeutic agent for the prevention and treatment of hepatic post-ischemic injury.
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Affiliation(s)
- B Cavalieri
- Laboratory of Experimental Liver Pathology, Department of Clinical and Biological Sciences, University of Turin, L'Aquila, Italy
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Moore SM, Holt VV, Malpass LR, Hines IN, Wheeler MD. Fatty acid-binding protein 5 limits the anti-inflammatory response in murine macrophages. Mol Immunol 2015; 67:265-75. [PMID: 26105806 DOI: 10.1016/j.molimm.2015.06.001] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 05/27/2015] [Accepted: 06/01/2015] [Indexed: 12/16/2022]
Abstract
The beginning stages of liver damage induced by various etiologies (i.e. high fat diet, alcohol consumption, toxin exposure) are characterized by abnormal accumulation of lipid in liver. Alterations in intracellular lipid transport, storage, and metabolism accompanied by cellular insult within the liver play an important role in the pathogenesis of liver disease, often involving a sustained inflammatory response. The intracellular lipid transporter, fatty acid binding protein 5 (FABP5), is highly expressed in macrophages and may play an important role in the hepatic inflammatory response after endotoxin exposure in mice. This study tested the hypothesis that FABP5 regulates macrophage response to LPS in male C57bl/6 (wild type) and FABP5 knockout mice, both in vitro and in vivo. Treatment with LPS revealed that loss of FABP5 enhances the number of hepatic F4/80(+) macrophages in the liver despite limited liver injury. Conversely, FABP5 knock out mice display higher mRNA levels of anti-inflammatory cytokines IL-10, arginase, YM-1, and Fizz-1 in liver compared to wild type mice. Bone marrow derived macrophages stimulated with inflammatory (LPS and IFN-γ) or anti-inflammatory (IL-4) mediators also showed significantly higher expression of anti-inflammatory/regulatory factors. These findings reveal a regulatory role of FABP5 in the acute inflammatory response to LPS-induced liver injury, which is consistent with the principle finding that FABP5 is a regulator of macrophage phenotype. Specifically, these findings demonstrate that loss of FABP5 promotes a more anti-inflammatory response.
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Affiliation(s)
- Sherri M Moore
- Department of Nutrition Science, College of Human Ecology, East Carolina University, Greenville, NC 27858, United States.
| | - Vivian V Holt
- Department of Nutrition Science, College of Human Ecology, East Carolina University, Greenville, NC 27858, United States.
| | - Lillie R Malpass
- Department of Nutrition Science, College of Human Ecology, East Carolina University, Greenville, NC 27858, United States.
| | - Ian N Hines
- Department of Nutrition Science, College of Human Ecology, East Carolina University, Greenville, NC 27858, United States.
| | - Michael D Wheeler
- Department of Nutrition Science, College of Human Ecology, East Carolina University, Greenville, NC 27858, United States.
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van Golen RF, Reiniers MJ, Olthof PB, van Gulik TM, Heger M. Sterile inflammation in hepatic ischemia/reperfusion injury: present concepts and potential therapeutics. J Gastroenterol Hepatol 2013; 28:394-400. [PMID: 23216461 DOI: 10.1111/jgh.12072] [Citation(s) in RCA: 110] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/23/2012] [Indexed: 12/12/2022]
Abstract
Ischemia and reperfusion (I/R) injury is an often unavoidable consequence of major liver surgery and is characterized by a sterile inflammatory response that jeopardizes the viability of the organ. The inflammatory response results from acute oxidative and nitrosative stress and consequent hepatocellular death during the early reperfusion phase, which causes the release of endogenous self-antigens known as damage-associated molecular patterns (DAMPs). DAMPs, in turn, are indirectly responsible for a second wave of reactive oxygen and nitrogen species (ROS and RNS) production by driving the chemoattraction of various leukocyte subsets that exacerbate oxidative liver damage during the later stages of reperfusion. In this review, the molecular mechanisms underlying hepatic I/R injury are outlined, with emphasis on the interplay between ROS/RNS, DAMPs, and the cell types that either produce ROS/RNS and DAMPs or respond to them. This theoretical background is subsequently used to explain why current interventions for hepatic I/R injury have not been very successful. Moreover, novel therapeutic modalities are addressed, including MitoSNO and nilotinib, and metalloporphyrins on the basis of the updated paradigm of hepatic I/R injury.
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Affiliation(s)
- Rowan F van Golen
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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Yang Q, Shi Y, He J, Chen Z. The evolving story of macrophages in acute liver failure. Immunol Lett 2012; 147:1-9. [PMID: 22820147 DOI: 10.1016/j.imlet.2012.07.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Revised: 06/15/2012] [Accepted: 07/10/2012] [Indexed: 12/21/2022]
Abstract
Acute liver failure (ALF) remains a worldwide problem. The innate immune system acts as an important regulator of ALF. Kupffer cells (KCs), the resident macrophages in liver, play a key role in liver innate immune response. Recent researches have shown that macrophages display a remarkable plasticity and can differentiate into functionally diverse subsets. However, the dynamic polarized phenotypes and functional status of macrophages at different stage of ALF are not clear. In this paper, we present a review of evidence that KCs play a significant role in the pathogenesis of ALF, including the phenotype and functions of macrophages, signaling pathways involved in macrophage functional status and cell-crosstalks of KCs with other immune cells. More information on macrophages will promote a better understanding of the cellular molecular mechanisms of ALF and provide new insights for the development of therapeutic targets for ALF.
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Affiliation(s)
- Qiao Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Medical College, Zhejiang University, Zhejiang, PR China.
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El-Mahdy NA, El-Sisi AE, Dewidar BI, El-Desouky KI. Histamine protects against the acute phase of experimentally-induced hepatic ischemia/re-perfusion. J Immunotoxicol 2012; 10:9-16. [PMID: 22793375 DOI: 10.3109/1547691x.2012.684158] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Histamine, involved in many inflammatory reactions and immune responses, is reported to suppress--via H4R stimulation--injury concomitant with the late phase of warm hepatic ischemia/re-perfusion (I/R). The current study investigated the possible effects of histamine on the acute phase of hepatic I/R injury, and the possible underlying mechanisms like oxidative stress and release of inflammatory cytokines (e.g., tumor necrosis factor (TNF)-α nd interleukin [IL]-12). Rats were divided into naïve, sham-operated, and I/R groups. The I/R group was divided into sub-groups and pre-treated with histaminergic ligands before induction of ischemia. Anesthetized rats were subjected to warm ischemia for 30 min by occlusion of the portal vein and hepatic artery, then re-perfused for 90 min. Rats in the control I/R group showed significant increases in hepatic malondialdehyde (MDA), TNFα, and IL-12 contents, and in plasma alanine transaminase (ALT) and aspartate transaminase (AST) levels, along with significant decreases in hepatic reduced glutathione (GSH) content and marked diffuse histopathologic damage. Pre-treatment with histamine resulted in significant mitigation of each of these end-points. The protective effect of histamine was not antagonized by pre-treatment with mepyramine (H1R antagonist) or ranitidine (H2R antagonist) and completely reversed by pre-treatment with thioperamide (H3R and H4R antagonist). In addition, the histamine protective effect was mimicked by pre-treatment of rats with clozapine (H4R agonist). These observations strongly suggested that histamine has a protective effect against hepatic I/R-mediated tissue injury during the acute phase, and this effect was mediated through an H4R stimulation that led to a decrease in IL-12 and TNFα production--outcomes that consequently decreased localized oxidative stress and afforded hepatic protection in general.
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Affiliation(s)
- Nageh A El-Mahdy
- Department of Pharmacology and Toxicology, Tanta University, Tanta, Egypt
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Hwang TL, Chen CY. Gender different response to immunonutrition in liver cirrhosis with sepsis in rats. Nutrients 2012; 4:231-42. [PMID: 22666548 PMCID: PMC3347029 DOI: 10.3390/nu4030231] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2012] [Revised: 02/27/2012] [Accepted: 03/05/2012] [Indexed: 01/06/2023] Open
Abstract
Females with sepsis have a better prognosis than males, while those of both genders with cirrhosis have a high mortality. Impaired immunity accompanies liver cirrhosis. The potential association between sex and immunologic response of cirrhotic rats in sepsis following immunonutrition was investigated. One hundred and forty-three rats were randomly divided into groups. Liver cirrhosis was produced by weekly feeding of CCl(4) for 8 weeks. Among them, 24 male and 19 female underwent castration one month before studying. The rats were fed with either immune enhancing diet or control diet for five days, then sepsis was induced with cecal ligation and two holes puncture. Main outcomes included mortality and serum cytokines (IL-1β, 6, and 10). Comparisons were made both within and between genders. Cirrhotic non-castrated male rats showed a significant decrease in mortality (64.1% vs. 32.1%, p = 0.032) with better survival than control diet following immune enhancing diet. Lower mortality of cirrhotic non-castrated female rats was found after immune enhancing diet (69.6% vs. 52.1%, p = 0.365). Cirrhotic castrated male rats showed a lower mortality (44.4%) following immune enhancing diet, and cirrhotic castrated female rats also showed significantly lower mortality and better survival than control diet after immune enhancing diet (87.5% vs. 33.3%, p = 0.004). Plasma concentrations of IL-1β were higher in non-oophorectomized female rats fed with control diet compared to immune enhancing diet. Non-orchidectomized males and non-oophorectomized females exhibited similar increases in IL-10 after immune enhancing diet. Our results demonstrated that immunonutrition was more beneficial for male than female cirrhotic rats following sepsis. Though orchidectomy was not found to be more advantageous for the normal male rats in sepsis, immunonutrition seemed to be as important as sex hormone for female rats in sepsis.
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Affiliation(s)
- Tsann-Long Hwang
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Tao-Yuan 333, Taiwan.
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11
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Tapuria N, Junnarkar S, Abu-Amara M, Fuller B, Seifalian AM, Davidson BR. Modulation of microcirculatory changes in the late phase of hepatic ischaemia-reperfusion injury by remote ischaemic preconditioning. HPB (Oxford) 2012; 14:87-97. [PMID: 22221569 PMCID: PMC3277050 DOI: 10.1111/j.1477-2574.2011.00407.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Remote ischaemic preconditioning (RIPC) is a novel method of protecting the liver from ischaemia-reperfusion (I-R) injury. Protective effects in the early phase (4-6 h) have been demonstrated, but no studies have focused on the late phase (24 h) of hepatic I-R. This study analysed events in the late phase of I-R following RIPC and focused on the microcirculation, inflammatory cascade and the role of cytokine-induced neutrophil chemoattractant-1 (CINC-1). METHODS A standard animal model was used. Remote preconditioning prior to I-R was induced by intermittent limb ischaemia. Ischaemia was induced in the left and median lobes of the liver (70%). The animals were recovered after 45 min of liver ischaemia. At 24 h, the animals were re-evaluated under anaesthesia. Hepatic microcirculation, sinusoidal leukocyte adherence and hepatocellular death were assessed by intravital microscopy, hepatocellular injury by standard biochemistry and serum CINC-1 by enzyme-linked immunosorbent assay (ELISA). RESULTS At 24 h post I-R, RIPC was found to have improved sinusoidal flow by increasing the sinusoidal diameter. There was no effect of preconditioning on the velocity of red blood cells, by contrast with the early phase of hepatic I-R. Remote ischaemic preconditioning significantly reduced hepatocellular injury, neutrophil-induced endothelial injury and serum CINC-1 levels. CONCLUSIONS Remote ischaemic preconditioning is amenable to translation into clinical practice and may improve outcomes in liver resection surgery and transplantation.
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Affiliation(s)
- Niteen Tapuria
- Hepatopancreatobiliary and Liver Transplant Unit, Department of Surgery, Royal Free Hospital, University College London, London, UK.
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12
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Feng M, Wang Q, Zhang F, Lu L. Ex vivo induced regulatory T cells regulate inflammatory response of Kupffer cells by TGF-beta and attenuate liver ischemia reperfusion injury. Int Immunopharmacol 2011; 12:189-96. [PMID: 22155100 DOI: 10.1016/j.intimp.2011.11.010] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2011] [Revised: 10/29/2011] [Accepted: 11/23/2011] [Indexed: 02/06/2023]
Abstract
In the presence of TGF-β, CD4+CD62L+T cells can be induced to CD4+CD25+FoxP3+ regulatory T cells (iTregs). In our previous work, we have shown that adoptive transfer of iTregs promoted liver recovery from ischemia reperfusion injury (IRI). In this study, we examined the molecular mechanism underlying the liver IRI attenuation by iTregs in a mouse partial hepatic IRI model. We found that the population of hepatic Tregs decreased significantly at 24 h after reperfusion. Adoptive transfer of iTregs before IRI markedly increased the numbers of hepatic Tregs and attenuated liver IRI as indicated by reduced serum aminotransferases and proinflammatory cytokines, such as interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α). Ex vivo study indicated that iTregs suppressed IL-1β and TNF-α expression, promoted transcription of interleukin-10 (IL-10), and elevated phosphorylation of SMAD3 in Kupffer cells (KCs). Furthermore, inhibition of TGF-β signaling by anti-TGF-β abolished the effects on KCs. Treatment with TGF-β suppressed matrix metalloprotease (MMP9) production in KCs and protected liver from IRI. In conclusion, our results suggest that iTregs play a critical role in hepatic IRI by regulating pro-inflammatory and anti-inflammatory function of KCs through TGF-β.
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Affiliation(s)
- Min Feng
- Department of Liver Transplantation, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
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Perry BC, Soltys D, Toledo AH, Toledo-Pereyra LH. Tumor Necrosis Factor-α in Liver Ischemia/Reperfusion Injury. J INVEST SURG 2011; 24:178-88. [DOI: 10.3109/08941939.2011.568594] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Wu C, Wang P, Rao J, Wang Z, Zhang C, Lu L, Zhang F. Triptolide alleviates hepatic ischemia/reperfusion injury by attenuating oxidative stress and inhibiting NF-κB activity in mice. J Surg Res 2010; 166:e205-13. [PMID: 21227469 DOI: 10.1016/j.jss.2010.10.005] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2010] [Revised: 09/14/2010] [Accepted: 10/08/2010] [Indexed: 01/26/2023]
Abstract
BACKGROUND Hepatic I/R injury is unavoidable in liver transplantation and surgery. This remains a significant problem in surgical procedures. The purpose of this study was to investigate the effects of triptolide on liver ischemia/reperfusion (I/R) injury and related mechanisms in mice. MATERIALS AND METHODS Male C57BL/6 mice were randomized into four groups: (1) sham group; (2) sham-triptolide group; (3) I/R group; and (4) I-R/triptolide group. Ninety minutes of warm ischemia was induced and flow by 24 h reperfusion. Serum alanine aminotransferase and aspartate aminotransferase were assayed, pathologic alterations and (NF)-κB p65 immunohistochemistry were observed. Liver malondialdehyde (MDA) level, activity of endogenous antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities, and activity of neutrophil accumulation marker myeloperoxidase (MPO) were measured. TNF-α, IL-6, and IL-1β mRNA were detected by RT-PCR, whereas nuclear factor (NF)-κB p65 and IκBα were assessed with Western blotting. RESULTS Plasma aminotransferase activity was higher in the I/R group than in the I/R-triptolide group. MDA level and neutrophil infiltration were also markedly reduced, while SOD, CAT, and GSH-Px levels increased in I/R-triptolide group compared with I/R group. In group 4, histopathologic changes were significantly attenuated in triptolide-treated livers. In comparison with group 3, triptolide reduced NF-κB p65 nuclear and IκBα expression, and effectively suppressed pro-inflammatory cytokine level during the I/R. CONCLUSIONS These results suggest that triptolide has protective effects against hepatic I/R injury. Its mechanisms might be related to reduction of oxidative stress and neutrophil infiltration and inhibition NF-κB p65 activity.
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Affiliation(s)
- Chuanxing Wu
- Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, China
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Klune JR, Tsung A. Molecular biology of liver ischemia/reperfusion injury: established mechanisms and recent advancements. Surg Clin North Am 2010; 90:665-77. [PMID: 20637940 DOI: 10.1016/j.suc.2010.04.003] [Citation(s) in RCA: 161] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Hepatic ischemia/reperfusion (I/R) injury occurs in a variety of clinical contexts, including transplantation, liver resection surgery, trauma, and hypovolemic shock. The mechanism of organ damage after I/R has been studied extensively and consists of complex interactions of multiple inflammatory pathways. The major contributors to I/R injury include production of reactive oxygen species, release of proinflammatory cytokines and chemokines, and activation of immune cells to promote inflammation and tissue damage. Recent research has focused on the mechanisms by which these immune responses are initially activated through signaling molecules and their cellular receptors. Thorough understanding of the pathophysiology of liver I/R may yield novel therapeutic strategies to reduce I/R injury and lead to improved clinical outcomes.
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Affiliation(s)
- John R Klune
- Department of Surgery, F675 UPMC Presbyterian Hospital, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA
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Dold S, Laschke MW, Zhau Y, Schilling M, Menger MD, Jeppsson B, Thorlacius H. P-selectin glycoprotein ligand-1-mediated leukocyte recruitment regulates hepatocellular damage in acute obstructive cholestasis in mice. Inflamm Res 2009; 59:291-8. [PMID: 19826766 DOI: 10.1007/s00011-009-0099-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2009] [Revised: 09/15/2009] [Accepted: 09/17/2009] [Indexed: 02/01/2023] Open
Abstract
OBJECTIVE Leukocytes mediate hepatocellular injury in obstructive cholestasis. The aim of the present study was to define the role of P-selectin glycoprotein ligand-1 (PSGL-1) in cholestasis-induced leukocyte recruitment and liver damage. METHODS C57BL/6 mice were pre-treated with an anti-PSGL-1 antibody or a control antibody prior to bile duct ligation (BDL) for 12 h. Hepatic recruitment of leukocytes and sinusoidal perfusion were determined by means of intravital fluorescence microscopy. Liver damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Hepatic levels of CXC chemokines were determined by ELISA. RESULTS BDL caused significant hepatocellular damage indicated by increased serum activities of ALT and AST as well as decreased sinusoidal perfusion and clear-cut hepatic infiltration of leukocytes. Administration of the anti-PSGL-1 antibody reduced BDL-induced levels of ALT by 78% and AST by 77%. Inhibition of PSGL-1 decreased BDL-provoked leukocyte rolling and adhesion in post-sinusoidal venules by more than 81%. Moreover, we found that immunoneutralisation of PSGL-1 restored sinusoidal perfusion and decreased hepatic formation of CXC chemokines in cholestatic mice. CONCLUSIONS Our novel data show that PSGL-1 plays an important role in cholestatic liver damage by regulating leukocyte rolling in post-sinusoidal venules. Consequently, interference with PSGL-1 attenuates cholestasis-provoked leukocyte adhesion and extravasation in the liver. Thus, inhibition of PSGL-1 may help to protect against hepatocellular damage in cholestatic diseases.
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Affiliation(s)
- Stefan Dold
- Department of Surgery, Malmö University Hospital, Lund University, Malmö, Sweden
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Kurabayashi M, Takeyoshi I, Yoshinari D, Matsumoto K, Maruyama I, Morishita Y. 2-Arachidonoylglycerol Increases in Ischemia–Reperfusion Injury of the Rat Liver. J INVEST SURG 2009; 18:25-31. [PMID: 15804949 DOI: 10.1080/08941930590905189] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Several studies have implicated endocannabinoids in various forms of shock. However, the role of endocannabinoids in hepatic ischemia-reperfusion injury remains unclear. The purpose of this study was to evaluate the changes of two endocannabinoidsin hepatic ischemia-reperfusion injury: anandamide (ANA) and 2-arachidonoylglycerol (2-AG). Male Sprague-Dawley rats were divided into 2 groups: the short (15 min) ischemic group and the long (60 min)ischemic group in the segmental (70%) hepatic tissue. Blood levels of aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), ANA, and 2-AG were examined. Serum lev-els of AST, ALT, and LDH were significantly higher in the long-ischemia group than in the short-ischemia group. Plasma levels of 2-AG showed similar augmentation prior to and after reperfusion in both the short- and long-ischemia groups, although plasma 2-AG lev-els tended to be higher in the long-ischemia group than in the short-ischemia group. Plasma levels of ANA were augmented in the early phase of reperfusion in the short-ischemia group and did not differ significantly from the normal level with time after reperfusion in the long-ischemia group. These results suggest that the endocannabinoid 2-AG increases in hepatic ischemia-reperfusion injury of rats, rather than ANA.
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Affiliation(s)
- Makoto Kurabayashi
- Second Department of Surgery, Gunma University School of Medicine, Maebashi, Japan
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Uji Y, Yamamoto H, Maeda K, Tsuchihashi H, Akabori H, Shimizu T, Endo Y, Shimomura I, Tani T. Adiponectin deficiency promotes the production of inflammatory mediators while severely exacerbating hepatic injury in mice with polymicrobial sepsis. J Surg Res 2009; 161:301-11. [PMID: 19481767 DOI: 10.1016/j.jss.2008.12.021] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2008] [Revised: 12/12/2008] [Accepted: 12/15/2008] [Indexed: 10/21/2022]
Abstract
BACKGROUND Adiponectin (APN), which is an adipose tissue-derived hormone, is known as an anti-inflammatory cytokine. The effects of APN on the production of inflammatory mediators and hepatic injury during polymicrobial sepsis were evaluated using APN-knockout (KO) mice that had undergone a cecal ligation and puncture (CLP) and rosiglitazone, a selective peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, which increases the plasma APN concentration. MATERIALS AND METHODS Wild type (WT) and APN-KO mice were underwent CLP. The plasma and hepatic levels of inflammatory mediators, including tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1), were measured before, at 24, and 48 h after CLP. A histological analysis of the liver and the plasma alanine aminotransferase (ALT) levels were examined to evaluate hepatic injury. The plasma levels of inflammatory mediators after CLP with pretreatment of rosiglitazone were compared with those without rosiglitazone. RESULTS APN deficiency resulted in significant increases in the plasma levels of TNF-alpha, IL-6, and MCP-1 at 24 h after CLP. Hepatic MCP-1 and plasma AST levels in APN-KO mice were significantly higher than those in WT mice at 48 h after CLP. A steatosis change and MCP-1 expressions in hepatocytes were induced in APN-KO mice during sepsis. The administration of rosiglitazone significantly lowered the plasma levels of inflammatory mediators, including TNF-alpha, IL-6, and MCP-1, in WT mice but not in APN-KO mice during sepsis. CONCLUSION These results suggest that an APN deficiency induces an excessive systemic inflammatory status and exacerbates hepatic injury during polymicrobial sepsis.
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Affiliation(s)
- Yoshitaka Uji
- Department of Surgery, Shiga University of Medical Science, Shiga, Japan
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Tomiyama K, Ikeda A, Ueki S, Nakao A, Stolz DB, Koike Y, Afrazi A, Gandhi C, Tokita D, Geller DA, Murase N. Inhibition of Kupffer cell-mediated early proinflammatory response with carbon monoxide in transplant-induced hepatic ischemia/reperfusion injury in rats. Hepatology 2008; 48:1608-20. [PMID: 18972563 DOI: 10.1002/hep.22482] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
UNLABELLED Proinflammatory responses play critical roles in hepatic ischemia/reperfusion (I/R) injury associating with liver transplantation (LTx), and carbon monoxide (CO) can effectively down-regulate them. Using wild-type (WT) to enhanced green fluorescent protein (EGFP)-transgenic rat LTx with 18-hour cold preservation in University of Wisconsin solution, this study analyzed the relative contribution of donor and host cells during early posttransplantation period and elucidated the mechanism of hepatic protection by CO. CO inhibited hepatic I/R injury and reduced peak alanine aminotransferase levels at 24 hours and hepatic necrosis at 48 hours. Abundant EGFP(+) host cells were found in untreated WT liver grafts at 1 hour and included nucleated CD45(+) leukocytes (myeloid, T, B, and natural killer cells) and EGFP(+) platelet-like depositions in the sinusoids. However, reverse transcription polymerase chain reaction (RT-PCR) analysis of isolated graft nonparenchymal cells (NPCs) revealed that I/R injury-induced proinflammatory mediators [for example, tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS)] were not up-regulated in purified CD45(+) cells of donor or host origin. Instead, TNF-alpha and IL-6 messenger RNA (mRNA) elevation was exclusively seen in isolated CD68(+) cells, whereas iNOS mRNA up-regulation was seen in hepatocytes. Nearly all CD68(+) cells at 1 hour after LTx were EGFP(-) donor Kupffer cells, and CO efficiently inhibited TNF-alpha and IL-6 up-regulation in the CD68(+) Kupffer cell fraction. When graft Kupffer cells were inactivated with gadolinium chloride, activation of inflammatory mediators in liver grafts was significantly inhibited. Furthermore, in vitro rat primary Kupffer cell culture also showed significant down-regulation of lipopolysaccharide (LPS)-induced inflammatory responses by CO. CONCLUSION These results indicate that CO ameliorates hepatic I/R injury by down-regulating graft Kupffer cells in early postreperfusion period. The study also suggests that different cell populations play diverse roles by up-regulating distinctive sets of mediators in the acute phase of hepatic I/R injury.
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Affiliation(s)
- Koji Tomiyama
- Department of Surgery, Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA
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Hwang TL, Yang YM. Sex differences in response to immunonutrition in sepsis. Nutrition 2008; 24:761-6. [PMID: 18549928 DOI: 10.1016/j.nut.2008.03.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2007] [Revised: 03/18/2008] [Accepted: 03/20/2008] [Indexed: 11/26/2022]
Abstract
BACKGROUND Cell-mediated immune response is superior in females compared to males. Whether sex differences influenced mortality in sepsis while on immune-enhancing nutrients was investigated. MATERIALS AND METHODS Seventy-two non-orchitectomized male and non-oophorectomized female rats (n = 36/group) were randomized into four groups. Rats were fed either an immune-enhancing diet or control diet for five days. Sepsis was induced with caecal ligation and puncture (CLP). An additional group of orchitectomized and oophorectomized rats (n = 36/group) were divided into four groups; fed either an immune-enhancing or control diet of one month, then following castration. Sepsis was induced with CLP. The influence of immune-enhancing nutrients on the effect of the rat's sex on mortality rates and serum cytokines were compared. RESULTS Non-orchitectomized male rats had a decreased mortality (88.9% vs. 16.7%) on immune-enhancing diet. Low mortality among non-oophorectomized female rats persisted, on immune-enhancing diet (27.8% vs. 11.1%). Orchitectomized rats demonstrated reduced mortality (88.8% vs. 50%) on immune-enhancing diet. Oophorectomized rats showed a similar trend (55.6% vs. 44.4%). Orchitectomy increased mortality in spite of immune-enhancing diet (50% vs. 16.7%). Oophorectomy increased mortality on immune-enhancing diet (44.4% vs. 11.1%). Circulating IL-1beta was higher in non-oophorectomized female rats on control diet compared to immune-enhancing diet. Non-orchitectomized male and non-oophorectomized female rats had similar increases in IL-10 on immune-enhancing diet. CONCLUSIONS Mortality rates on immunonutrition were less in male than female rats following sepsis. Orchitectomy did not confer an advantage for septic rats. Sex hormone was more important than immunonutrition in septic female rats.
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Affiliation(s)
- Tsann-Long Hwang
- Department of Nutritional Therapy, Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan.
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Abstract
Hepatic ischemia/reperfusion (I/R) results in a chain of events that culminate in liver dysfunction and injury. I/R injury is characterized by early oxidant stress followed by an intense acute inflammatory response that involves the transcription factor nuclear factor (NF)-kappaB. In addition to being a primary regulator of pro-inflammatory gene expression, NF-kappaB may play other roles in the hepatic response to I/R, such as mediating the expression of anti-apoptotic genes, preventing the accumulation of damaging reactive oxygen species, facilitating liver regeneration, and mediating the protective effects of ischemic preconditioning. In the present study, we review the diverse functions of NF-kappaB during hepatic I/R injury.
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Affiliation(s)
- Thomas Shin
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA
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Platelet-dependent accumulation of leukocytes in sinusoids mediates hepatocellular damage in bile duct ligation-induced cholestasis. Br J Pharmacol 2007; 153:148-56. [PMID: 18026126 DOI: 10.1038/sj.bjp.0707578] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Although it is well known that extrahepatic cholestasis induces liver damage, the mechanisms are still not completely understood. The aim of the present study was to evaluate the role of platelets and P-selectin in cholestasis-induced liver injury. EXPERIMENTAL APPROACH C57BL/6 mice underwent bile duct ligation (BDL) and pretreatment with an anti-GP1balpha antibody, which depletes platelets, an anti-P-selectin antibody or a control antibody. Hepatic platelet and leukocyte recruitment as well as microvascular perfusion were determined by intravital fluorescence microscopy. KEY RESULTS BDL caused significant liver damage and sinusoidal perfusion failure. BDL further induced hepatic platelet accumulation with widespread intravascular platelet aggregates, increased platelet adhesion in postsinusoidal venules and massive platelet accumulation in liver sinusoids. Administration of the anti-GP1balpha antibody reduced systemic platelet count by 90%. Depletion of platelets in BDL mice not only abolished accumulation and adhesion of platelets in sinusoids and venules but also restored sinusoidal perfusion and reduced liver enzymes by more than 83%. Platelet depletion further reduced BDL-associated sinusoidal leukocyte accumulation by 48% although leukocyte-endothelium interactions in venules were not affected. Immunoneutralization of P-selectin also inhibited hepatic microvascular accumulation of platelets and leukocytes, and protected against cholestasis-provoked hepatocellular damage. CONCLUSIONS AND IMPLICATIONS Platelets play an important role in BDL-induced liver injury by promoting leukocyte recruitment and deteriorating microvascular perfusion. Moreover, our findings demonstrate that cholestasis-induced accumulation of platelets is mediated by P-selectin. Thus, targeting platelet accumulation may be a useful strategy against liver damage associated with obstructive jaundice.
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Yamanouchi K, Eguchi S, Kamohara Y, Yanaga K, Okudaira S, Tajima Y, Kanematsu T. Glycine reduces hepatic warm ischaemia-reperfusion injury by suppressing inflammatory reactions in rats. Liver Int 2007; 27:1249-54. [PMID: 17919237 DOI: 10.1111/j.1478-3231.2007.01564.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND Glycine, a non-essential amino acid, is known to have an anti-inflammatory effect on haemorrhagic and endotoxic shock in animals. In the present study, we examined the effects of glycine on inflammatory reactions and hepatocellular damage after hepatic warm ischaemia-reperfusion (I-R) in rats. METHODS Using Sprague-Dawley rats, ischaemia was induced in 92% of the liver by clamping the hepatic inflows for 60 min, and part of the non-ischaemic lobe was resected after reperfusion. Before the induction of I-R, rats were treated by an intravenous administration of either glycine (Glycine group) or normal saline (Control group). The severity of hepatocellular injury was determined by serum levels of hepatic enzymes and histological necrosis. To evaluate the effect of glycine on inflammatory reactions, tumour necrosis factor (TNF)-alpha mRNA expression in the liver, serum levels of TNF-alpha and chemokine-induced neutrophil chemoattractant (CINC) and the number of neutrophils in the liver were compared between the groups. RESULTS At 60 min after reperfusion, the serum levels of hepatic enzymes in the Glycine group were significantly lower than those in the Control group (P<0.05). TNF-alpha mRNA expression was also suppressed in the livers in the Glycine group. Furthermore, the serum levels of TNF-alpha and CINC in the Glycine group were significantly lower than those in the Control group (P<0.05). Pretreatment with glycine also significantly reduced hepatic necrosis and the number of neutrophils at 24 h after reperfusion. CONCLUSION Glycine has a protective effect against inflammatory reactions, and reduces hepatocellular injury induced by hepatic warm I-R in rats.
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Affiliation(s)
- Kosho Yamanouchi
- Department of Liver Transplantation and Digestive Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
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Kincius M, Liang R, Nickkholgh A, Hoffmann K, Flechtenmacher C, Ryschich E, Gutt CN, Gebhard MM, Schmidt J, Büchler MW, Schemmer P. Taurine protects from liver injury after warm ischemia in rats: the role of kupffer cells. Eur Surg Res 2007; 39:275-283. [PMID: 17519554 DOI: 10.1159/000102982] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2006] [Accepted: 02/24/2007] [Indexed: 11/19/2022]
Abstract
BACKGROUND/AIMS Warm ischemia to liver with subsequent Kupffer cell-dependent pathology is associated with many clinical conditions. Taurine prevents Kupffer cell activation and improves graft survival after experimental cold ischemia and liver transplantation. Thus this study was designed to assess its effects after warm hepatic ischemia. METHODS The left liver lobe of female Sprague-Dawley rats (170-210 g) underwent 60 min of warm ischemia. Animals were given either intravenous taurine or Ringer's solution 10 min prior to warm ischemia. Transaminases, histology, in vivo microscopy, intercellular adhesion molecules-1 (ICAM-1) expression, TNF-alpha and tissue hydroperoxide were compared between groups using analysis of variance (ANOVA) or ANOVA on ranks as appropriate. RESULTS Taurine significantly decreased transaminases and improved histologic outcome. Phagocytosis of latex beads, serum TNF-alpha levels and tissue hydroperoxide concentrations were also significantly reduced. Stickers in sinusoids and post-sinusoidal venules significantly decreased. In parallel, both leukocyte infiltration and ICAM-1 expression decreased (p < 0.05), while flow velocity of red blood cells as well as sinusoidal perfusion rate were improved (p < 0.05). CONCLUSION This study demonstrates that taurine blunts Kupffer cell-dependent hepatic pathology after warm ischemia in vivo via mechanisms including leukocyte-endothelial interaction, microcirculation disturbances and protection against lipid peroxidation.
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Affiliation(s)
- M Kincius
- Department of General Surgery, Ruprecht Karls University, Heidelberg, Germany
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Di Paola R, Cuzzocrea S. Peroxisome proliferator-activated receptors ligands and ischemia-reperfusion injury. Naunyn Schmiedebergs Arch Pharmacol 2007; 375:157-75. [PMID: 17394034 DOI: 10.1007/s00210-007-0141-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2006] [Accepted: 01/28/2007] [Indexed: 12/19/2022]
Abstract
Peroxisome proliferator-activated receptors (PPARs) belong to a subfamily of transcription nuclear factors. Three isoforms of PPARs have been identified: alpha, beta/delta and gamma, encoded by different genes and distributed in various tissues. They play important roles in metabolic processes like regulation of glucose and lipid redistribution. They also have anti-atherogenic, anti-inflammatory as well as antihypertensive functions. There is good evidence that ligands of PPARs reduce tissue injury associated with ischemia and reperfusion. The potential utility of PPAR ligands in ischemia and reperfusion will be discussed in this review.
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Affiliation(s)
- Rosanna Di Paola
- Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Torre Biologica-Policlinico Universitario, Via C. Valeria-Gazzi, 98100 Messina, Italy
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Yuki T, Ishihara S, Rumi MAK, Ortega-Cava CF, Kadowaki Y, Kazumori H, Ishimura N, Amano Y, Moriyama N, Kinoshita Y. Increased expression of midkine in the rat colon during healing of experimental colitis. Am J Physiol Gastrointest Liver Physiol 2006; 291:G735-43. [PMID: 16959957 DOI: 10.1152/ajpgi.00388.2005] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Midkine (MK) is a unique growth and differentiation factor that modulates the proliferation and migration of various cells; however, little is known regarding its relationship to intestinal diseases. The aim of this study was to investigate MK expression and its role in dextran sulfate sodium (DSS)-induced colitis in rats. The expressions of MK, receptor-like protein-tyrosine phosphatase (RPTP)-beta, and proinflammatory cytokines were examined in rat colonic tissues after the development of DSS-induced colitis using Northern blotting, immunohistochemistry, and laser-capture microdissection (LCM) coupled with RT-PCR. The effects of MK on the migration of intestinal epithelial cells (IEC-6) were also evaluated in vitro using an intestinal wound repair model. MK expression was significantly increased in damaged colonic mucosa, mainly from day 3 to day 5 after the end of DSS administration, with abundant MK immunoreactive signals detected in submucosal fibroblasts. Expressions of proinflammatory cytokines were most strongly induced on day 1, which preceded the augmentation of MK expression. Results of LCM coupled with RT-PCR clearly indicated RPTP-beta expression in colonic epithelial cells. The migration assay showed that wound repair in the MK-treated groups was accelerated dose dependently. The present results showed for the first time that intestinal inflammation upregulates the MK-RPTP-beta system, which may stimulate mucosal regeneration during the process of healing of colitis. Additional investigations regarding the role of MK may contribute to the development of new options for the treatment of inflammatory bowel diseases.
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Affiliation(s)
- Takafumi Yuki
- Dept. of Gastroenterology and Hepatology, Shimane Medical Univ. School of Medicine, 89-1, Enya-cho, Izumo, Shimane 693-0021, Japan
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Akao T, Takeyoshi I, Totsuka O, Arakawa K, Muraoka M, Kobayashi K, Konno K, Matsumoto K, Morishita Y. Effect of the free radical scavenger MCI-186 on pulmonary ischemia-reperfusion injury in dogs. J Heart Lung Transplant 2006; 25:965-71. [PMID: 16890118 DOI: 10.1016/j.healun.2006.03.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2005] [Revised: 02/15/2006] [Accepted: 03/02/2006] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Free radical scavengers and superoxide dismutase have been found to protect against cerebral ischemic damage, and it was suggested that oxygen free radicals contribute to ischemia-reperfusion injury induced by cerebral ischemic damage. MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one) is a potent scavenger and inhibitor of hydroxyl radicals and protective agent of peroxidative injury. The purpose of this study was to evaluate the effects of MCI-186 on pulmonary ischemia-reperfusion injury in a simulated transplanted lung model. METHODS Fourteen dogs were divided into two groups (n = 7 each). In the MCI group, MCI-186 was continuously administered at 3 mg/kg/hour intravenously (IV) from 30 minutes before reperfusion until 30 minutes after reperfusion (total administration time 1 hour). Vehicle was administered in the control group. Warm ischemia was induced for 3 hours by clamping the left pulmonary artery and veins. Simultaneously, the left stem bronchus was bisected and then anastomosed before reperfusion. The right pulmonary artery was ligated 15 minutes after reperfusion, and the right stem bronchus was then bisected. RESULTS The respiratory gas exchange, hemodynamic changes, wet-to-dry weight ratio (WDR) and malondialdehyde (MDA) concentration in the tissue were significantly improved (p < 0.05) in the MCI group. The histologic damage was more severe in the control group and polymorphonuclear neutrophil (PMN) infiltration was reduced in the MCI group. CONCLUSION MCI-186 has a protective effect on pulmonary ischemia-reperfusion injury through the inhibition of lipid peroxidation.
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Affiliation(s)
- Takahiko Akao
- Department of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
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Anderson SI, Shiner R, Brown MD, Hudlicka O. ICAM-1 expression and leukocyte behavior in the microcirculation of chronically ischemic rat skeletal muscles. Microvasc Res 2006; 71:205-11. [PMID: 16647725 DOI: 10.1016/j.mvr.2006.03.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2005] [Revised: 02/22/2006] [Accepted: 03/14/2006] [Indexed: 11/21/2022]
Abstract
In muscle microcirculation, short periods of ischemia followed by reperfusion are known to upregulate leukocyte and endothelial adhesion molecules, but little is known about leukocyte adherence and ICAM-1 expression during chronic ischemia or any likely effect of muscle activity which is recommended in chronic ischemia due to peripheral arterial disease. Leukocyte rolling and stationary adhesion were observed in post-capillary venules in ischemic and contralateral rat extensor digitorum longus (EDL) muscles 3 and 7 days after unilateral ligation of the common iliac artery and in 3-day ischemic EDLs that were electrically stimulated on days 1 and 2 post-ligation (7 x 15 min per day). ICAM-1 was localized immunohistochemically to venular vessels in all muscles. Following ligation, use of the ischemic leg was observed to be restricted for the first 3 days, returning to normal by 7 days. After 3 days, leukocyte rolling/adherence and ICAM-1 expression were no different in ischemic than control muscles, but all were increased in contralateral muscles. In ischemic muscles, electrical stimulation doubled the numbers of rolling leukocytes and upregulated ICAM-1 expression. After 7 days, increased muscle activity as a result of natural movement also resulted in greater ICAM-1 expression, a 4- to 5-fold increase in rolling leukocyte numbers and a 3-fold increase in stationary adherent leukocytes. Chronic ischemia thus increases ICAM-1 and leukocyte adherence in muscle microcirculation only when combined with contractile activity. Post-capillary venular endothelium may be modified by muscle acidosis when contractions are performed under low flow conditions or by changes in rheological (shear force) factors.
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Jung JY, Lee SM. The roles of Kupffer cells in hepatic dysfunction induced by ischemia/reperfusion in rats. Arch Pharm Res 2006; 28:1386-91. [PMID: 16392673 DOI: 10.1007/bf02977906] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
This study examined the role of Kupffer cells in altering the hepatic secretory and microsomal function during ischemia and reperfusion (Is/Rp). Rats were subjected to 60 min of hepatic ischemia, followed by 1 and 5 h of reperfusion. Gadolinium chloride (GdCl3, 7.5 mg/kg body weight, intravenously) was used to inactivate the Kupffer cells 1 day prior to ischemia. Is/Rp markedly increased the serum aminotransferase level and the extent of lipid peroxidation. GdCl3 significantly attenuated these increases. Is/Rp markedly decreased the bile flow and cholate output, and GdCl3 restored their secretion. The cytochrome P450 content was decreased by Is/Rp. However, these decreases were not prevented by GdCl3. The aminopyrine N-demethylase activity was decreased by Is/Rp, while the aniline p-hydroxylase activity was increased. GdCl3 prevented the increase in the aniline p-hydroxylase activity. Overall, Is/Rp diminishes the hepatic secretory and microsomal drug-metabolizing functions, and Kupffer cells are involved in this hepatobiliary dysfunction.
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Affiliation(s)
- Joo-Yeon Jung
- Narcotic and Neuropharmacological Drug Division, Drug Evaluation Department, Korea Food and Drug Administration, Seoul, Korea
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31
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Dorman RB, Gujral JS, Bajt ML, Farhood A, Jaeschke H. Generation and functional significance of CXC chemokines for neutrophil-induced liver injury during endotoxemia. Am J Physiol Gastrointest Liver Physiol 2005; 288:G880-6. [PMID: 15576625 DOI: 10.1152/ajpgi.00317.2004] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The hypothesis that the neutrophil chemoattractant CXC chemokines KC and macrophage inflammatory protein-2 (MIP-2) are involved in neutrophil transmigration and liver injury was tested in C3Heb/FeJ mice treated with galactosamine (Gal, 700 mg/kg), endotoxin (ET, 100 microg/kg), or Gal + ET (Gal/ET). Hepatic KC and MIP-2 mRNA levels and plasma CXC chemokine concentrations were dramatically increased 1.5 h after Gal/ET or ET alone and gradually declined up to 7 h. Murine recombinant cytokines (TNF-alpha, IL-1 alpha, and IL-1 beta), but not Gal/ET, induced CXC chemokine formation in the ET-resistant C3H/HeJ strain. To assess the functional importance of KC and MIP-2, C3Heb/FeJ mice were treated with Gal/ET and control IgG or a combination of anti-KC and anti-MIP-2 antibodies. Anti-CXC chemokine antibodies did not attenuate hepatocellular apoptosis, sinusoidal neutrophil sequestration and extravasation, or liver injury at 7 h. Furthermore, there was no difference in liver injury between BALB/cJ wild-type and CXC receptor-2 gene knockout (CXCR2-/-) mice treated with Gal/ET. The higher neutrophil count in livers of CXCR2-/- than in wild-type mice after Gal/ET was caused by the elevated number of neutrophils located in sinusoids of untreated CXCR2-/- animals. The pancaspase inhibitor Z-Val-Ala-Asp-fluoromethylketone eliminated Gal/ET-induced apoptosis and neutrophil extravasation and injury but not CXC chemokine formation. Thus Gal/ET induced massive, cytokine-dependent CXC chemokine formation in the liver. However, neutrophil extravasation and injury occurred in response to apoptotic cell injury at 6-7 h and was independent of CXC chemokine formation.
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Affiliation(s)
- Robert B Dorman
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
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32
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Laurens M, Defamie V, Scozzari G, Schmid-Alliana A, Gugenheim J, Crenesse D. Hypoxia-reoxygenation-induced chemokine transcription is not prevented by preconditioning or intermittent hypoxia, in mice hepatocytes. Transpl Int 2005; 18:444-52. [PMID: 15773965 DOI: 10.1111/j.1432-2277.2004.00064.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Prolonged ischemia used in liver surgery and/or transplantation causes cellular damage resulting in apoptosis and necrosis. Ischemia-reperfusion (I/R) led Kupffer cells to pro-inflammatory cytokines secretion [tumor necrosis factor (TNF)-alpha, interleukin-1] which involve chemokines secretion by hepatocytes. These chemokines have neutrophil chemotactic properties and neutrophils are involved in the development of I/R-induced necrosis. The aim of this study was to specify the consequence of partial oxygen pressure variation on hepatocyte chemokines synthesis and to verify if intermittent hypoxia and/or preconditioning could decrease it. It was performed on primary cultured mice hepatocytes and Kupffer cells, subjected to continuous, intermittent hypoxia or preconditioning phases, mimicking surgical processes. The chemokine secretion was evaluated by RNase protection assay and enzyme-linked immunosorbent assay method. Only monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) mRNA formation were observed, especially after 1-h hypoxia followed by 10-h (for MCP-1) or 24-h reoxygenation (for MIP-2). In conclusion, TNF-alpha and coculture with Kupffer cells increased hepatocyte chemokines mRNA transcription, whereas surgical split up protocols (intermittent hypoxia and preconditioning) had no significant effect.
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Affiliation(s)
- Marina Laurens
- Laboratoire de Recherches Chirurgicales, Faculté de Médecine, Université de Nice-Sophia Antipolis, France
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Loi P, Paulart F, Pajak B, Nagy N, Salmon I, Moser M, Goldman M, Flamand V. The fate of dendritic cells in a mouse model of liver ischemia/reperfusion injury. Transplant Proc 2004; 36:1275-9. [PMID: 15251311 DOI: 10.1016/j.transproceed.2004.05.052] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Ischemia/reperfusion during liver transplantation triggers a complex cascade of inflammatory events that may lead to organ dysfunction. Herein, we investigated the consequences of hepatic ischemia/reperfusion on liver dendritic cells. Liver damage was documented by increased levels of serum alanine aminotransferase and by histopathology showing large areas of hepatocyte cytolysis. MHC class II+ CD45-B220 F4/80 dendritic cells were detected in necrotic areas 20 hours after reperfusion. Dendritic cells freshly isolated from reperfused livers displayed a mature phenotype characterized by upregulated expression of B7 costimulatory molecules; MHC-class II, and CD1d molecules. As shown by real-time PCR, IL-10, and TGF-beta mRNA accumulated in liver dendritic cells isolated after reperfusion, whereas IL-12p40 mRNA levels were decreased and IFN-gamma mRNA levels were unchanged. These results suggest that hepatic ischemia/reperfusion results in maturation of dendritic cells, which preferentially produce inhibitory cytokines.
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Affiliation(s)
- P Loi
- Institute for Medical Immunology-Laboratory of Experimental Immunology, Universite Libre de Bruxelles, Brussels
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Kim YH, Lee SM. Role of kupffer cells in the vasoregulatory gene expression during hepatic ischemia/reperfusion. Arch Pharm Res 2004; 27:111-7. [PMID: 14969349 DOI: 10.1007/bf02980056] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Hepatic microcirculatory failure is a major component of reperfusion injury in the liver. Recent data provided some evidence that endothelium-derived vasoconstrictors and vasodilators may be functionally important to the control of the total hepatic blood flow under these conditions of circulatory failure. Since Kupffer cells provide signals that regulate the hepatic response in ischemia/reperfusion (I/R), the aim of this study was to investigate the role of Kupffer cells in the I/R-induced imbalance of vasoregulatory gene expression. Rats were subjected to 60 min hepatic ischemia, followed by 5 h of reperfusion. The Kupffer cells were inactivated by gadolinium chloride (GdCl3, 7.5 mg/kg body weight, intravenously) 1 day prior to ischemia. Liver samples were obtained 5 hrs after reperfusion for RT-PCR analysis of the mRNA for genes of interest: endothelin-1 (ET-1), its receptors ETA and ETB, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1). ET-1 mRNA expression was increased by I/R. mRNA levels for ETA receptors showed no change, whereas ETB receptor transcripts increased in the I/R group. The increases in ET-1 and ETB mRNA were not prevented by the GdCl3 pretreatment. The mRNA levels for iNOS and eNOS significantly increased within the I/R group with no significant difference between the I/R group and the GdCl3-treated I/R group. HO-1 mRNA expression significantly increased in the I/R group and this increase was attenuated by GdCl3. In conclusion, we have demonstrated that an imbalance in hepatic vasoregulatory gene expression occurs during I/R. Our findings suggest that the activation of Kupffer cells is not required for I/R-induced hepatic microvascular dysfunction.
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Affiliation(s)
- Yong-Hyuk Kim
- College of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu Suwon-si, Gyeonggi-do 440-746, Korea
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Teoh NC, Farrell GC. Hepatic ischemia reperfusion injury: pathogenic mechanisms and basis for hepatoprotection. J Gastroenterol Hepatol 2003; 18:891-902. [PMID: 12859717 DOI: 10.1046/j.1440-1746.2003.03056.x] [Citation(s) in RCA: 299] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
This review highlights recent advances in our understanding of mechanisms underlying reperfusion injury to the liver after warm hepatic ischemia. Sinusoidal endothelial cells and hepatocytes are targets of injury in the early 'cytotoxic' phase, although participation of apoptosis in the cell-death process remains contentious. Kupffer cells may play an important role as the initial cytotoxic cell type and are likely a source of reactive oxygen species and proinflammatory mediators, particularly tumor necrosis factor (TNF)-alpha. The latter are involved with subsequent neutrophil activation and recruitment. Microcirculatory disruption results from an imbalance between the actions of vasoconstrictors and vasodilators, such as nitric oxide, and also has a major impact on reperfusion injury. There is growing evidence that a brief prior ischemia-reperfusion period, termed 'ischemic preconditioning', is hepatoprotective. This can be mimicked by drugs that produce oxidative stress, and by interleukin-6 and TNF-alpha; both these cytokines are involved with priming hepatocytes to enter the cell cycle. Several mechanisms have been implicated including mobilization of adenosine and activation of adenosine type 2 receptors, nitric oxide, abrogation of TNF synthesis, preservation of energy metabolism, protection of the microcirculation and accelerated cell-cycle entry. A better understanding of preconditioning mechanisms will lead to novel approaches to improve outcomes of liver surgery.
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Affiliation(s)
- Narci C Teoh
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, New South Wales, Australia
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36
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Hines IN, Hoffman JM, Scheerens H, Day BJ, Harada H, Pavlick KP, Bharwani S, Wolf R, Gao B, Flores S, McCord JM, Grisham MB. Regulation of postischemic liver injury following different durations of ischemia. Am J Physiol Gastrointest Liver Physiol 2003; 284:G536-45. [PMID: 12444015 DOI: 10.1152/ajpgi.00400.2002] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The objective of this study was to define the relationship among Kupffer cells, O(2)(-) production, and TNF-alpha expression in the pathophysiology of postischemic liver injury following short and long periods of ischemia. Using different forms of superoxide dismutase with varying circulating half-lives, a monoclonal antibody directed against mouse TNF-alpha, and NADPH oxidase-deficient mice, we found that 45 or 90 min of partial (70%) liver ischemia and 6 h of reperfusion (I/R) produced time-dependent increases in liver injury and TNF-alpha expression in the absence of neutrophil infiltration. Furthermore, we observed that hepatocellular injury induced by short periods of ischemia were not dependent on formation of TNF-alpha but were dependent on Kupffer cells and NADPH oxidase-independent production of O(2)(-). However, liver injury induced by extended periods of ischemia appeared to require the presence of Kupffer cells, NADPH oxidase-derived O(2)(-), and TNF-alpha expression. We conclude that the sources for O(2)(-) formation and the relative importance of TNF-alpha in the pathophysiology of I/R-induced hepatocellular injury differ depending on the duration of ischemia.
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Affiliation(s)
- Ian N Hines
- Department of Molecular and Cellular Physiology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA
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Jaeschke H. Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol 2003; 284:G15-26. [PMID: 12488232 DOI: 10.1152/ajpgi.00342.2002] [Citation(s) in RCA: 611] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Ischemia-reperfusion injury is, at least in part, responsible for the morbidity associated with liver surgery under total vascular exclusion or after liver transplantation. The pathophysiology of hepatic ischemia-reperfusion includes a number of mechanisms that contribute to various degrees in the overall injury. Some of the topics discussed in this review include cellular mechanisms of injury, formation of pro- and anti-inflammatory mediators, expression of adhesion molecules, and the role of oxidant stress during the inflammatory response. Furthermore, the roles of nitric oxide in preventing microcirculatory disturbances and as a substrate for peroxynitrite formation are reviewed. In addition, emerging mechanisms of protection by ischemic preconditioning are discussed. On the basis of current knowledge, preconditioning or pharmacological interventions that mimic these effects have the greatest potential to improve clinical outcome in liver surgery involving ischemic stress and reperfusion.
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Affiliation(s)
- Hartmut Jaeschke
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock 72205, USA
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Mizunuma K, Ohdan H, Tashiro H, Fudaba Y, Ito H, Asahara T. ROCK inhibitor Y-27632 prevents primary graft non-function caused by warm ischemia/reperfusion in rat liver transplantation. Transpl Int 2002. [DOI: 10.1111/j.1432-2277.2002.tb00121.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Cutrn JC, Perrelli MG, Cavalieri B, Peralta C, Rosell Catafau J, Poli G. Microvascular dysfunction induced by reperfusion injury and protective effect of ischemic preconditioning. Free Radic Biol Med 2002; 33:1200-1208. [PMID: 12398928 DOI: 10.1016/s0891-5849(02)01017-1] [Citation(s) in RCA: 124] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Hepatic ischemia/reperfusion injury has immediate and deleterious effects on the outcome of patients after liver surgery. The precise mechanisms leading to the damage have not been completely elucidated. However, there is substantial evidence that the generation of oxygen free radicals and disturbances of the hepatic microcirculation are involved in this clinical syndrome. Microcirculatory dysfunction of the liver seems to be mediated by sinusoidal endothelial cell damage and by the imbalance of vasoconstrictor and vasodilator molecules, such as endothelin (ET), reactive oxygen species (ROS), and nitric oxide (NO). This may lead to no-reflow phenomenon with release of proinflammatory cytokines, sinusoidal plugging of neutrophils, oxidative stress, and as an ultimate consequence, hypoxic cell injury and parenchymal failure. An inducible potent endogenous mechanism against ischemia/reperfusion injury has been termed ischemic preconditioning. It has been suggested that preconditioning could inhibit the effects of different mediators involved in the microcirculatory dysfunction, including endothelin, tumor necrosis factor-alpha, and oxygen free radicals. In this review, we address the mechanisms of liver microcirculatory dysfunction and how ischemic preconditioning could help to provide new surgical and/or pharmacological strategies to protect the liver against reperfusion damage.
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Affiliation(s)
- Juan C Cutrn
- Laboratory of Experimental Liver Pathology, Department of Clinical and Biological Sciences, University of Torino, Italy.
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40
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Hirokawa F, Nakai T, Yamaue H. Storage solution containing fructose-1,6-bisphosphate inhibits the excess activation of Kupffer cells in cold liver preservation. Transplantation 2002; 74:779-83. [PMID: 12364855 DOI: 10.1097/00007890-200209270-00008] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND In liver transplantation, the activation of Kupffer cells at the time of cold preservation and reperfusion is considered to play an important role. In the present study, the usefulness of cold storage solution containing fructose-1,6-bisphosphate (FBP) was compared with University of Wisconsin (UW) solution in the function of Kupffer cells. METHODS Kupffer cells were separated from rat liver stored at 4 degrees C in each storage solution. Four kinds of storage solutions were used: UW, simplified UW without FBP (0-FBP), and solutions with 10 or 20 mM FBP (10-FBP, 20-FBP). Lipopolysaccharide (LPS) labeled by fluorescein was loaded after 12 or 24 hr of cold preservation in each solution. The rates of cells uptaking LPS as phagocytic ability were measured using flow cytometry. Tumor necrosis factor-alpha, cytokine-induced neutrophil chemoattractant, and nitric oxide (NO) were measured in the supernatant. RESULTS Tumor necrosis factor-alpha values in the 20-FBP group were significantly lower than those in the UW group. Cytokine-induced neutrophil chemoattractant values at 60 min after loading LPS were significantly lower in the 20-FBP group than in the UW group. NO values at 24 hr after loading LPS were significantly lower in the 20-FBP group compared with the UW group. The 20-FBP group was highest in the rates of cells uptaking LPS after 24-hr cold preservation. CONCLUSIONS The storage solution containing FBP controlled the secretion of cytokines and NO from Kupffer cells and maintained phagocytic ability. This solution was considered to be more useful than UW solution for Kupffer cell protection.
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Affiliation(s)
- Fumitoshi Hirokawa
- Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
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41
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Kataoka M, Shimizu H, Mitsuhashi N, Ohtsuka M, Wakabayashi Y, Ito H, Kimura F, Nakagawa K, Yoshidome H, Shimizu Y, Miyazaki M. Effect of cold-ischemia time on C-X-C chemokine expression and neutrophil accumulation in the graft liver after orthotopic liver transplantation in rats. Transplantation 2002; 73:1730-5. [PMID: 12084994 DOI: 10.1097/00007890-200206150-00007] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND The precise mechanisms leading to polymorphonuclear neutrophil (PMN) recruitment and activation in the extended cold-preserved liver after transplantation are not yet fully understood. METHODS We histologically evaluated the number of accumulated PMNs in graft livers, with varying time periods of cold ischemia (1, 6, and 24 hr in University of Wisconsin solution at 4 degrees C), after liver transplantation in rats. Intragraft expression of macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (CINC) mRNA, as well as immunohistochemical expression of MIP-2 and CINC in the graft liver, were investigated after reperfusion. The levels of MIP-2 and CINC in the hepatic vein, and tumor necrosis factor (TNF)-alpha, which stimulates these chemokine production, were also monitored. RESULTS The number of accumulated PMNs in sinusoids significantly increased in the 24-hr cold-ischemia group within 3 hr after reperfusion, compared with the 1-hr and 6-hr groups. Serum MIP-2 levels in the 24-hr group significantly increased at 3, 6, and 12 hr after reperfusion, compared with the other groups. Intragraft MIP-2 mRNA was also up-regulated to a greater extent in the 24-hr group. Similarly, serum CINC levels in the 24-hr group significantly increased at 3 hr, compared with the 1-hr group. CINC mRNA also increased as cold-ischemia time was prolonged. Immunohistochemical staining revealed that hepatocytes were the main source of both MIP-2 and CINC protein. In addition, TNF-alpha in the hepatic vein was detected only in the 24-hr group after reperfusion. CONCLUSION Extended cold preservation of the graft liver might up-regulate MIP-2 and CINC expression of hepatocytes, most probably through elevated TNF-alpha, and might contribute to PMN recruitment and activation after reperfusion.
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Affiliation(s)
- Masaaki Kataoka
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-0856, Japan
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Hsu CM, Wang JS, Liu CH, Chen LW. Kupffer cells protect liver from ischemia-reperfusion injury by an inducible nitric oxide synthase-dependent mechanism. Shock 2002; 17:280-5. [PMID: 11954827 DOI: 10.1097/00024382-200204000-00007] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The aim of this study was to investigate the role of nitric oxide (NO) in rat hepatic ischemia-reperfusion (I/R) injury. Animals were divided into four groups: Group I, control; Group II, gadolinium chloride (GdCl3), a Kupffer cell depleting agent, pretreated; Group III, S-methylisothiourea (SMT), a potent inducible NO synthase (iNOS) inhibitor, pretreated; Group IV, pretreated with SMT, then treated with S-Nitroso-N-acetylpenicillamine (SNAP), a NO donor, after ischemia. Sprague-Dawley rats underwent left lateral and median lobe ischemia for 60 min and reperfusion for 120 min. The left lateral and median lobes were used as ischemic lobes, and the right lateral lobe in the same rat was used as a control lobe. The total NOS (tNOS), iNOS, constitutive NOS (cNOS) activity, and liver protein were determined. The liver tissue malonaldehyde (MDA) level was measured as an index of lipid peroxidation. Liver histology was also examined. The liver tNOS activity in ischemic lobes of Group I, II, III, and IV was increased by 214%, 86%, 61%, and 45%, respectively. The increase in tNOS activity is mainly due to the induction of iNOS activity in the ischemic lobes of rat liver. GdCl3 significantly decreased the tNOS by 66% in the ischemic lobes. GdCl3 significantly increased MDA by 39% in the ischemic lobes. SMT significantly decreased tNOS and iNOS activity by 66% and 85% in ischemic lobes. SMT increased MDA by 67% in the ischemic lobes. SMT + SNAP treatment increased iNOS activity by 117% in the ischemic lobes in comparison with the ischemic lobes of the SMT group. SMT + SNAP treatment decreased MDA by 39% in the ischemic lobes. SMT + SNAP treatment also decreased the sinusoidal congestion and spotty necrosis of hepatocytes in the ischemic lobes. iNOS immunostaining showed an obvious increase in sinusodial area of the ischemic lobes where most Kupffer cells were interspersed. In conclusion, in this model of liver I/R injury, I/R increased the activity of tNOS and iNOS, but not the cNOS activity. Kupffer cells might be the major source of the induction of iNOS activity. The iNOS specific inhibitor SMT increased the lipid peroxidation and the tissue damage in hepatic I/R injury. On the contrary, the NO donor SNAP increased the activity of iNOS and decreased the hepatic injury in this study. Kupffer cells could protect liver from I/R injury by an iNOS-dependent mechanism, thus NO production has a beneficial role in hepatic IR injury.
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Affiliation(s)
- Ching-Mei Hsu
- Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
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Bajt ML, Farhood A, Jaeschke H. Effects of CXC chemokines on neutrophil activation and sequestration in hepatic vasculature. Am J Physiol Gastrointest Liver Physiol 2001; 281:G1188-95. [PMID: 11668027 DOI: 10.1152/ajpgi.2001.281.5.g1188] [Citation(s) in RCA: 99] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The initiating step of neutrophil-induced cytotoxicity in the liver is the recruitment of these phagocytes into sinusoids. The aim of our study was to compare the efficacy of systemic exposure with individual inflammatory mediators on neutrophil activation and sequestration in the hepatic vasculature of C3Heb/FeJ mice as assessed by flow cytometry and histochemistry, respectively. The CXC chemokine macrophage inflammatory protein-2 (MIP-2; 20 microg/kg) induced a time-dependent upregulation of Mac-1 (318% at 4 h) and shedding of L-selectin (41% at 4 h). MIP-2 treatment caused a temporary increase of sinusoidal neutrophil accumulation at 0.5 h [97 +/- 6 polymorphonuclear leukocytes (PMN)/50 high-power fields (HPF)], which declined to baseline (8 +/- 2) at 4 h. The CXC chemokine KC was largely ineffective in activating neutrophils or recruiting them into the liver. Cytokines (tumor necrosis factor-alpha and interleukin-1alpha) and cobra venom factor substantially increased Mac-1 expression and L-selectin shedding on neutrophils and caused stable sinusoidal neutrophil accumulation (170-220 PMN/50 HPF). Only cytokines induced venular neutrophil margination. Thus CXC chemokines in circulation are less effective than cytokines or complement in activation of neutrophils and their recruitment into the hepatic vasculature in vivo.
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Affiliation(s)
- M L Bajt
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
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44
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Yonezawa K, Yamamoto Y, Yamamoto H, Ishikawa Y, Uchinami H, Taura K, Nakajima A, Yamaoka Y. Suppression of tumor necrosis factor-alpha production and neutrophil infiltration during ischemia-reperfusion injury of the liver after heat shock preconditioning. J Hepatol 2001; 35:619-27. [PMID: 11690708 DOI: 10.1016/s0168-8278(01)00191-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS Heat shock preconditioning provides the liver with ischemic tolerance. In this study we examined the effects of heat shock preconditioning on hepatic nonparenchymal cells in light of tumor necrosis factor-alpha (TNF-alpha) production and neutrophil infiltration. METHODS Rats were exposed to heat shock pretreatment at 42 degrees C in the heat shock group (group HS) and at 37 degrees C in the control group (group C). After a 48-h recovery, the left hepatic lobes were given a 90-min ischemia and reperfused. Plasma concentrations of TNF-alpha, cytokine-induced neutrophil chemoattractant (CINC) and alanine aminotransferase (ALT) were measured. Liver tissues were checked for the presence of TNF-alpha mRNA. Histological staining for CINC and polymorphonuclear leukocyte (PMN) was also evaluated. RESULTS In group HS, plasma TNF-alpha levels were significantly more suppressed than in group C (P<0.0001). Expressions of TNF-alpha mRNA in the liver was suppressed in group HS. Production of CINC 2 h after reperfusion was reduced in group HS (P<0.05). PMN infiltration was significantly reduced in group HS (P<0.01). In group HS, liver histology revealed less cellular damage and the plasma level of ALT was significantly reduced (P<0.0001). CONCLUSIONS Heat shock preconditioning suppressed the production of TNF-alpha and CINC in the liver during reperfusion and consequently reduced neutrophil infiltration.
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Affiliation(s)
- K Yonezawa
- Department of Gastroenterological Surgery, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
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45
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Adding LC, Bannenberg GL, Gustafsson LE. Basic experimental studies and clinical aspects of gadolinium salts and chelates. CARDIOVASCULAR DRUG REVIEWS 2001; 19:41-56. [PMID: 11314600 DOI: 10.1111/j.1527-3466.2001.tb00182.x] [Citation(s) in RCA: 95] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Gadolinium is a lanthanide that has in recent years become more commonly present in our society. Organic chelates of gadolinium are increasingly used as contrast agents for the imaging of body fluids. Although adverse reactions to these agents are uncommon, it is known that gadolinium salts can bring about a wide variety of changes in physiology. Gadolinium chloride is widely used experimentally as an inhibitor of stretch-activated ion channels and physiological responses of tissues to mechanical stimulation. It is also employed as a selective inhibitor of macrophages in vivo. In this review, the known biochemical actions of gadolinium are brought together with its in vivo pharmacology and toxicology.
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Affiliation(s)
- L C Adding
- Dept. of Physiology and Pharmacology, Karolinska Institute, S-17177 Stockholm, Sweden.
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Mosher B, Dean R, Harkema J, Remick D, Palma J, Crockett E. Inhibition of Kupffer cells reduced CXC chemokine production and liver injury. J Surg Res 2001; 99:201-10. [PMID: 11469888 DOI: 10.1006/jsre.2001.6217] [Citation(s) in RCA: 91] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Cytokine production is a critical component of ischemia/reperfusion (IR) injury. In the liver, Kupffer cells produce cytokines and chemokines (i.e., cytokines with chemoattractant properties) that are important mediators in neutrophil recruitment and subsequent hepatocellular injury. Therefore, the role of Kupffer cells in chemokine production in hepatic IR injury was investigated. METHODS Adult male C57BL/6 mice underwent 90 min of partial hepatic ischemia followed by various reperfusion times (i.e., 0, 1.5, 3, and 6 h). Gadolinium chloride (GC), which inhibits Kupffer cell activity, was administered to mice 48 and 24 h prior to ischemia. The control group received a corresponding volume of normal saline. Plasma levels of the cytokine macrophage inflammatory protein-2 (MIP-2), KC, and tumor necrosis factor (TNF)-alpha and liver mRNA were measured. Liver injury was assessed by plasma level of alanine transaminase (ALT) and histopathology. RESULTS A reperfusion time-dependent liver injury occurred as indicated by increased levels of plasma ALT and histopathology. The injury was associated with increased plasma TNF-alpha, MIP-2, and KC and their hepatic mRNA expression and neutrophil infiltration into ischemic lobes of the liver. GC treatment significantly reduced the number of Kupffer cells as determined by the immunostained liver tissue sections. The extent of liver injury significantly decreased in GC-treated mice that were associated with decreased levels of plasma ALT, TNF-alpha, MIP-2, and KC and neutrophil infiltration. CONCLUSIONS This study suggests that Kupffer cells are major contributors to cytokine production in hepatic IR and their modulation may serve as a potential target for therapeutic intervention.
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Affiliation(s)
- B Mosher
- Department of Surgery, College of Human Medicine, Michigan State University, East Lansing, MI 48824-1315, USA
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Yamaguchi Y, Ohshiro H, Nagao Y, Odawara K, Okabe K, Hidaka H, Ishihara K, Uchino S, Furuhashi T, Yamada S, Mori K, Ogawa M. Urinary trypsin inhibitor reduces C-X-C chemokine production in rat liver ischemia/reperfusion. J Surg Res 2000; 94:107-15. [PMID: 11104650 DOI: 10.1006/jsre.2000.5999] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND AND AIM Protease inhibitors attenuate ischemia/reperfusion injury. However, the underlying mechanisms by which protease inhibitors prevent reperfusion injury remain obscure. Neutrophils play an important role in reperfusion injury. We studied the effects of urinary trypsin inhibitor (UTI) on production of the C-X-C chemokine, cytokine-induced neutrophil chemoattractant (CINC), by Kupffer cells during ischemia/reperfusion of the liver. METHODS Liver ischemia was induced in rats by occlusion of the portal vein for 30 min. UTI (50,000 U/kg) was injected intravenously 5 min before vascular clamping. Serum CINC concentrations were measured by enzyme-linked immunosorbent assay. Levels of CINC mRNA in the liver were determined by Northern blot analysis. We also examined the inhibitory effects of UTI on in vitro CINC production by peritoneal macrophages in response to neutrophil elastase (NE). RESULTS Serum CINC concentrations increased and peaked 6 h after reperfusion. However, pretreatment of animals with UTI blunted this increase in CINC and significantly reduced CINC mRNA levels in the liver after ischemia/reperfusion. UTI also decreased neutrophil accumulation in the liver 24 h after reperfusion. In vitro CINC production by Kupffer cells from rats pretreated with UTI 3 h after ischemia/reperfusion was significantly decreased compared to those from untreated animals. UTI reduced NE activity in vitro in a dose-dependent manner, and UTI significantly reduced in vitro CINC production by peritoneal macrophages stimulated with NE. CONCLUSION UTI reduces the production of CINC by Kupffer cells stimulated with NE, attenuating ischemia/reperfusion injury of the liver.
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Affiliation(s)
- Y Yamaguchi
- Department of Surgery II, Kumamoto University Medical School, Kumamoto, Japan
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Kazumori H, Ishihara S, Hoshino E, Kawashima K, Moriyama N, Suetsugu H, Sato H, Adachi K, Fukuda R, Watanabe M, Takasawa S, Okamoto H, Fukui H, Chiba T, Kinoshita Y. Neutrophil chemoattractant 2 beta regulates expression of the Reg gene in injured gastric mucosa in rats. Gastroenterology 2000; 119:1610-1622. [PMID: 11113082 DOI: 10.1053/gast.2000.20262] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Regenerating (Reg) protein has a trophic effect on gastric mucosal cells. We have shown that Reg gene expression is increased in enterochromaffin-like (ECL) cells during the healing of damaged gastric mucosa around mucosal erosion. This study was designed to explore the stimulants of Reg expression during the healing of gastric mucosal damage. METHODS Time course changes of the expression of genes for various proinflammatory cytokines and Reg were investigated after induction of gastric mucosal lesions in rats. The direct effect of proinflammatory cytokines on Reg gene expression and Reg protein production were investigated in vitro using counterflow elutriation-enriched rat ECL cells. CXC receptor 2 (CXCR-2) expression was investigated in ECL cells by reverse-transcription polymerase chain reaction. Reg gene expression was also investigated in rats treated by the neutralizing antibody of cytokine-induced neutrophil chemoattractant (CINC-2 beta). RESULTS During healing, the gene expression of several proinflammatory cytokines and Reg was markedly augmented. Among the proinflammatory cytokines, CINC-2 beta is the only cytokine in which augmented expression preceded the increase of Reg gene expression. In rats treated with CINC-2 beta neutralizing antibody, the augmentation of Reg gene expression was significantly inhibited. When ECL cells were incubated with these proinflammatory cytokines, CINC-2 beta dose-dependently increased Reg messenger RNA and Reg protein in ECL cells. CXCR-2 was identified in isolated ECL cells. CONCLUSIONS CINC-2 beta, expressed in damaged gastric mucosa, stimulates the production of Reg protein in ECL cells via CXCR-2 and may be involved in the accelerated healing of injured gastric mucosa.
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Affiliation(s)
- H Kazumori
- Second Department of Internal Medicine, Shimane Medical University, Izumo, Japan
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Kubota Y, Takahashi S, Takahashi I, Patrick G. Different cytotoxic response to gadolinium between mouse and rat alveolar macrophages. Toxicol In Vitro 2000; 14:309-19. [PMID: 10906437 DOI: 10.1016/s0887-2333(00)00027-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The cytotoxicity of gadolinium (Gd) chloride was investigated in alveolar macrophages (AM) cultured in vitro. A marked difference in the cytotoxic response to Gd was found between mouse and rat AM. The viability of rat AM was decreased by exposure to Gd at doses more than 3 microM, while mouse AM appeared to be resistant even up to 1000 microM Gd exposure. The decrease in the viability of rat AM exposed to Gd at doses up to 1000 microM was mitigated by centrifugation and filtration of the culture medium containing Gd, or by the treatment of AM with lysosomotropic agents such as NH(4)Cl or chloroquine, suggesting that the cytotoxic response of rat AM to Gd at doses up to 1000 microM was dependent on the intracellular uptake and subsequent dissolution of Gd present in the culture medium in colloidal form. The phagocytic activity of mouse AM, evaluated by the uptake of latex particles, was higher than that of rat AM. Furthermore, quantitative analysis of Gd with inductively coupled plasma-mass spectrometry revealed that mouse AM took up a larger amount of Gd than rat AM. Therefore, the marked difference in the cytotoxic response to Gd between mouse and rat AM could not be attributed to the phagocytic activities for the colloidal form of Gd. The cytotoxic sensitivity of AM to Gd present in non-colloidal form was almost the same between mouse and rat AM. Therefore, it is suggested that the extent to which Gd-colloid phagocytosed is dissolved in the phago-lysosome or the subsequent process to exhibit the cytotoxicity may be different between mouse and rat AM.
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Affiliation(s)
- Y Kubota
- Environmental and Toxicological Sciences Research Group, National Institute of Radiological Sciences, Chiba, Japan.
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50
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Yamada S, Iida T, Tabata T, Nomoto M, Kishikawa H, Kohno K, Eto S. Alcoholic fatty liver differentially induces a neutrophil-chemokine and hepatic necrosis after ischemia-reperfusion in rat. Hepatology 2000; 32:278-88. [PMID: 10915734 DOI: 10.1053/jhep.2000.9604] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Primary graft nonfunction of steatotic liver allograft is one of the factors causing shortage of donor livers. Ischemia/reperfusion (I/R) injury is an important contributory factor to primary graft nonfunction. In this study, we investigated the complex chain of events from transcription factor activation to necrosis through cytokine induction and apoptosis in steatotic rat liver after warm I/R. Rats with alcoholic or nonalcoholic fatty liver were subjected to hepatic warm I/R and compared with control rats. Rats fed an ethanol diet for 6 to 8 weeks developed severe hepatic necrosis accompanied by increased neutrophil recruitment after I/R, compared with rats with nonalcoholic fatty liver or control. Hepatic apoptosis as assessed by DNA fragmentation at 4 hours after I/R, however, increased to a similar degree in each of the 2 fatty liver models compared with the control. Alcoholic fatty liver exposed to I/R showed a rapid increase in nuclear factor-kappaB (NF-kappaB) binding activity at 1 hour after I/R, which preceded an increased expression of tumor necrosis factor alpha (TNF-alpha) and cytokine-induced neutrophil chemoattractant-1 (CINC-1). In contrast, nonalcoholic fatty liver did not show such potentiation of either NF-kappaB activation or cytokine induction after I/R. Our results have indicated that alcoholic fatty liver may differentially induce CINC-1 production and hepatic necrosis after I/R. Furthermore, our results suggest that apoptosis per se does not always lead to necrosis in the liver following I/R.
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Affiliation(s)
- S Yamada
- Department of Clinical Pathophysiology, University of Occupational Environmental Health, Fukuoka, Japan.
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