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Bloomer SA, Wagner BA, Buettner GR, Brown KE. Liver iron stores and effectors of ferroptosis are dependent on age and sex. Exp Physiol 2024; 109:2046-2056. [PMID: 39422319 PMCID: PMC11607622 DOI: 10.1113/ep092035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 09/27/2024] [Indexed: 10/19/2024]
Abstract
Ferroptosis is a form of cell death characterized by a pro-oxidative cellular milieu and iron-dependent lipid peroxidation. Ferroptosis has been implicated in various forms of liver injury, in keeping with the major role of the liver in iron metabolism. Limited research has addressed potential differences in ferroptosis mediators with age and sex, especially in an in vivo model. The goal of this investigation was to evaluate hepatic labile iron and mediators of ferroptosis with ageing in both sexes. Because female animals generally display greater antioxidant defences than males, we hypothesized that females would display a phenotype resistant to ferroptosis. Here, we determined iron contents, protein expression of ferroptosis mediators and measures of oxidative injury in liver samples from 12- and 24-month-old male and female Fischer 344 rats. In comparison to males, the livers of female rats at both ages contained more non-haem iron, which was associated with greater ferritin heavy chain expression and attenuated expression of transferrin receptor-1. In female rats, the 24-month-old group had higher contents of thiobarbituric acid reactive substances compared with their 12-month-old counterparts, yet similar contents of labile iron. These results suggest a disconnect between labile iron contents and oxidative injury with age. Female animals also displayed greater expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), a modulator of ferroptosis, and greater abundance of high molecular weight 4-hydroxnonenal-modified proteins. These results demonstrate clear differences in iron and ferroptosis mediators between sexes and suggest that female rats of this strain might be more susceptible to ferroptosis.
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Affiliation(s)
- Steven A. Bloomer
- Division of Science and EngineeringPenn State AbingtonAbingtonPennsylvaniaUSA
| | - Brett A. Wagner
- Free Radical and Radiation Biology, Department of Radiation OncologyUniversity of Iowa Carver College of MedicineIowa CityIowaUSA
| | - Garry R. Buettner
- Free Radical and Radiation Biology, Department of Radiation OncologyUniversity of Iowa Carver College of MedicineIowa CityIowaUSA
| | - Kyle E. Brown
- Free Radical and Radiation Biology, Department of Radiation OncologyUniversity of Iowa Carver College of MedicineIowa CityIowaUSA
- Iowa City Veterans Administration Medical CenterIowa CityIowaUSA
- Division of Gastroenterology‐Hepatology, Department of Internal MedicineUniversity of Iowa Carver College of MedicineIowa CityIowaUSA
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Duarte TL, Viveiros N, Godinho C, Duarte D. Heme (dys)homeostasis and liver disease. Front Physiol 2024; 15:1436897. [PMID: 39135705 PMCID: PMC11317413 DOI: 10.3389/fphys.2024.1436897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 07/15/2024] [Indexed: 08/15/2024] Open
Abstract
Heme is essential for a variety of proteins involved in vital physiological functions in the body, such as oxygen transport, drug metabolism, biosynthesis of steroids, signal transduction, antioxidant defense and mitochondrial respiration. However, free heme is potentially cytotoxic due to the capacity of heme iron to promote the oxidation of cellular molecules. The liver plays a central role in heme metabolism by significantly contributing to heme synthesis, heme detoxification, and recycling of heme iron. Conversely, enzymatic defects in the heme biosynthetic pathway originate multisystemic diseases (porphyrias) that are highly associated with liver damage. In addition, there is growing evidence that heme contributes to the outcomes of inflammatory, metabolic and malignant liver diseases. In this review, we summarize the contribution of the liver to heme metabolism and the association of heme dyshomeostasis with liver disease.
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Affiliation(s)
- Tiago L. Duarte
- i3S–Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- IBMC–Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
| | - Nicole Viveiros
- i3S–Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Catarina Godinho
- i3S–Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Faculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal
| | - Delfim Duarte
- i3S–Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Serviço de Hematologia e Transplantação da Medula Óssea, Instituto Português de Oncologia do Porto Francisco Gentil, E.P.E. (IPO Porto), Porto, Portugal
- Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal
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3
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Salloom RJ, Ahmad IM, Abdalla MY. Targeting heme degradation pathway augments prostate cancer cell sensitivity to docetaxel-induced apoptosis and attenuates migration. Front Oncol 2024; 14:1431362. [PMID: 39091910 PMCID: PMC11291216 DOI: 10.3389/fonc.2024.1431362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 07/02/2024] [Indexed: 08/04/2024] Open
Abstract
Introduction Chemotherapy, notably docetaxel (Doc), stands as the primary treatment for castration-resistant prostate cancer (CRPC). However, its efficacy is hindered by side effects and chemoresistance. Hypoxia in prostate cancer (PC) correlates with chemoresistance to Doc-induced apoptosis via Heme Oxygenase-1 (HO-1) modulation, a key enzyme in heme metabolism. This study investigated targeting heme degradation pathway via HO-1 inhibition to potentiate the therapeutic efficacy of Doc in PC. Methods Utilizing diverse PC cell lines, we evaluated HO-1 inhibition alone and with Doc on viability, apoptosis, migration, and epithelial- to- mesenchymal transition (EMT) markers and elucidated the underlying mechanisms. Results HO-1 inhibition significantly reduced PC cell viability under hypoxic and normoxic conditions, enhancing Doc-induced apoptosis through interconnected mechanisms, including elevated reactive oxygen species (ROS) levels, glutathione cycle disruption, and modulation of Signal Transducer and Activator of Transcription 1 (STAT1) pathway. The interplay between STAT1 and HO-1 suggests its reliance on HO-1 activation. Additionally, a decrease in cell migration and downregulation of EMT markers (vimentin and snail) were observed, indicating attenuation of mesenchymal phenotype. Discussion In conclusion, the combination of HO-1 inhibition with Doc holds promise for improving therapeutic outcomes and advancing clinical management in PC.
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Affiliation(s)
- Ramia J. Salloom
- Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Iman M. Ahmad
- Department of Clinical, Diagnostic, and Therapeutic Sciences, University of Nebraska Medical Center, Omaha, NE, United States
| | - Maher Y. Abdalla
- Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, NE, United States
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Xiang S, Wang Y, Lei D, Luo Y, Peng D, Zong K, Liu Y, Huang Z, Mo S, Pu X, Zheng J, Wu Z. Donor graft METTL3 gene transfer ameliorates rat liver transplantation ischemia-reperfusion injury by enhancing HO-1 expression in an m 6A-dependent manner. Clin Immunol 2023; 251:109325. [PMID: 37030526 DOI: 10.1016/j.clim.2023.109325] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 04/04/2023] [Indexed: 04/10/2023]
Abstract
Ischemia-reperfusion injury (IRI) is one of the most common complications in liver transplantation. METTL3 regulates inflammation and various cellular stress responses via modulating RNA m6A modification level. Here, the study aimed to investigate the role and mechanism of METTL3 in IRI after rat orthotopic liver transplantation. Firstly, m6A dot blot assay showed that total RNA m6A modification level in grafts was down-regulated, which echoed with the downregulation of METTL3. Furthermore, METTL3 pretreatment in donor significantly reduced liver grafts necrosis formation, apoptosis, improved liver function and depressed the proinflammatory cytokine/chemokine expression. Mechanistically, western blot and immunohistochemical showed that METTL3 inhibited apoptosis via upregulating HO-1. Moreover, MeRIP-qPCR assay revealed that METTL3 promoted HO-1 expression in an m6A-dependent manner. Additionally, METTL3 alleviated primary hepatocytes apoptosis by upregulating HO-1 under hypoxia/reoxygenation condition. Taken together, these results demonstrated that METTL3 exerted a cytoprotective role against IRI via inducing HO-1 in an m6A-dependent manner.
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Affiliation(s)
- Song Xiang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yihua Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dengliang Lei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yunhai Luo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dadi Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Kezhen Zong
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yanyao Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zuotian Huang
- Chongqing University Cancer Hospital, Chongqing, China
| | - Shaojiang Mo
- Chongqing University Cancer Hospital, Chongqing, China
| | - Xingyu Pu
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Jinli Zheng
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Zhongjun Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Yang Q, Wang W. The Nuclear Translocation of Heme Oxygenase-1 in Human Diseases. Front Cell Dev Biol 2022; 10:890186. [PMID: 35846361 PMCID: PMC9277552 DOI: 10.3389/fcell.2022.890186] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 06/10/2022] [Indexed: 12/30/2022] Open
Abstract
Heme oxygenase-1 (HO-1) is a rate-limiting enzyme in the degradation of heme to generate carbon monoxide (CO), free iron and biliverdin, which could then be converted to bilirubin by biliverdin reductase. HO-1 exhibits cytoprotective effects of anti-apoptosis, anti-oxidation, and anti-inflammation via these byproducts generated during the above process. In the last few years, despite the canonical function of HO-1 and possible biological significance of its byproducts, a noncanonical function, through which HO-1 exhibits functions in diseases independent of its enzyme activity, also has been reported. In this review, the noncanonical functions of HO-1 and its translocation in other subcellular compartments are summarized. More importantly, we emphasize the critical role of HO-1 nuclear translocation in human diseases. Intriguingly, this translocation was linked to tumorigenesis and tumor progression in lung, prostate, head, and neck squamous cell carcinomas and chronic myeloid leukemia. Given the importance of HO-1 nuclear translocation in human diseases, nuclear HO-1 as a novel target might be attractive for the prevention and treatment of human diseases.
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Affiliation(s)
- Qing Yang
- Department of Breast Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wenqian Wang
- Department of Plastic Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
- *Correspondence: Wenqian Wang,
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Bloomer SA. Hepatic Macrophage Abundance and Phenotype in Aging and Liver Iron Accumulation. Int J Mol Sci 2022; 23:ijms23126502. [PMID: 35742946 PMCID: PMC9223835 DOI: 10.3390/ijms23126502] [Citation(s) in RCA: 1] [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: 05/18/2022] [Revised: 06/07/2022] [Accepted: 06/09/2022] [Indexed: 12/14/2022] Open
Abstract
Liver macrophages serve important roles in iron homeostasis through phagocytosis of effete erythrocytes and the export of iron into the circulation. Conversely, intracellular iron can alter macrophage phenotype. Aging increases hepatic macrophage number and nonparenchymal iron, yet it is unknown whether age-related iron accumulation alters macrophage number or phenotype. To evaluate macrophages in a physiological model of iron loading that mimicked biological aging, young (6 mo) Fischer 344 rats were given one injection of iron dextran (15 mg/kg), and macrophage number and phenotype were evaluated via immunohistochemistry. A separate group of old (24 mo) rats was treated with 200 mg/kg deferoxamine every 12 h for 4 days. Iron administration to young rats resulted in iron concentrations that matched the values and pattern of tissue iron deposition observed in aged animals; however, iron did not alter macrophage number or phenotype. Aging resulted in significantly greater numbers of M1 (CD68+) and M2 (CD163+) macrophages in the liver, but neither macrophage number nor phenotype were affected by deferoxamine. Double-staining experiments demonstrated that both M1 (iNOS+) and M2 (CD163+) macrophages contained hemosiderin, suggesting that macrophages of both phenotypes stored iron. These results also suggest that age-related conditions other than iron excess are responsible for the accumulation of hepatic macrophages with aging.
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Affiliation(s)
- Steven A Bloomer
- Division of Science and Engineering, Penn State Abington, 1600 Woodland Rd, Abington, PA 19001, USA
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7
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Heme oxygenase-1, carbon monoxide, and malaria – The interplay of chemistry and biology. Coord Chem Rev 2022. [DOI: 10.1016/j.ccr.2021.214285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Puentes-Pardo JD, Moreno-SanJuan S, Carazo Á, León J. Heme Oxygenase-1 in Gastrointestinal Tract Health and Disease. Antioxidants (Basel) 2020; 9:antiox9121214. [PMID: 33276470 PMCID: PMC7760122 DOI: 10.3390/antiox9121214] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/25/2020] [Accepted: 11/29/2020] [Indexed: 12/14/2022] Open
Abstract
Heme oxygenase 1 (HO-1) is the rate-limiting enzyme of heme oxidative degradation, generating carbon monoxide (CO), free iron, and biliverdin. HO-1, a stress inducible enzyme, is considered as an anti-oxidative and cytoprotective agent. As many studies suggest, HO-1 is highly expressed in the gastrointestinal tract where it is involved in the response to inflammatory processes, which may lead to several diseases such as pancreatitis, diabetes, fatty liver disease, inflammatory bowel disease, and cancer. In this review, we highlight the pivotal role of HO-1 and its downstream effectors in the development of disorders and their beneficial effects on the maintenance of the gastrointestinal tract health. We also examine clinical trials involving the therapeutic targets derived from HO-1 system for the most common diseases of the digestive system.
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Affiliation(s)
- Jose D. Puentes-Pardo
- Research Unit, Instituto de Investigacion Biosanitaria de Granada, ibs.GRANADA, 18012 Granada, Spain
- Department of Pharmacology, Faculty of Pharmacy, University of Granada, 18011 Granada, Spain
- Correspondence: (J.D.P.-P.); (J.L.); Tel.: +34-958-023-706 (J.L.)
| | - Sara Moreno-SanJuan
- Cytometry and Microscopy Research Service, Instituto de Investigacion Biosanitaria de Granada, ibs.GRANADA, 18012 Granada, Spain;
| | - Ángel Carazo
- Genomic Research Service, Instituto de Investigacion Biosanitaria de Granada, ibs.GRANADA, 18012 Granada, Spain;
| | - Josefa León
- Research Unit, Instituto de Investigacion Biosanitaria de Granada, ibs.GRANADA, 18012 Granada, Spain
- Clinical Management Unit of Digestive Disease, San Cecilio University Hospital, 18016 Granada, Spain
- Correspondence: (J.D.P.-P.); (J.L.); Tel.: +34-958-023-706 (J.L.)
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Xie J, He X, Fang H, Liao S, Liu Y, Tian L, Niu J. Identification of heme oxygenase-1 from golden pompano (Trachinotus ovatus) and response of Nrf2/HO-1 signaling pathway to copper-induced oxidative stress. CHEMOSPHERE 2020; 253:126654. [PMID: 32464761 DOI: 10.1016/j.chemosphere.2020.126654] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 03/28/2020] [Accepted: 03/29/2020] [Indexed: 06/11/2023]
Abstract
Heme oxygenase-1(HO-1) is a stress-inducible enzyme that mediates antioxidative and cytoprotective effects to maintain cellular redox homeostasis. In the present study, the full sequence of HO-1 was cloned from golden pompano(Trachinotus ovatus) by RT-PCR and RACE-PCR. The full cDNA sequence of HO-1 was 1349 bp in length which comprised of a 726 bp open reading frame (ORF) preceded by 262 bp 5'-untranslated region (UTR), and followed by a 360 bp 3'UTR, encoding 241 amino acid residues. Phylogenetic analysis revealed that HO-1 showed highest similarity to that of Takifugu rubripes. Tissue distribution analysis showed that the expression level of HO-1 was relatively high in heart, liver and spleen. A trial was conducted to investigate the response of Nrf2/HO-1 signaling pathway to oxidative stress induced by copper. The results showed that mRNA expression of NF-E2-related nuclear factor2 (Nrf2), Kelch-like-ECH-associated protein1 (keap1), superoxide dismutase (SOD), catalase (CAT), HO-1, NAD(P)H quinone oxidoreductase 1 (NQO1) and Glutathione peroxidase (GSH-PX) all significantly increased in copper treated group than that in the control group. This work provides new insight into the molecular mechanism underlying the Nrf2/HO-1 pathway in oxidative response in T. ovatus.
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Affiliation(s)
- Jiajun Xie
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animal and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Science, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Xuanshu He
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animal and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Science, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Haohang Fang
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animal and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Science, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Shiyu Liao
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animal and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Science, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Yongjian Liu
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animal and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Science, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Lixia Tian
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animal and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Science, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Jin Niu
- State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animal and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Science, Sun Yat-sen University, Guangzhou, 510275, PR China.
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Canesin G, Hejazi SM, Swanson KD, Wegiel B. Heme-Derived Metabolic Signals Dictate Immune Responses. Front Immunol 2020; 11:66. [PMID: 32082323 PMCID: PMC7005208 DOI: 10.3389/fimmu.2020.00066] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 01/10/2020] [Indexed: 12/21/2022] Open
Abstract
Heme is one of the most abundant molecules in the body acting as the functional core of hemoglobin/myoglobin involved in the O2/CO2 carrying in the blood and tissues, redox enzymes and cytochromes in mitochondria. However, free heme is toxic and therefore its removal is a significant priority for the host. Heme is a well-established danger-associated molecular pattern (DAMP), which binds to toll-like receptor 4 (TLR4) to induce immune responses. Heme-derived metabolites including the bile pigments, biliverdin (BV) and bilirubin (BR), were first identified as toxic drivers of neonatal jaundice in 1800 but have only recently been appreciated as endogenous drivers of multiple signaling pathways involved in protection from oxidative stress and regulators of immune responses. The tissue concentration of heme, BV and BR is tightly controlled. Heme oxygenase-1 (HO-1, encoded by HMOX1) produces BV by heme degradation, while biliverdin reductase-A (BLVR-A) generates BR by the subsequent conversion of BV. BLVR-A is a fascinating protein that possesses a classical protein kinase domain, which is activated in response to BV binding to its enzymatic site and initiates the downstream mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. This links BLVR-A activity to cell growth and survival pathways. BLVR-A also contains a bZip DNA binding domain and a nuclear export sequence (NES) and acts as a transcription factor to regulate the expression of immune modulatory genes. Here we will discuss the role of heme-related immune response and the potential for targeting the heme system for therapies directed toward hepatitis and cancer.
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Affiliation(s)
- Giacomo Canesin
- Department of Surgery, Cancer Research Institute and Transplant Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
| | - Seyed M. Hejazi
- Department of Surgery, Cancer Research Institute and Transplant Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
| | - Kenneth D. Swanson
- Brain Tumor Center and Neuro-Oncology Unit, Beth Israel Deaconess Medical Center, Boston, MA, United States
| | - Barbara Wegiel
- Department of Surgery, Cancer Research Institute and Transplant Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
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11
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Bloomer SA, Moyer ED, Brown KE, Kregel KC. Aging results in accumulation of M1 and M2 hepatic macrophages and a differential response to gadolinium chloride. Histochem Cell Biol 2019; 153:37-48. [PMID: 31691025 DOI: 10.1007/s00418-019-01827-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/25/2019] [Indexed: 02/06/2023]
Abstract
Macrophages have vital roles in innate immunity by modulating the inflammatory response via their ability to alter their phenotype from pro-inflammatory (M1) to anti-inflammatory (M2). Aging increases activation of the innate immune system, and macrophage numbers increase in the aged liver. Since macrophages also produce free radical molecules, they are a potential source of age-related oxidative injury in the liver. This study evaluated macrophage phenotype in the aged liver and whether the increase in the number of macrophages with aging is associated with enhanced hepatic oxidative stress. Hepatic macrophage phenotype and oxidative stress were evaluated 2 days after a single intraperitoneal injection of saline or gadolinium chloride (GdCl3, 10 mg/kg) in young (6 months) and aged (24 months) Fischer 344 rats. GdCl3 has been shown to decrease the expression of macrophage-specific markers and impair macrophage phagocytosis in the liver. Saline-treated aged rats demonstrated greater numbers of both M1 (HO-1+/iNOS+) and M2 (HO-1+/CD163+) macrophages, without evidence of a phenotypic shift. GdCl3 did not alter levels of dihydroethidium fluorescence or malondialdehyde, suggesting that macrophages are not a major contributor to steady-state levels of oxidative stress. However, GdCl3 decreased M1 and M2 macrophage markers in both age groups, an effect that was attenuated in aged rats. In old animals, GdCl3 decreased iNOS expression to a greater extent than HO-1 or CD163. These results suggest a novel effect of aging on macrophage biology and that GdCl3 shifts hepatic macrophage polarization to the M2 phenotype in aged animals.
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Affiliation(s)
- Steven A Bloomer
- Division of Science and Engineering, Penn State University, Abington College, 1600 Woodland Rd., Abington, PA, 19001, USA.
| | - Eric D Moyer
- Division of Science and Engineering, Penn State University, Abington College, 1600 Woodland Rd., Abington, PA, 19001, USA
| | - Kyle E Brown
- Iowa City Veterans Administration Medical Center, Iowa City, IA, 52242, USA.,Division of Gastroenterology-Hepatology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, 52242, USA.,Program in Free Radical and Radiation Biology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Kevin C Kregel
- Department of Health and Human Physiology, The University of Iowa, Iowa City, IA, 52242, USA
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The Role of Heme Oxygenase-1 in Remote Ischemic and Anesthetic Organ Conditioning. Antioxidants (Basel) 2019; 8:antiox8090403. [PMID: 31527528 PMCID: PMC6770180 DOI: 10.3390/antiox8090403] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 09/12/2019] [Accepted: 09/12/2019] [Indexed: 12/14/2022] Open
Abstract
The cytoprotective effects of the heme oxygenase (HO) pathway are widely acknowledged. These effects are mainly mediated by degradation of free, pro-oxidant heme and the generation of carbon monoxide (CO) and biliverdin. The underlying mechanisms of protection include anti-oxidant, anti-apoptotic, anti-inflammatory and vasodilatory properties. Upregulation of the inducible isoform HO-1 under stress conditions plays a crucial role in preventing or reducing cell damage. Therefore, modulation of the HO-1 system might provide an efficient strategy for organ protection. Pharmacological agents investigated in the context of organ conditioning include clinically used anesthetics and sedatives. A review from Hoetzel and Schmidt from 2010 nicely summarized the effects of anesthetics on HO-1 expression and their role in disease models. They concluded that HO-1 upregulation by anesthetics might prevent or at least reduce organ injury due to harmful stimuli. Due to its clinical safety, anesthetic conditioning might represent an attractive pharmacological tool for HO-1 modulation in patients. Remote ischemic conditioning (RIC), first described in 1993, represents a similar secure option to induce organ protection, especially in its non-invasive form. The efficacy of RIC has been intensively studied herein, including on patients. Studies on the role of RIC in influencing HO-1 expression to induce organ protection are emerging. In the first part of this review, recently published pre-clinical and clinical studies investigating the effects of anesthetics on HO-1 expression patterns, the underlying signaling pathways mediating modulation and its causative role in organ protection are summarized. The second part of this review sums up the effects of RIC.
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Qu S, Yuan B, Zhang H, Huang H, Zeng Z, Yang S, Ling J, Jin L, Wu P. Heme Oxygenase 1 Attenuates Hypoxia-Reoxygenation Injury in Mice Liver Sinusoidal Endothelial Cells. Transplantation 2018; 102:426-432. [PMID: 29189483 DOI: 10.1097/tp.0000000000002028] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Heme oxygenase 1 (HO-1), a heat shock protein, can be involved in the resolution of inflammation by modulating cytokine expression and apoptotic cell death. Based on recent evidence that liver sinusoidal endothelial cells (LSECs) is the critical target in early period of liver ischemia-reperfusion injury (IRI), this study aims to clarify whether overexpression of HO-1 gene provides a protective effect on mice LSECs. METHODS LSECs were transfected with adenovirus vectors encoding mice HO-1 gene (Ad-HO-1) or green fluorescent protein. Controls were not infected with any vector. LSECs were then treated with hypoxic or normoxic culture. We used low serum culture medium and hypoxia-reoxygenation (H-R) conditions to cause IRI in vitro. The transfection efficiency of HO-1 gene in LSECs, after 48 hours of transfection, and the effect of HO-1 on the model of H-R injury in LSECs were observed. RESULTS Transfection of LSECs with Ad-HO-1 was at an optimal dose (multiplicity of infection = 80) to markedly express HO-1 mRNA and protein. Groups of overexpressed HO-1 showed lower levels of inflammatory factor mediators IL-6 and TNF-α. Survival rate of the cells after H-R injury was higher and attributed to overexpressed HO-1. In contrast, the control adenovirus expressing the enhanced green fluorescent protein failed to induce HO-1 expression and stimulated cell apoptosis. HO-1 expression was downregulated in all H-R groups compared with normoxia groups, which may be related to the disruption of the LSEC structure. CONCLUSIONS Upregulation of HO-1 can attenuate H-R injury in LSECs by inhibiting proinflammatory cytokine release and diminishing apoptotic cell death.
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Affiliation(s)
- Siming Qu
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Bo Yuan
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Hongbin Zhang
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Hanfei Huang
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Zhong Zeng
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Shikun Yang
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Jie Ling
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Li Jin
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Pu Wu
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
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The macrophage heme-heme oxygenase-1 system and its role in inflammation. Biochem Pharmacol 2018; 153:159-167. [PMID: 29452096 DOI: 10.1016/j.bcp.2018.02.010] [Citation(s) in RCA: 165] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 02/12/2018] [Indexed: 02/07/2023]
Abstract
Heme oxygenase (HO)-1, the inducible isoform of the heme-degrading enzyme HO, plays a critical role in inflammation and iron homeostasis. Regulatory functions of HO-1 are mediated via the catalytic breakdown of heme, which is an iron-containing tetrapyrrole complex with potential pro-oxidant and pro-inflammatory effects. In addition, the HO reaction produces the antioxidant and anti-inflammatory compounds carbon monoxide (CO) and biliverdin, subsequently converted into bilirubin, along with iron, which is reutilized for erythropoiesis. HO-1 is up-regulated by a plethora of stimuli and injuries in most cell types and tissues and provides salutary effects by restoring physiological homeostasis. Notably, HO-1 exhibits critical immuno-modulatory functions in macrophages, which are a major cell population of the mononuclear phagocyte system. Macrophages play key roles as sentinels and regulators of the immune system and HO-1 in these cells appears to be of critical importance for driving resolution of inflammatory responses. In this review, the complex functions and regulatory mechanisms of HO-1 in macrophages will be high-lighted. A particular focus will be the intricate interactions of HO-1 with its substrate heme, which play a contradictory role in distinct physiological and pathophysiological settings. The therapeutic potential of targeted modulation of the macrophage heme-HO-1 system will be discussed in the context of inflammatory disorders.
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Abstract
The microvasculature plays a central role in the pathophysiology of hemorrhagic shock and is also involved in arguably all therapeutic attempts to reverse or minimize the adverse consequences of shock. Microvascular studies specific to hemorrhagic shock were reviewed and broadly grouped depending on whether data were obtained on animal or human subjects. Dedicated sections were assigned to microcirculatory changes in specific organs, and major categories of pathophysiological alterations and mechanisms such as oxygen distribution, ischemia, inflammation, glycocalyx changes, vasomotion, endothelial dysfunction, and coagulopathy as well as biomarkers and some therapeutic strategies. Innovative experimental methods were also reviewed for quantitative microcirculatory assessment as it pertains to changes during hemorrhagic shock. The text and figures include representative quantitative microvascular data obtained in various organs and tissues such as skin, muscle, lung, liver, brain, heart, kidney, pancreas, intestines, and mesentery from various species including mice, rats, hamsters, sheep, swine, bats, and humans. Based on reviewed findings, a new integrative conceptual model is presented that includes about 100 systemic and local factors linked to microvessels in hemorrhagic shock. The combination of systemic measures with the understanding of these processes at the microvascular level is fundamental to further develop targeted and personalized interventions that will reduce tissue injury, organ dysfunction, and ultimately mortality due to hemorrhagic shock. Published 2018. Compr Physiol 8:61-101, 2018.
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Affiliation(s)
- Ivo Torres Filho
- US Army Institute of Surgical Research, JBSA Fort Sam Houston, Texas, USA
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16
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McMahon M, Ding S, Acosta-Jimenez LP, Frangova TG, Henderson CJ, Wolf CR. Measuring in vivo responses to endogenous and exogenous oxidative stress using a novel haem oxygenase 1 reporter mouse. J Physiol 2017; 596:105-127. [PMID: 29086419 PMCID: PMC5746521 DOI: 10.1113/jp274915] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 10/24/2017] [Indexed: 12/31/2022] Open
Abstract
Key points
Haem oxygenase 1 (Hmox1) is a cytoprotective enzyme with anti‐inflammatory and anti‐oxidant properties that is induced in response to multiple noxious environmental stimuli and disease states. Tools to enable its expression to be monitored in vivo have been unavailable until now. In a new Hmox1 reporter model we provide high‐fidelity, single‐cell resolution blueprints for Hmox1 expression throughout the body of mice. We show for the first time that Hmox1 is constitutively expressed at barrier tissues at the interface between the internal and external environments, and that it is highly induced in muscle cells during systemic inflammation. These data suggest novel biological insights into the role of Hmox1 and pave the way for the use of the model to study the role of environmental stress in disease pathology. Abstract Hmox1 protein holds great promise as a biomarker of in vivo stress responses as it is highly induced in stressed or damaged cells. However, Hmox1 expression patterns have thus far only been available in simple model organisms with limited relevance to humans. We now report a new Hmox1 reporter line that makes it possible to obtain this information in mice, a premiere model system for studying human disease and toxicology. Using a state‐of‐the‐art strategy, we expressed multiple complementary reporter molecules from the murine Hmox1 locus, including firefly luciferase, to allow long‐term, non‐invasive imaging of Hmox1 expression, and β‐galactosidase for high‐resolution mapping of expression patterns post‐mortem. We validated the model by confirming the fidelity of reporter expression, and its responsiveness to oxidative and inflammatory stimuli. In addition to providing blueprints for Hmox1 expression in mice that provide novel biological insights, this work paves the way for the broad application of this model to establish cellular stresses induced by endogenous processes and those resulting from exposure to drugs and environmental agents. It will also enable studies on the role of oxidative stress in the pathogenesis of disease and its prevention.
Haem oxygenase 1 (Hmox1) is a cytoprotective enzyme with anti‐inflammatory and anti‐oxidant properties that is induced in response to multiple noxious environmental stimuli and disease states. Tools to enable its expression to be monitored in vivo have been unavailable until now. In a new Hmox1 reporter model we provide high‐fidelity, single‐cell resolution blueprints for Hmox1 expression throughout the body of mice. We show for the first time that Hmox1 is constitutively expressed at barrier tissues at the interface between the internal and external environments, and that it is highly induced in muscle cells during systemic inflammation. These data suggest novel biological insights into the role of Hmox1 and pave the way for the use of the model to study the role of environmental stress in disease pathology.
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Affiliation(s)
- Michael McMahon
- School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK
| | - Shaohong Ding
- School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK
| | - Lourdes P Acosta-Jimenez
- School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK
| | - Tania G Frangova
- School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK
| | - Colin J Henderson
- School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK
| | - C Roland Wolf
- School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK
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Li Volti G, Avola R, Tibullo D. Commentary: The apolipoprotein A-I mimetic peptide, D-4F, restrains neointimal formation through heme oxygenase-1 up-regulation. Front Pharmacol 2017; 8:708. [PMID: 29033843 PMCID: PMC5626836 DOI: 10.3389/fphar.2017.00708] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 09/21/2017] [Indexed: 11/13/2022] Open
Affiliation(s)
- Giovanni Li Volti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Roberto Avola
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Daniele Tibullo
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
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18
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Li Volti G, Tibullo D, Vanella L, Giallongo C, Di Raimondo F, Forte S, Di Rosa M, Signorelli SS, Barbagallo I. The Heme Oxygenase System in Hematological Malignancies. Antioxid Redox Signal 2017; 27:363-377. [PMID: 28257621 DOI: 10.1089/ars.2016.6735] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
SIGNIFICANCE Several lines of evidence suggest that hematological malignancies exhibit an altered redox balance homeostasis that can lead to the activation of various survival pathways that, in turn, lead to the progression of disease and chemoresistance. Among these pathways, the heme oxygenase-1 (HO-1) pathway is likely to play a major role. HO catalyzes the enzymatic degradation of heme with the simultaneous release of carbon monoxide (CO), ferrous iron (Fe2+), and biliverdin. This review focuses on the role of HO-1 in various hematological malignancies and the possibility of exploiting such targets to improve the outcome of well-established chemotherapeutic regimens. Recent Advances and Critical Issues: Interestingly, the inhibition of the expression of HO-1 (e.g., with siRNA) or HO activity (with competitive inhibitors) contributes to the increased efficacy of chemotherapy and improves the outcome in animal models. Furthermore, some hematological malignancies (e.g., chronic myeloid leukemia and multiple myeloma) have served to explore the non-canonical functions of HO-1, such as the association between nuclear compartmentalization and genetic instability and/or chemoresistance. FUTURE DIRECTIONS The HO system may serve as an important tool in the field of hematological malignancies because it can be exploited to counteract chemoresistance and to monitor the outcome of bone marrow transplants and may be an additional target for combined therapies. Antioxid. Redox Signal. 27, 363-377.
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Affiliation(s)
- Giovanni Li Volti
- 1 Department of Biomedical and Biotechnological Sciences, University of Catania , Catania, Italy .,2 EuroMediterranean Institute of Science and Technology , Palermo, Italy
| | - Daniele Tibullo
- 3 Division of Haematology, AOU "Policlinico - Vittorio Emanuele", University of Catania , Catania, Italy
| | - Luca Vanella
- 4 Department of Drug Sciences, University of Catania , Catania, Italy
| | - Cesarina Giallongo
- 3 Division of Haematology, AOU "Policlinico - Vittorio Emanuele", University of Catania , Catania, Italy
| | - Francesco Di Raimondo
- 3 Division of Haematology, AOU "Policlinico - Vittorio Emanuele", University of Catania , Catania, Italy
| | - Stefano Forte
- 1 Department of Biomedical and Biotechnological Sciences, University of Catania , Catania, Italy .,5 Istituto Oncologico del Mediterraneo Ricerca srl Viagrande , Catania, Italy
| | - Michelino Di Rosa
- 1 Department of Biomedical and Biotechnological Sciences, University of Catania , Catania, Italy
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Seidel RA, Claudel T, Schleser FA, Ojha NK, Westerhausen M, Nietzsche S, Sponholz C, Cuperus F, Coldewey SM, Heinemann SH, Pohnert G, Trauner M, Bauer M. Impact of higher-order heme degradation products on hepatic function and hemodynamics. J Hepatol 2017; 67:272-281. [PMID: 28412296 DOI: 10.1016/j.jhep.2017.03.037] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 03/13/2017] [Accepted: 03/20/2017] [Indexed: 01/24/2023]
Abstract
BACKGROUND & AIMS Biliverdin and bilirubin were previously considered end products of heme catabolism; now, however, there is evidence for further degradation to diverse bioactive products. Z-BOX A and Z-BOX B arise upon oxidation with unknown implications for hepatocellular function and integrity. We studied the impact of Z-BOX A and B on hepatic functions and explored their alterations in health and cholestatic conditions. METHODS Functional implications and mechanisms were investigated in rats, hepatocytic HepG2 and HepaRG cells, human immortalized hepatocytes, and isolated perfused livers. Z-BOX A and B were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in acute and acute-on-chronic liver failure and hereditary unconjugated hyperbilirubinemia. RESULTS Z-BOX A and B are found in similar amounts in humans and rodents under physiological conditions. Serum concentrations increased ∼20-fold during cholestatic liver failure in humans (p<0.001) and in hereditary deficiency of bilirubin glucuronidation in rats (p<0.001). Pharmacokinetic studies revealed shorter serum half-life of Z-BOX A compared to its regio-isomer Z-BOX B (p=0.035). While both compounds were taken up by hepatocytes, Z-BOX A was enriched ∼100-fold and excreted in bile. Despite their reported vasoconstrictive properties in the brain vasculature, BOXes did not affect portal hemodynamics. Both Z-BOX A and B showed dose-dependent cytotoxicity, affected the glutathione redox state, and differentially modulated activity of Rev-erbα and Rev-erbβ. Moreover, BOXes-triggered remodeling of the hepatocellular cytoskeleton. CONCLUSIONS Our data provide evidence that higher-order heme degradation products, namely Z-BOX A and B, impair hepatocellular integrity and might mediate intra- and extrahepatic cytotoxic effects previously attributed to hyperbilirubinemia. LAY SUMMARY Degradation of the blood pigment heme yields the bile pigment bilirubin and the oxidation products Z-BOX A and Z-BOX B. Serum concentrations of these bioactive molecules increase in jaundice and can impair liver function and integrity. Amounts of Z-BOX A and Z-BOX B that are observed during liver failure in humans have profound effects on hepatic function when added to cultured liver cells or infused into healthy rats.
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Affiliation(s)
- Raphael A Seidel
- Department of Anesthesiology and Intensive Care Medicine/Center for Sepsis Control and Care, Jena University Hospital, Germany; Institute of Inorganic and Analytical Chemistry, Bioorganic Analytics, Friedrich Schiller University Jena, Germany
| | - Thierry Claudel
- HansPopper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Franziska A Schleser
- Department of Anesthesiology and Intensive Care Medicine/Center for Sepsis Control and Care, Jena University Hospital, Germany
| | - Navin K Ojha
- Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena & Jena University Hospital, Germany
| | - Matthias Westerhausen
- Institute of Inorganic and Analytical Chemistry, Inorganic Chemistry I, Friedrich Schiller University Jena, Germany
| | | | - Christoph Sponholz
- Department of Anesthesiology and Intensive Care Medicine/Center for Sepsis Control and Care, Jena University Hospital, Germany
| | - Frans Cuperus
- HansPopper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria; Pediatric Gastroenterology and Hepatology, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, The Netherlands
| | - Sina M Coldewey
- Department of Anesthesiology and Intensive Care Medicine/Center for Sepsis Control and Care, Jena University Hospital, Germany
| | - Stefan H Heinemann
- Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena & Jena University Hospital, Germany
| | - Georg Pohnert
- Institute of Inorganic and Analytical Chemistry, Bioorganic Analytics, Friedrich Schiller University Jena, Germany
| | - Michael Trauner
- HansPopper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Michael Bauer
- Department of Anesthesiology and Intensive Care Medicine/Center for Sepsis Control and Care, Jena University Hospital, Germany.
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Abstract
Ischemic disorders, such as myocardial infarction, stroke, and peripheral vascular disease, are the most common causes of debilitating disease and death in westernized cultures. The extent of tissue injury relates directly to the extent of blood flow reduction and to the length of the ischemic period, which influence the levels to which cellular ATP and intracellular pH are reduced. By impairing ATPase-dependent ion transport, ischemia causes intracellular and mitochondrial calcium levels to increase (calcium overload). Cell volume regulatory mechanisms are also disrupted by the lack of ATP, which can induce lysis of organelle and plasma membranes. Reperfusion, although required to salvage oxygen-starved tissues, produces paradoxical tissue responses that fuel the production of reactive oxygen species (oxygen paradox), sequestration of proinflammatory immunocytes in ischemic tissues, endoplasmic reticulum stress, and development of postischemic capillary no-reflow, which amplify tissue injury. These pathologic events culminate in opening of mitochondrial permeability transition pores as a common end-effector of ischemia/reperfusion (I/R)-induced cell lysis and death. Emerging concepts include the influence of the intestinal microbiome, fetal programming, epigenetic changes, and microparticles in the pathogenesis of I/R. The overall goal of this review is to describe these and other mechanisms that contribute to I/R injury. Because so many different deleterious events participate in I/R, it is clear that therapeutic approaches will be effective only when multiple pathologic processes are targeted. In addition, the translational significance of I/R research will be enhanced by much wider use of animal models that incorporate the complicating effects of risk factors for cardiovascular disease. © 2017 American Physiological Society. Compr Physiol 7:113-170, 2017.
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Affiliation(s)
- Theodore Kalogeris
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
| | - Christopher P. Baines
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
- Department of Biomedical Sciences, University of Missouri College of Veterinary Medicine, Columbia, Missouri, USA
| | - Maike Krenz
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
| | - Ronald J. Korthuis
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
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21
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EETs and HO-1 cross-talk. Prostaglandins Other Lipid Mediat 2016; 125:65-79. [DOI: 10.1016/j.prostaglandins.2016.06.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Revised: 06/03/2016] [Accepted: 06/20/2016] [Indexed: 01/26/2023]
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22
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Immenschuh S, Baumgart-Vogt E, Tan M, Iwahara SI, Ramadori G, Fahimi HD. Differential Cellular and Subcellular Localization of Heme-Binding Protein 23/Peroxiredoxin I and Heme Oxygenase-1 in Rat Liver. J Histochem Cytochem 2016; 51:1621-31. [PMID: 14623930 DOI: 10.1177/002215540305101206] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Heme-binding protein 23 (HBP23), also termed peroxiredoxin (Prx) I, and heme oxygenase-1 (HO-1) are distinct antioxidant stress proteins that are co-ordinately induced by oxidative stress. HBP23/Prx I has thioredoxin-dependent peroxidase activity with high binding affinity for the pro-oxidant heme, while HO-1 is the inducible isoform of the rate-limiting enzyme of heme degradation. We investigated the cellular and subcellular localization of both proteins in rat liver. Whereas by immunohistochemistry (IHC) a uniformly high level of HBP23/Prx I expression was observed in liver parenchymal and different sinusoidal cells, HO-1 expression was restricted to Kupffer cells. By immunoelectron microscopy using the protein A-gold technique, HBP23/Prx I immunoreactivity was detected in cytoplasm, nuclear matrix, mitochondria, and peroxisomes of parenchymal and non-parenchymal liver cell populations. In contrast, the secretory pathway, i.e., the endoplasmic reticulum and Golgi complex, was free of label. As determined by immunocytochemical (ICC) studies in liver cell cultures and by Western and Northern blotting analysis, HBP23/Prx I was highly expressed in cultures of isolated hepatocytes and Kupffer cells. In contrast, HO-1 was constitutively expressed only in Kupffer cell cultures but was also inducible in hepatocytes. These data suggest that HBP23/Prx I and HO-1 may have complementary antioxidant functions in different cell populations in rat liver.
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Affiliation(s)
- Stephan Immenschuh
- Institute of Clinical Chemistry and Pathobiochemistry, University of Giessen, Giessen, Germany.
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Sano N, Tamura T, Toriyabe N, Nowatari T, Nakayama K, Tanoi T, Murata S, Sakurai Y, Hyodo M, Fukunaga K, Harashima H, Ohkohchi N. New drug delivery system for liver sinusoidal endothelial cells for ischemia-reperfusion injury. World J Gastroenterol 2015; 21:12778-12786. [PMID: 26668502 PMCID: PMC4671033 DOI: 10.3748/wjg.v21.i45.12778] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 07/22/2015] [Accepted: 09/15/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the cytoprotective effects in hepatic ischemia-reperfusion injury, we developed a new formulation of hyaluronic acid (HA) and sphingosine 1-phophate.
METHODS: We divided Sprague-Dawley rats into 4 groups: control, HA, sphingosine 1-phosphate (S1P), and HA-S1P. After the administration of each agent, we subjected the rat livers to total ischemia followed by reperfusion. After reperfusion, we performed the following investigations: alanine aminotransferase (ALT), histological findings, TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining, and transmission electron microscopy (TEM). We also investigated the expression of proteins associated with apoptosis, hepatoprotection, and S1P accumulation.
RESULTS: S1P accumulated in the HA-S1P group livers more than S1P group livers. Serum ALT levels, TUNEL-positive hepatocytes, and expression of cleaved caspase-3 expression, were significantly decreased in the HA-S1P group. TEM revealed that the liver sinusoidal endothelial cell (LSEC) lining was preserved in the HA-S1P group. Moreover, the HA-S1P group showed a greater increase in the HO-1 protein levels compared to the S1P group.
CONCLUSION: Our results suggest that HA-S1P exhibits cytoprotective effects in the liver through the inhibition of LSEC apoptosis. HA-S1P is an effective agent for hepatic ischemia/reperfusion injury.
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24
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Gomez H, Kautza B, Escobar D, Nassour I, Luciano J, Botero AM, Gordon L, Martinez S, Holder A, Ogundele O, Loughran P, Rosengart MR, Pinsky M, Shiva S, Zuckerbraun BS. Inhaled Carbon Monoxide Protects against the Development of Shock and Mitochondrial Injury following Hemorrhage and Resuscitation. PLoS One 2015; 10:e0135032. [PMID: 26366865 PMCID: PMC4569171 DOI: 10.1371/journal.pone.0135032] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 07/16/2015] [Indexed: 01/08/2023] Open
Abstract
Aims Currently, there is no effective resuscitative adjunct to fluid and blood products to limit tissue injury for traumatic hemorrhagic shock. The objective of this study was to investigate the role of inhaled carbon monoxide (CO) to limit inflammation and tissue injury, and specifically mitochondrial damage, in experimental models of hemorrhage and resuscitation. Results Inhaled CO (250 ppm for 30 minutes) protected against mortality in severe murine hemorrhagic shock and resuscitation (HS/R) (20% vs. 80%; P<0.01). Additionally, CO limited the development of shock as determined by arterial blood pH (7.25±0.06 vs. 7.05±0.05; P<0.05), lactate levels (7.2±5.1 vs 13.3±6.0; P<0.05), and base deficit (13±3.0 vs 24±3.1; P<0.05). A dose response of CO (25–500 ppm) demonstrated protection against HS/R lung and liver injury as determined by MPO activity and serum ALT, respectively. CO limited HS/R-induced increases in serum tumor necrosis factor-α and interleukin-6 levels as determined by ELISA (P<0.05 for doses of 100–500ppm). Furthermore, inhaled CO limited HS/R induced oxidative stress as determined by hepatic oxidized glutathione:reduced glutathione levels and lipid peroxidation. In porcine HS/R, CO did not influence hemodynamics. However, CO limited HS/R-induced skeletal muscle and platelet mitochondrial injury as determined by respiratory control ratio (muscle) and ATP-linked respiration and mitochondrial reserve capacity (platelets). Conclusion These preclinical studies suggest that inhaled CO can be a protective therapy in HS/R; however, further clinical studies are warranted.
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MESH Headings
- Adenosine Triphosphate/metabolism
- Administration, Inhalation
- Animals
- Carbon Monoxide/administration & dosage
- Carbon Monoxide/pharmacology
- Carbon Monoxide/therapeutic use
- Cells, Cultured
- Interleukin-6/blood
- Lactic Acid/blood
- Male
- Mice
- Mice, Inbred C57BL
- Mitochondria, Liver/drug effects
- Mitochondria, Liver/metabolism
- Mitochondria, Muscle/drug effects
- Mitochondria, Muscle/metabolism
- Oxidative Stress
- Resuscitation
- Shock, Hemorrhagic/metabolism
- Shock, Hemorrhagic/prevention & control
- Shock, Hemorrhagic/therapy
- Swine
- Tumor Necrosis Factor-alpha/blood
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Affiliation(s)
- Hernando Gomez
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
- The Center for Critical Care Nephrology University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Benjamin Kautza
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Daniel Escobar
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Ibrahim Nassour
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Jason Luciano
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Ana Maria Botero
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Lisa Gordon
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Silvia Martinez
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Andre Holder
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Olufunmilayo Ogundele
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Patricia Loughran
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Matthew R. Rosengart
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
- The Center for Critical Care Nephrology University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Michael Pinsky
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Sruti Shiva
- Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA, United States of America
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Brian S. Zuckerbraun
- The Center for Critical Care Nephrology University of Pittsburgh, Pittsburgh, PA, United States of America
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States of America
- VA Pittsburgh Healthcare System, Pittsburgh, PA, United States of America
- * E-mail:
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Hepatocellular heme oxygenase-1: a potential mechanism of erythropoietin-mediated protection after liver ischemia-reperfusion injury. Shock 2015; 42:424-31. [PMID: 25004066 DOI: 10.1097/shk.0000000000000231] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Hepatic ischemia-reperfusion (IR) results in progressive injury; initiated by oxidative stress during ischemia and compounded by cytokine-mediated inflammation during reperfusion. Recovery requires strict regulation of these events. Recombinant human erythropoietin (rhEPO) is thought to mitigate hepatocellular IR injury by altering the nonparenchymal liver microenvironment. This study sought to identify additional mechanisms whereby rhEPO is protective after liver IR injury. Mice were treated with rhEPO (4 units/g s.c.) at the onset of partial liver ischemia and assessed for transaminase and histologic injury at intervals after reperfusion. Induction of cytokines, activation of signal transducers and activators of transcription (STATs), suppressors of cytokine signaling (Socs1, Socs3, Cis), caspase-3 activation, and heme oxygenase-1 (HO-1) expression were assessed in postischemic liver. Effects of rhEPO stimulation were further characterized in whole-liver lysates from mice undergoing rhEPO injection alone and in cultured AML-12 hepatocytes. Recombinant human erythropoietin treatment at the onset of severe (90 min) hepatic IR confirmed commensurate biochemical and histological protection without affecting tissue cytokine levels. Although Socs3 and STAT5 activation were induced in normal liver after in vivo rhEPO injection, this treatment did not augment expression beyond that seen with IR alone, and neither was induced in cultured hepatocytes treated with rhEPO. Recombinant human erythropoietin inhibited caspase-3 activation in nonparenchymal cells, whereas hepatocellular HO-1 was rapidly induced both in vivo and in vitro with rhEPO treatment. These data suggest HO-1 as a potent mechanism of rhEPO-mediated protection after liver IR, which involves both direct hepatocellular and nonparenchymal mechanisms.
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Müllebner A, Moldzio R, Redl H, Kozlov AV, Duvigneau JC. Heme Degradation by Heme Oxygenase Protects Mitochondria but Induces ER Stress via Formed Bilirubin. Biomolecules 2015; 5:679-701. [PMID: 25942605 PMCID: PMC4496691 DOI: 10.3390/biom5020679] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 04/08/2015] [Accepted: 04/16/2015] [Indexed: 01/16/2023] Open
Abstract
Heme oxygenase (HO), in conjunction with biliverdin reductase, degrades heme to carbon monoxide, ferrous iron and bilirubin (BR); the latter is a potent antioxidant. The induced isoform HO-1 has evoked intense research interest, especially because it manifests anti-inflammatory and anti-apoptotic effects relieving acute cell stress. The mechanisms by which HO mediates the described effects are not completely clear. However, the degradation of heme, a strong pro-oxidant, and the generation of BR are considered to play key roles. The aim of this study was to determine the effects of BR on vital functions of hepatocytes focusing on mitochondria and the endoplasmic reticulum (ER). The affinity of BR to proteins is a known challenge for its exact quantification. We consider two major consequences of this affinity, namely possible analytical errors in the determination of HO activity, and biological effects of BR due to direct interaction with protein function. In order to overcome analytical bias we applied a polynomial correction accounting for the loss of BR due to its adsorption to proteins. To identify potential intracellular targets of BR we used an in vitro approach involving hepatocytes and isolated mitochondria. After verification that the hepatocytes possess HO activity at a similar level as liver tissue by using our improved post-extraction spectroscopic assay, we elucidated the effects of increased HO activity and the formed BR on mitochondrial function and the ER stress response. Our data show that BR may compromise cellular metabolism and proliferation via induction of ER stress. ER and mitochondria respond differently to elevated levels of BR and HO-activity. Mitochondria are susceptible to hemin, but active HO protects them against hemin-induced toxicity. BR at slightly elevated levels induces a stress response at the ER, resulting in a decreased proliferative and metabolic activity of hepatocytes. However, the proteins that are targeted by BR still have to be identified.
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Affiliation(s)
- Andrea Müllebner
- Institute for Medical Biochemistry, Veterinary University Vienna, Veterinaerplatz 1, 1210 Vienna, Austria.
| | - Rudolf Moldzio
- Institute for Medical Biochemistry, Veterinary University Vienna, Veterinaerplatz 1, 1210 Vienna, Austria.
| | - Heinz Redl
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Donaueschingenstraße 13, 1200 Vienna, Austria.
| | - Andrey V Kozlov
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Donaueschingenstraße 13, 1200 Vienna, Austria.
| | - J Catharina Duvigneau
- Institute for Medical Biochemistry, Veterinary University Vienna, Veterinaerplatz 1, 1210 Vienna, Austria.
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Wen YT, Liu TT, Lin YF, Chen CC, Kung WM, Huang CC, Lin TJ, Wang YH, Wei L. Heatstroke Effect on Brain Heme Oxygenase-1 in Rats. Int J Med Sci 2015; 12:737-41. [PMID: 26392811 PMCID: PMC4571551 DOI: 10.7150/ijms.12517] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Accepted: 08/09/2015] [Indexed: 02/05/2023] Open
Abstract
Exposure to high environmental temperature leading to increased core body temperature above 40°C and central nervous system abnormalities such as convulsions, delirium, or coma is defined as heat stroke. Studies in humans and animals indicate that the heat shock responses of the host contribute to multiple organ injury and death during heat stroke. Heme oxygenase-1 (HO-1)-a stress-responsive enzyme that catabolizes heme into iron, carbon monoxide, and biliverdin-has an important role in the neuroprotective mechanism against ischemic stroke. Here, we investigated the role of endogenous HO-1 in heat-induced brain damage in rats. RT-PCR results revealed that levels of HO-1 mRNA peaked at 0 h after heat exposure and immunoblot analysis revealed that the maximal protein expression occurred at 1 h post-heat exposure. Subsequently, we detected the HO-1 expression in the cortical brain cells and revealed the neuronal cell morphology. In conclusion, HO-1 is a potent protective molecule against heat-induced brain damage. Manipulation of HO-1 may provide a potential therapeutic approach for heat-related diseases.
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Affiliation(s)
- Ya-Ting Wen
- 1. Department of Neurosurgery, Taipei Medical University-Wan Fang Hospital, Taipei 11696, Taiwan
| | - Tsung-Ta Liu
- 2. Department of Biology and Anatomy, National Defense Medical Center, Taipei 114, Taiwan
| | - Yuh-Feng Lin
- 3. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Chun-Chi Chen
- 4. Division of Nephrology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Woon-Man Kung
- 5. Department of Neurosurgery, Lo-Hsu Foundation, Lotung Poh-Ai Hospital, Luodong, Yilan 265, Taiwan
- 6. Department of Exercise and Health Promotion, College of Education, Chinese Culture University, Taipei 11114, Taiwan
| | - Chi-Chang Huang
- 7. Graduate Institute of Sports Science, National Taiwan Sport University, Taoyuan 33301, Taiwan
| | - Tien-Jen Lin
- 1. Department of Neurosurgery, Taipei Medical University-Wan Fang Hospital, Taipei 11696, Taiwan
- 8. Graduate Institute of Injury Prevention and Control, College of Public Health and Nutrition, Taipei Medical University, Taipei 11031, Taiwan
| | - Yuan-Hung Wang
- 3. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- 9. Division of General Surgery, Department of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
- ✉ Corresponding authors: Dr. Li Wei: Department of Neurosurgery, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan. Tel.: +886-2-29307930 (ext. 6942). E-Mail: . Dr. Yuan-Hung Wang: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Tel.: +886-2-22490088 (ext. 8891). E-Mail:
| | - Li Wei
- 1. Department of Neurosurgery, Taipei Medical University-Wan Fang Hospital, Taipei 11696, Taiwan
- 10. The PhD Program of Translational Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- ✉ Corresponding authors: Dr. Li Wei: Department of Neurosurgery, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan. Tel.: +886-2-29307930 (ext. 6942). E-Mail: . Dr. Yuan-Hung Wang: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Tel.: +886-2-22490088 (ext. 8891). E-Mail:
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Melatonin Receptors Mediate Improvements of Survival in a Model of Polymicrobial Sepsis. Crit Care Med 2014; 42:e22-31. [DOI: 10.1097/ccm.0b013e3182a63e2b] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Li L, Han ZY, Li CM, Jiang XQ, Wang GL. Upregulation of heat shock protein 32 in Sertoli cells alleviates the impairments caused by heat shock-induced apoptosis in mouse testis. Cell Stress Chaperones 2013; 18:333-51. [PMID: 23188493 PMCID: PMC3631093 DOI: 10.1007/s12192-012-0385-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2012] [Revised: 11/05/2012] [Accepted: 11/09/2012] [Indexed: 11/30/2022] Open
Abstract
Heat stress results in apoptosis in testicular germ cells. A small heat shock protein (hsp), hsp32, is induced by heat stress in the testis, but little is known about its definitive function in physiological processes. To clarify the underlying role of hsp32, hsp32 expression and related signals in the heat shock pathway were analysed in mouse testes and Sertoli cells after heat stress in vivo and in vitro; meanwhile, expression of hsp32 was silenced only in the Sertoli cells using three different small interfering RNAs (siRNAs) to further verify the functional role of hsp32 in Sertoli cells, and hsp32-derived carbon monoxide (CO) contents in cultured media were analysed to clarify whether hsp32-derived CO involve in the apoptosis regulation mechanisms. The results from the in vivo experiment showed that the high expression levels of hsp32 (P < 0.05) were observed whether chronic, moderate or acute, transient heat exposure. The in vitro experiment showed that acute, transient heat exposure resulted in increases in Sertoli cells apoptosis (P < 0.01), the expression of hsp32 and caspase-3 activity; hsp32-siRNA knockdown of hsp32 expression resulted in upregulated apoptosis (P < 0.01) and caspase-3 activity (P < 0.01) in the Sertoli cells and hyperthermia increases CO (P < 0.01) release by Sertoli cells. The results suggested that upregulating hsp32 in Sertoli cells inhibits caspase-3 activity and alleviates heat-induced impairments in mouse testis; hsp32-derived CO may involve in the regulation mechanism.
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Affiliation(s)
- Lian Li
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095 China
| | - Zhao-Yu Han
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095 China
| | - Cheng-Min Li
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095 China
| | - Xiao-Qiang Jiang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095 China
| | - Gen-Lin Wang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095 China
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Abstract
Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in heme degradation producing equimolar amounts of carbon monoxide, iron, and biliverdin. Induction of HO-1 is a beneficial response to tissue injury in diverse animal models of diseases including acute kidney injury. In vitro analysis has shown that the human HO-1 gene is transcriptionally regulated by changes in chromatin conformation but whether such control occurs in vivo is not known. To enable such analysis, we generated transgenic mice, harboring an 87-kb bacterial artificial chromosome expressing human HO-1 mRNA and protein and bred these mice with HO-1 knockout mice to generate humanized BAC transgenic mice. This successfully rescued the phenotype of the knockout mice including reduced birth rates, tissue iron overload, splenomegaly, anemia, leukocytosis, dendritic cell abnormalities and survival after acute kidney injury induced by rhabdomyolysis or cisplatin nephrotoxicity. Transcription factors such as USF1/2, JunB, Sp1, and CTCF were found to associate with regulatory regions of the human HO-1 gene in the kidney following rhabdomyolysis. Chromosome Conformation Capture and ChIP-loop assays confirmed this in the formation of chromatin looping in vivo. Thus, these bacterial artificial chromosome humanized HO-1 mice are a valuable model to study the human HO-1 gene providing insight to the in vivo architecture of the gene in acute kidney injury and other diseases.
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Abshagen K, Eipel C, Vollmar B. A critical appraisal of the hemodynamic signal driving liver regeneration. Langenbecks Arch Surg 2012; 397:579-90. [PMID: 22311102 DOI: 10.1007/s00423-012-0913-0] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Accepted: 01/20/2012] [Indexed: 12/25/2022]
Abstract
BACKGROUND Many aspects of the signaling mechanisms involved in the initiation of hepatic regeneration are under current investigation. Nevertheless, the actual mechanisms switching liver regeneration on and off are still unknown. Hemodynamic changes in the liver following partial hepatectomy have been suggested to be a primary stimulus in triggering liver regeneration. Most of the new knowledge about the impact of hemodynamic changes on liver regeneration is both conceptually important and directly relevant to clinical problems. PURPOSE The purpose of this review is therefore to exclusively address the hemodynamic signal driving the liver regeneration process.
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Affiliation(s)
- Kerstin Abshagen
- Institute for Experimental Surgery, University of Rostock, 18055 Rostock, Germany.
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Ábrahám S, Hermesz E, Szabó A, Ferencz Á, Jancsó Z, Duda E, Ábrahám M, Lázár G, Lázár G. Effects of Kupffer cell blockade on the hepatic expression of metallothionein and heme oxygenase genes in endotoxemic rats with obstructive jaundice. Life Sci 2012; 90:140-6. [DOI: 10.1016/j.lfs.2011.10.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2011] [Revised: 09/07/2011] [Accepted: 10/18/2011] [Indexed: 01/11/2023]
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Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell biology of ischemia/reperfusion injury. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2012; 298:229-317. [PMID: 22878108 PMCID: PMC3904795 DOI: 10.1016/b978-0-12-394309-5.00006-7] [Citation(s) in RCA: 1455] [Impact Index Per Article: 111.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Disorders characterized by ischemia/reperfusion (I/R), such as myocardial infarction, stroke, and peripheral vascular disease, continue to be among the most frequent causes of debilitating disease and death. Tissue injury and/or death occur as a result of the initial ischemic insult, which is determined primarily by the magnitude and duration of the interruption in the blood supply, and then subsequent damage induced by reperfusion. During prolonged ischemia, ATP levels and intracellular pH decrease as a result of anaerobic metabolism and lactate accumulation. As a consequence, ATPase-dependent ion transport mechanisms become dysfunctional, contributing to increased intracellular and mitochondrial calcium levels (calcium overload), cell swelling and rupture, and cell death by necrotic, necroptotic, apoptotic, and autophagic mechanisms. Although oxygen levels are restored upon reperfusion, a surge in the generation of reactive oxygen species occurs and proinflammatory neutrophils infiltrate ischemic tissues to exacerbate ischemic injury. The pathologic events induced by I/R orchestrate the opening of the mitochondrial permeability transition pore, which appears to represent a common end-effector of the pathologic events initiated by I/R. The aim of this treatise is to provide a comprehensive review of the mechanisms underlying the development of I/R injury, from which it should be apparent that a combination of molecular and cellular approaches targeting multiple pathologic processes to limit the extent of I/R injury must be adopted to enhance resistance to cell death and increase regenerative capacity in order to effect long-lasting repair of ischemic tissues.
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Affiliation(s)
- Theodore Kalogeris
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, USA
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Balibrea JM, García-Martín MC, Cuesta-Sancho S, Olmedilla Y, Arias-Díaz J, Fernández-Sevilla E, Vara E, Balibrea JL. Tacrolimus modulates liver and pancreas nitric oxide synthetase and heme-oxygenase isoforms and cytokine production after endotoxemia. Nitric Oxide 2011; 24:113-22. [PMID: 21255669 DOI: 10.1016/j.niox.2011.01.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Revised: 12/08/2010] [Accepted: 01/10/2011] [Indexed: 12/16/2022]
Abstract
Cytoprotective effects of tacrolimus are due to its unspecific anti-inflammatory and anti-oxidant properties. Neither the exact mechanisms nor if there is any organ-specificity or dose-dependent response have not been yet elucidated. Our aim was to evaluate the effect of tacrolimus on oxidative stress and mediator production in liver and pancreatic tissue secondary to endotoxemia. Wistar rats were pretreated with intraperitoneal injection of tacrolimus (0.07, 0.15, and 0.3mg/kg) 24h before Escherichia coli LPS was administrated. Animals were sacrificed 24h after LPS administration and iNOS, eNOS, and nNOS and type 1 and 2 heme-oxygenase (HO) expression were measured. TNF-α and IL-1 tissue expression and plasmatic NO, CO, TNF-α, and IL-1 were also determined. LPS exposure increased iNOS expression in both organs, eNOS did not show variations and liver nNOS expression was significantly lower. Tacrolimus diminished both pancreas and liver iNOS and nNOS expression. Both liver and pancreatic eNOS expression augmented when tacrolimus was administrated. High doses of tacrolimus were correlated with ameliorated liver HO-1 plus HO-2 and pancreas HO-1 expression after LPS stimulation. Tacrolimus treatment diminished TNF-α but not IL-1 expression increase after LPS challenge in hepatic tissue. Pancreatic TNF-α and IL-1 values diminished partially when high doses were employed. Plasmatic NO, CO, TNF-α, and IL-1 concentrations increase after LPS challenge was diminished when highest doses of tacrolimus were given. In conclusion, tacrolimus exerts a protective effect on commonly observed harmful phenomena after LPS stimulation by modulating liver and pancreas oxidative enzyme expression and cytokine production.
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Affiliation(s)
- José M Balibrea
- Department of Surgery, Germans Trias i Pujol Hospital, Universitat Autònoma, Ctra Del Canyet s/n, 08916 Badalona, Barcelona, Spain.
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Shih RH, Yang CM. Induction of heme oxygenase-1 attenuates lipopolysaccharide-induced cyclooxygenase-2 expression in mouse brain endothelial cells. J Neuroinflammation 2010; 7:86. [PMID: 21118574 PMCID: PMC3002338 DOI: 10.1186/1742-2094-7-86] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2010] [Accepted: 11/30/2010] [Indexed: 12/18/2022] Open
Abstract
Background Prostaglandin E2 (PGE2), an arachidonic acid metabolite converted by cyclooxygenase-2 (COX-2), plays important roles in the regulation of endothelial functions in response to bacterial infection. The enzymatic activity of COX-2 can be down-regulated by heme oxygenase-1 (HO-1) induction. However, the mechanisms underlying HO-1 modulating COX-2 protein expression are not known. Objective The aim of the present study was to investigate whether the up-regulation of HO-1 regulates COX-2 expression induced by lipopolysaccharide (LPS), an endotoxin produced by Gram negative bacteria, in mouse brain endothelial cells (bEnd.3) Methods Cultured bEnd.3 cells were used to investigate LPS-induced COX-2 expression and PGE2 production. Cobalt protoporphyrin IX (CoPP, an HO-1 inducer), infection with a recombinant adenovirus carried with HO-1 gene (Adv-HO-1), or zinc protoporphyrin (ZnPP, an HO-1 inhibitor) was used to stimulate HO-1 induction or inhibit HO-1 activity. The expressions of COX-2 and HO-1 were evaluated by western blotting. PGE2 levels were detected by an enzyme-linked immunoassay. Hemoglobin (a chelator of carbon monoxide, CO, one of metabolites of HO-1) and CO-RM2 (a CO releasing molecule) were used to investigate the mechanisms of HO-1 regulating COX-2 expression. Results We found that LPS-induced COX-2 expression and PGE2 production were mediated through NF-κB (p65) via activation of Toll-like receptor 4 (TLR4). LPS-induced COX-2 expression was inhibited by HO-1 induction by pretreatment with CoPP or infection with Adv-HO-1. This inhibitory effect of HO-1 was reversed by pretreatment with either ZnPP or hemoglobin. Pretreatment with CO-RM2 also inhibited TLR4/MyD88 complex formation, NF-κB (p65) activation, COX-2 expression, and PGE2 production induced by LPS. Conclusions We show here a novel inhibition of HO-1 on LPS-induced COX-2/PGE2 production in bEnd.3. Our results reinforce the emerging role of cerebral endothelium-derived HO-1 as a protector against cerebral vascular inflammation triggered by bacterial infection.
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Affiliation(s)
- Ruey-Horng Shih
- Department of Physiology and Pharmacology, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan
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Heme oxygenase is involved in cobalt chloride-induced lateral root development in tomato. Biometals 2010; 24:181-91. [PMID: 20978927 DOI: 10.1007/s10534-010-9386-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2010] [Accepted: 10/15/2010] [Indexed: 12/24/2022]
Abstract
In animals, heme oxygenase (HO), a rate-limiting enzyme responsible for carbon monoxide (CO) production, was regarded as a protective system maintaining cellular homeostasis. It was also established that metal ions are powerful HO-inducing agents and cobalt chloride (CoCl(2)) was the first metal ion identified with an inducing property. Previous study suggests that CoCl(2) stimulates adventitious root formation in tomato and cucumber cuttings. In this test, we discover that both CoCl(2) and an inducer of HO-1, hemin, could lead to the promotion of lateral root development, as well as the induction of HO-1 protein expression, HO activity, or LeHO-1/2 transcripts, in lateral root initiation zone of tomato seedlings. The effect is specific for HO since the potent HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX) blocked the above actions of CoCl(2), and the inhibitory effect was reversed partially when 50% CO aqueous solution was added. However, the addition of ascorbic acid (AsA), a well-known antioxidant, exhibited no obvious effect on lateral root formation. Molecular evidence further showed that CoCl(2)-induced the up-regulation of target genes responsible for lateral root formation, including LeCDKA1, LeCYCA2;1, and LeCYCA3;1, was suppressed differentially by ZnPPIX. And these decreases were reversed further by the addition of CO. All together, these results suggest a novel role for HO in the CoCl(2)-induced tomato lateral root formation.
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Paine A, Eiz-Vesper B, Blasczyk R, Immenschuh S. Signaling to heme oxygenase-1 and its anti-inflammatory therapeutic potential. Biochem Pharmacol 2010; 80:1895-903. [PMID: 20643109 DOI: 10.1016/j.bcp.2010.07.014] [Citation(s) in RCA: 596] [Impact Index Per Article: 39.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2010] [Revised: 07/05/2010] [Accepted: 07/08/2010] [Indexed: 12/13/2022]
Abstract
Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. Induction of HO-1 protects against the cytotoxicity of oxidative stress and apoptotic cell death. More recently, HO-1 has been recognized to have major immunomodulatory and anti-inflammatory properties, which have been demonstrated in HO-1 knockout mice and a human case of genetic HO-1 deficiency. Beneficial protective effects of HO-1 in inflammation are not only mediated via enzymatic degradation of proinflammatory free heme, but also via production of the anti-inflammatory compounds bilirubin and carbon monoxide. The immunomodulatory role of HO-1 is associated with its cell type-specific functions in myeloid cells (eg. macrophages and monocytes) and in endothelial cells, as both cell types are crucially involved in the regulation of inflammatory responses. This review covers the molecular mechanisms and signaling pathways that are involved in HO-1 gene expression. In particular, it is discussed how redox-dependent transcriptional activators such as NF-E2 related factor 2 (Nrf2), NF-κB and AP-1 along with the transcription repressor BTB and CNC homologue 1 (Bach1) control the inducible HO-1 gene expression. The role of central pro- and anti-inflammatory cellular signaling cascades including p38 MAPK and phosphatidylinositol-3 kinase (PI3K)/Akt in HO-1 regulation is highlighted. Finally, emerging strategies that apply targeted pharmacological induction of HO-1 for therapeutic interventions in inflammatory conditions are summarized.
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Affiliation(s)
- Ananta Paine
- Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
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Heme oxygenase 1 protects against hepatic hypoxia and injury from hemorrhage via regulation of cellular respiration. Shock 2010; 33:274-81. [PMID: 19536046 DOI: 10.1097/shk.0b013e3181b0f566] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Heme oxygenase 1 (HO-1) is an important regulator of the cellular response to stress and inflammation. These investigations test the hypothesis that HO-1 overexpression protects against hemorrhage-induced hypoxia by regulating cellular respiration and oxygen availability. Male C57BL/6 mice or primary mouse hepatocytes were treated with adenoviral gene transfer of HO-1 (AdHO-1) or beta-galactosidase (AdLacZ). Mice were subjected to hemorrhagic shock and resuscitation or cannulation without hemorrhage. AdHO-1 prevented hemorrhagic shock/resuscitation-induced liver injury. In addition, AdHO-1 prevented hemorrhage-induced liver hypoxia and depletion of adenosine triphosphate. In vitro, HO-1 overexpression resulted in decreased cellular respiration under hypoxic conditions as determined by oxygen consumption and cytochrome c oxidase activity. This resulted in increased intracellular oxygen levels in the setting of low oxygen tensions. In conclusion, HO-1 overexpression protects the liver against hemorrhage-induced injury. This may be secondary to the ability of HO-1 to protect against bioenergetic failure via regulation of cellular respiration.
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Mandal P, Park PH, McMullen MR, Pratt BT, Nagy LE. The anti-inflammatory effects of adiponectin are mediated via a heme oxygenase-1-dependent pathway in rat Kupffer cells. Hepatology 2010; 51:1420-9. [PMID: 20052772 PMCID: PMC2908267 DOI: 10.1002/hep.23427] [Citation(s) in RCA: 119] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
UNLABELLED Altered expression and activity of immunomodulatory cytokines plays a major role in the pathogenesis of alcoholic liver disease. Chronic ethanol feeding increases the sensitivity of Kupffer cells, the resident hepatic macrophage, to lipopolysaccharide (LPS), leading to increased tumor necrosis factor alpha (TNF-alpha) expression. This sensitization is normalized by treatment of primary cultures of Kupffer cells with adiponectin, an anti-inflammatory adipokine. Here we tested the hypothesis that adiponectin-mediated suppression of LPS signaling in Kupffer cells is mediated via an interleukin-10 (IL-10)/heme oxygenase-1 (HO-1) pathway after chronic ethanol feeding. Knockdown of IL-10 expression in primary cultures of Kupffer cells with small interfering RNA (siRNA) prevented the inhibitory effect of globular adiponectin (gAcrp) on LPS-stimulated TNF-alpha expression. gAcrp increased IL-10 mRNA and protein expression, as well as expression of the IL-10 inducible gene, HO-1; expression was higher in Kupffer cells from ethanol-fed rats compared with pair-fed controls. Although IL-10 receptor surface expression on Kupffer cells was not affected by ethanol feeding, IL-10-mediated phosphorylation of STAT3 and expression of HO-1 was higher in Kupffer cells after ethanol feeding. Inhibition of HO-1 activity, either by treatment with the HO-1 inhibitor zinc protoporphyrin or by siRNA knockdown of HO-1, prevented the inhibitory effect of gAcrp on LPS-stimulated TNF-alpha expression in Kupffer cells. LPS-stimulated TNF-alpha expression in liver was increased in mice after chronic ethanol exposure. When mice were treated with cobalt protoporphyrin to induce HO-1 expression, ethanol-induced sensitivity to LPS was ameliorated. CONCLUSION gAcrp prevents LPS-stimulated TNF-alpha expression in Kupffer cells through the activation of the IL-10/STAT3/HO-1 pathway. Kupffer cells from ethanol-fed rats are highly sensitive to the anti-inflammatory effects of gAcrp; this sensitivity is associated with both increased expression and sensitivity to IL-10.
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Affiliation(s)
- Palash Mandal
- Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195
| | - Pil-Hoon Park
- Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195
| | | | - Brian T. Pratt
- Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195
| | - Laura E. Nagy
- Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195, Department of Gastroenterology, Cleveland Clinic, Cleveland, OH 44195
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Mandal P, Pritchard MT, Nagy LE. Anti-inflammatory pathways and alcoholic liver disease: Role of an adiponectin/interleukin-10/heme oxygenase-1 pathway. World J Gastroenterol 2010; 16:1330-6. [PMID: 20238399 PMCID: PMC2842524 DOI: 10.3748/wjg.v16.i11.1330] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The development of alcoholic liver disease (ALD) is a complex process involving both the parenchymal and non-parenchymal cells in the liver. Enhanced inflammation in the liver during ethanol exposure is an important contributor to injury. Kupffer cells, the resident macrophages in liver, are particularly critical to the onset of ethanol-induced liver injury. Chronic ethanol exposure sensitizes Kupffer cells to activation by lipopolysaccharide via Toll-like receptor 4. This sensitization enhances production of inflammatory mediators, such as tumor necrosis factor-α and reactive oxygen species, that contribute to hepatocyte dysfunction, necrosis, apoptosis, and fibrosis. Impaired resolution of the inflammatory process probably also contributes to ALD. The resolution of inflammation is an active, highly coordinated response that can potentially be manipulated via therapeutic interventions to treat chronic inflammatory diseases. Recent studies have identified an adiponectin/interleukin-10/heme oxygenase-1 (HO-1) pathway that is profoundly effective in dampening the enhanced activation of innate immune responses in primary cultures of Kupffer cells, as well as in an in vivo mouse model of chronic ethanol feeding. Importantly, induction of HO-1 also reduces ethanol-induced hepatocellular apoptosis in this in vivo model. Based on these data, we hypothesize that the development of therapeutic agents to regulate HO-1 and its downstream targets could be useful in enhancing the resolution of inflammation during ALD and preventing progression of early stages of liver injury.
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Heme oxygenase (HO)-1 protects from lipopolysaccharide (LPS)-mediated liver injury by inhibition of hepatic leukocyte accumulation and improvement of microvascular perfusion. Langenbecks Arch Surg 2010; 395:387-94. [PMID: 20237939 DOI: 10.1007/s00423-010-0603-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2009] [Accepted: 01/26/2010] [Indexed: 02/06/2023]
Abstract
PURPOSE Lipopolysaccharide (LPS) represents a highly toxic substance which may aggravate morbidity and mortality in septic diseases. A recent study has reported that the induction of heme oxygenase (HO)-1 protects from LPS-induced liver injury. The mechanisms of action however, have not been clarified yet. Therefore, we analyzed in vivo the effects of HO-1 on the liver microcirculation under conditions of LPS exposure. METHODS In C57BL/6 mice, endotoxemia was induced by intraperitoneal (i.p.) administration of LPS (500 microg/kg) and D-galactosamine (Gal, 800 mg/kg). HO-1 was induced in vivo by pretreatment with hemin dissolved in DMSO (50 micromol/kg i.p.). Animals treated with DMSO only served as controls. Six hours after LPS exposure the hepatic microcirculation and leukocyte-endothelial cell interaction were analyzed by intravital fluorescence microscopy. HO-1 expression was determined by Western blot analysis. Hepatocellular damage was assessed by measuring the serum levels of aspartate aminotransferase and alanine aminotransferase. In addition, leukocyte transmigration and hepatocellular apoptosis were analyzed by histology and immunohistochemistry. RESULTS In controls, LPS/Gal caused severe liver injury, as indicated by increased liver enzyme levels and apoptotic cell death. This was associated with distinct sinusoidal perfusion failure and microvascular intrahepatic leukocyte accumulation. Of interest, induction of HO-1 significantly reduced numbers of adherent and extravascular leukocytes when compared to controls. Moreover, microvascular perfusion was significantly improved, resulting in a decrease of AST and ALT and a reduction of hepatocellular apoptosis. CONCLUSIONS Our novel data indicate that induction of HO-1 protects the liver from LPS-mediated injury by reducing leukocytic inflammation and improving intrahepatic microcirculation.
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Zeng Z, Huang HF, Chen MQ, Song F, Zhang YJ. Heme oxygenase-1 protects donor livers from ischemia/reperfusion injury: the role of Kupffer cells. World J Gastroenterol 2010; 16:1285-92. [PMID: 20222175 PMCID: PMC2839184 DOI: 10.3748/wjg.v16.i10.1285] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2009] [Revised: 01/03/2010] [Accepted: 01/10/2010] [Indexed: 02/06/2023] Open
Abstract
AIM To examine whether heme oxygenase (HO)-1 overexpression would exert direct or indirect effects on Kupffer cells activation, which lead to aggravation of reperfusion injury. METHODS Donors were pretreated with cobalt protoporphyrin (CoPP) or zinc protoporphyrin (ZnPP), HO-1 inducer and antagonist, respectively. Livers were stored at 4 degrees C for 24 h before transplantation. Kupffer cells were isolated and cultured for 6 h after liver reperfusion. RESULTS Postoperatively, serum transaminases were significantly lower and associated with less liver injury when donors were pretreated with CoPP, as compared with the ZnPP group. Production of the cytokines tumor necrosis factor-alpha and interleukin-6 generated by Kupffer cells decreased in the CoPP group. The CD14 expression levels (RT-PCR/Western blots) of Kupffer cells from CoPP-pretreated liver grafts reduced. CONCLUSION The study suggests that the potential utility of HO-1 overexpression in preventing ischemia/reperfusion injury results from inhibition of Kupffer cells activation.
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Lehmann E, El-Tantawy WH, Ocker M, Bartenschlager R, Lohmann V, Hashemolhosseini S, Tiegs G, Sass G. The heme oxygenase 1 product biliverdin interferes with hepatitis C virus replication by increasing antiviral interferon response. Hepatology 2010; 51:398-404. [PMID: 20044809 DOI: 10.1002/hep.23339] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
UNLABELLED The anti-inflammatory and antiapoptotic heme degrading enzyme heme oxygenase-1 (HO-1) has been shown recently to interfere with replication of hepatitis C virus (HCV). We investigated the effect of HO-1 products carbon monoxide (CO), iron and biliverdin on HCV replication using the replicon cell lines Huh-5-15 and LucUbiNeo-ET, stably expressing HCV proteins NS3 through NS5B. Incubation of these cell lines in the presence of the CO donor methylene chloride transiently reduced HCV replication, whereas an increase of iron in cell culture by administration of FeCl(3) or iron-saturated lactoferrin did not interfere with HCV replication. Likewise, depletion of iron by deferoxamine during induction of HO-1 by cobalt-protoporphyrin IX did not restore HCV replication. The most prominent effect was observed after incubation of replicon cell lines in the presence of biliverdin. Biliverdin seems to interfere with HCV replication-mediated oxidative stress by inducing expression of antiviral interferons, such as interferon alpha2 and alpha17. CONCLUSION The antioxidant biliverdin reduces HCV replication in vitro by triggering the antiviral interferon response and might improve HCV therapy in the future.
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Affiliation(s)
- Elisabeth Lehmann
- Division of Experimental Immunology and Hepatology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
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Devadas K, Hewlett IK, Dhawan S. Lipopolysaccharide suppresses HIV-1 replication in human monocytes by protein kinase C-dependent heme oxygenase-1 induction. J Leukoc Biol 2010; 87:915-24. [PMID: 20061555 DOI: 10.1189/jlb.0307172] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
LPS is an important component of the Gram-negative bacteria cell wall. It activates monocytes and induces multiple host immune and inflammatory responses. Interestingly, in spite of inducing host-inflammatory responses, LPS also protects monocyte-derived macrophages from infection by HIV-1. In this report, we have shown that LPS treatment of human monocyte-derived macrophages markedly suppressed HIV-1 replication, even on addition to infected cells 24 h after infection. Inhibition of HIV-1 replication was associated with PKC-dependent induction of HO-1, a cytoprotective enzyme known to catabolize heme. Pretreatment with the PKC inhibitor Go 6976 not only substantially inhibited LPS-mediated induction of HO-1 but also attenuated LPS-induced suppression of HIV replication. Significant reduction of HIV replication by inhibitors of JNK, NF-kappaB, and PI3K was independent of a LPS-mediated anti-HIV effect. Specificity of HO-1 was confirmed by substantial reversal of LPS-induced viral replication by pretreatment of cells with SnPP IX, an inhibitor of HO-1 enzyme activity. These results demonstrate a previously undefined function of HO-1 as a host defense mechanism in LPS-mediated inhibition of HIV-1 replication.
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Affiliation(s)
- Krishnakumar Devadas
- Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike (HFM-315), Rockville, MD 20852-1448, USA
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Kortgen A, Paxian M, Werth M, Recknagel P, Rauchfu F, Lupp A, Krenn CG, Müller D, Claus RA, Reinhart K, Settmacher U, Bauer M. PROSPECTIVE ASSESSMENT OF HEPATIC FUNCTION AND MECHANISMS OF DYSFUNCTION IN THE CRITICALLY ILL. Shock 2009; 32:358-65. [DOI: 10.1097/shk.0b013e31819d8204] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Kartikasari AER, Wagener FADTG, Yachie A, Wiegerinck ETG, Kemna EHJM, Swinkels DW, Winkels DW. Hepcidin suppression and defective iron recycling account for dysregulation of iron homeostasis in heme oxygenase-1 deficiency. J Cell Mol Med 2009; 13:3091-102. [PMID: 18774956 PMCID: PMC4516468 DOI: 10.1111/j.1582-4934.2008.00494.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Heme oxygenase-1 (HO-1) contribution to iron homeostasis has been postulated, because it facilitates iron recycling by liberating iron mostly from heme catabolism. This enzyme also appears to be responsible for the resolution of inflammatory conditions. In a patient with HO-1 deficiency, inflammation and dysregulation of body iron homeostasis, including anemia and liver and kidney hemosiderosis, are evidenced. Here we postulated that HO-1 is critical in the regulation of ferroportin, the major cellular iron exporter, and hepcidin, the key regulator of iron homeostasis central in the pathogenesis of anemia of inflammation. Our current experiments in human THP-1 monocytic cells indicate a HO-1-induced iron-mediated surface-ferroportin expression, consistent with the role of HO-1 in iron recycling. Surprisingly, we observed low hepcidin levels in the HO-1-deficient patient, despite the presence of inflammation and hemosiderosis, both inducers of hepcidin. Instead, we observed highly increased soluble transferrin receptor levels. This suggests that the decreased hepcidin levels in HO-1 deficiency reflect the increased need for iron in the bone marrow due to the anaemia. Using human hepatoma cells, we demonstrate that HO-activity did not have a direct modulating effect on expression of HAMP, the gene that encodes for hepcidin. Therefore, we argue that the decreased iron recycling may, in part, have contributed to the low hepcidin levels. These findings indicate that dysregulation of iron homeostasis in HO-1 deficiency is the result of both defective iron recycling and erythroid activity-associated inhibition of hepcidin expression. This study therefore shows a crucial role for HO-1 in maintaining body iron balance.
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Affiliation(s)
- Apriliana E R Kartikasari
- Department of Clinical Chemistry, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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Bauer I, Pannen BHJ. Bench-to-bedside review: Carbon monoxide--from mitochondrial poisoning to therapeutic use. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2009; 13:220. [PMID: 19691819 PMCID: PMC2750131 DOI: 10.1186/cc7887] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Carbon monoxide (CO) is generated during incomplete combustion of carbon-containing compounds and leads to acute and chronic toxicity in animals and humans depending on the concentration and exposure time. In addition to exogenous sources, CO is also produced endogenously by the activity of heme oxygenases (HOs) and the physiological significance of HO-derived CO has only recently emerged. CO exerts vasoactive, anti-proliferative, anti-oxidant, anti-inflammatory and anti-apoptotic effects and contributes substantially to the important role of the inducible isoform HO-1 as a mediator of tissue protection and host defense. Exogenous application of low doses of gaseous CO might provide a powerful tool to protect organs and tissues under various stress conditions. Experimental evidence strongly suggests a beneficial effect under pathophysiological conditions such as organ transplantation, ischemia/reperfusion, inflammation, sepsis, or shock states. The cellular and molecular mechanisms mediating CO effects are only partially characterized. So far, only a few studies in humans are available, which, however, do not support the promising results observed in experimental studies. The protective effects of exogenous CO may strongly depend on the pathological condition, the mode, time point and duration of application, the administered concentration, and on the target tissue and cell. Differences in bioavailability of endogenous CO production and exogenous CO supplementation might also provide an explanation for the lack of protective effects observed in some experimental and clinical studies. Further randomized, controlled clinical studies are needed to clarify whether exogenous application of CO may turn into a safe and effective preventive and therapeutic strategy to treat pathophysiological conditions associated with inflammatory or oxidative stress.
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Affiliation(s)
- Inge Bauer
- University Hospital Duesseldorf, Department of Anesthesiology, Moorenstrasse 5, D-40225 Duesseldorf, Germany.
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Suliburk JW, Ward JL, Helmer KS, Adams SD, Zuckerbraun BS, Mercer DW. Ketamine-induced hepatoprotection: the role of heme oxygenase-1. Am J Physiol Gastrointest Liver Physiol 2009; 296:G1360-9. [PMID: 19372106 PMCID: PMC2697945 DOI: 10.1152/ajpgi.00038.2009] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Lipopolysaccharide (LPS) causes hepatic injury that is mediated, in part, by upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Ketamine has been shown to prevent these effects. Because upregulation of heme oxygenase-1 (HO-1) has hepatoprotective effects, as does carbon monoxide (CO), an end product of the HO-1 catalytic reaction, we examined the effects of HO-1 inhibition on ketamine-induced hepatoprotection and assessed whether CO could attenuate LPS-induced hepatic injury. One group of rats received ketamine (70 mg/kg ip) or saline concurrently with either the HO-1 inhibitor tin protoporphyrin IX (50 micromol/kg ip) or saline. Another group of rats received inhalational CO (250 ppm over 1 h) or room air. All rats were given LPS (20 mg/kg ip) or saline 1 h later and euthanized 5 h after LPS or saline. Liver was collected for iNOS, COX-2, and HO-1 (Western blot), NF-kappaB and PPAR-gamma analysis (EMSA), and iNOS and COX-2 mRNA analysis (RT-PCR). Serum was collected to measure alanine aminotransferase as an index of hepatocellular injury. HO-1 inhibition attenuated ketamine-induced hepatoprotection and downregulation of iNOS and COX-2 protein. CO prevented LPS-induced hepatic injury and upregulation of iNOS and COX-2 proteins. Although CO abolished the ability of LPS to diminish PPAR-gamma activity, it enhanced NF-kappaB activity. These data suggest that the hepatoprotective effects of ketamine are mediated primarily by HO-1 and its end product CO.
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Affiliation(s)
- James W. Suliburk
- Department of Surgery, The University of Texas Medical School at Houston, Houston, Texas; and Department of Surgery, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Jeremy L. Ward
- Department of Surgery, The University of Texas Medical School at Houston, Houston, Texas; and Department of Surgery, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Kenneth S. Helmer
- Department of Surgery, The University of Texas Medical School at Houston, Houston, Texas; and Department of Surgery, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Sasha D. Adams
- Department of Surgery, The University of Texas Medical School at Houston, Houston, Texas; and Department of Surgery, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Brian S. Zuckerbraun
- Department of Surgery, The University of Texas Medical School at Houston, Houston, Texas; and Department of Surgery, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - David W. Mercer
- Department of Surgery, The University of Texas Medical School at Houston, Houston, Texas; and Department of Surgery, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Van Landeghem L, Laleman W, Vander Elst I, Zeegers M, van Pelt J, Cassiman D, Nevens F. Carbon monoxide produced by intrasinusoidally located haem-oxygenase-1 regulates the vascular tone in cirrhotic rat liver. Liver Int 2009; 29:650-60. [PMID: 18795901 DOI: 10.1111/j.1478-3231.2008.01857.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND/OBJECTIVE Carbon monoxide (CO) produced by haem-oxygenase isoforms (HO-1 & HO-2) is involved in the regulation of systemic vascular tone. We aimed to elucidate the vasoregulatory role of CO in the microcirculation in normal and thioacetamide cirrhotic rat livers. METHODS Haem-oxygenase expression was examined by Western blot. Total HO enzymatic activity was measured spectrophotometrically. Sensitivity of hepatic stellate cells (HSCs) to CO-mediated relaxation was studied by a stress-relaxed-collagen-lattice model. To define the relative role of CO, the CO-releasing molecule CORM-2, the HO-inhibitor zinc protoporphyrin-IX and the HO-1 inducer hemin were added to an in situ liver perfusion set-up. The topography of vasoactive CO production was evaluated by applying different CO- and nitric oxide-trapping reagents in the liver perfusion set-up and by immunohistochemistry. RESULTS Western blot showed decreased expression of both HO isoenzymes (P<0.036 for HO-1; P<0.001 for HO-2) in cirrhotic vs normal rat livers, confirmed by the HO-activity assay (P=0.004). HSCs relaxed on exposure to CORM-2 (P=0.013). The increased intrahepatic vascular resistance (IHVR) of cirrhotic rats was attenuated by perfusion with CORM-2 (P=0.016) and pretreatment with hemin (P<0.001). Inhibition of HO caused a dose-related increase in IHVR in normal and cirrhotic liver. In normal liver, the haemodynamically relevant CO production occurred extrasinusoidally, while intrasinusoidally HO-1 predominantly regulated the microcirculation in cirrhotic livers. CONCLUSION We demonstrate a role for CO and HO in the regulation of normal and cirrhotic microcirculation. These findings are of importance in the pathophysiology of portal hypertension and establish CO/HO as novel treatment targets.
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Affiliation(s)
- Lien Van Landeghem
- Department of Hepatology, University Hospital Gasthuisberg, KU Leuven, Belgium
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Ziegeler S, Raddatz A, Schneider SO, Sandmann I, Sasse H, Bauer I, Kubulus D, Mathes A, Lausberg HF, Rensing H. Effects of Haemofiltration and Mannitol Treatment on Cardiopulmonary-Bypass Induced Immunosuppression. Scand J Immunol 2009; 69:234-41. [DOI: 10.1111/j.1365-3083.2008.02216.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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