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Bauer M, Ermolaeva M, Singer M, Wetzker R, Soares MP. Hormesis as an adaptive response to infection. Trends Mol Med 2024; 30:633-641. [PMID: 38744580 DOI: 10.1016/j.molmed.2024.04.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 04/02/2024] [Accepted: 04/12/2024] [Indexed: 05/16/2024]
Abstract
Hormesis is a phenomenon whereby low-level stress can improve cellular, organ, or organismal fitness in response to a subsequent similar or other stress insult. Whereas hormesis is thought to contribute to the fitness benefits arising from symbiotic host-microbe interactions, the putative benefits of hormesis in host-pathogen interactions have yet to be explored. Hormetic responses have nonetheless been reported in experimental models of infection, a common feature of which is regulation of host mitochondrial function. We propose that these mitohormetic responses could be harnessed therapeutically to limit the severity of infectious diseases.
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Affiliation(s)
- Michael Bauer
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany; Cluster of Excellence Balance of the Microverse, Friedrich Schiller University Jena, Jena, Germany.
| | - Maria Ermolaeva
- Cluster of Excellence Balance of the Microverse, Friedrich Schiller University Jena, Jena, Germany; Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany
| | - Mervyn Singer
- Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK
| | - Reinhard Wetzker
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
| | - Miguel P Soares
- Cluster of Excellence Balance of the Microverse, Friedrich Schiller University Jena, Jena, Germany; Instituto Gulbenkian de Ciência, Oeiras, Portugal
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Liu RZ, Li WJ, Zhang JJ, Liu ZY, Li Y, Liu C, Qin S. The Inhibitory Effect of Phycocyanin Peptide on Pulmonary Fibrosis In Vitro. Mar Drugs 2022; 20:696. [PMID: 36355019 PMCID: PMC9694904 DOI: 10.3390/md20110696] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/27/2022] [Accepted: 11/02/2022] [Indexed: 07/29/2023] Open
Abstract
Phycocyanin is an excellent antioxidant with anti-inflammatory effects on which recent studies are growing; however, its specific target remains unclear. Linear tetrapyrrole compounds such as bilirubin have been shown to lead to the induction of heme oxygenase 1 expression in vivo, thus achieving antioxidant and anti-inflammatory effects. Phycocyanin is bound internally with linear tetrapyrrole phycocyanobilin in a similar structure to bilirubin. We speculate that there is probably a way of inducing the expression of heme oxygenase 1, with which tissue oxidative stress and inflammation can be inhibited, thus inhibiting pulmonary fibrosis caused by oxidative damage and inflammation of lung. By optimizing the enzymatic hydrolysis process, phycocyanobilin-bound phycocyanin peptide were obtained, and its in vitro antioxidant, anti-inflammatory, and anti-pulmonary fibrosis activities were investigated. The results show that the phycocyanobilin peptide was able to alleviate oxidative and inflammatory damage in cells through the Keap1-Nrf2-HO-1 pathway, which in turn relieved pulmonary fibrosis symptoms.
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Affiliation(s)
- Run-Ze Liu
- Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, China
- Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao 266071, China
| | - Wen-Jun Li
- Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, China
- Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao 266071, China
| | | | - Zheng-Yi Liu
- Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, China
- Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao 266071, China
| | - Ya Li
- Yantai Jiahui Biotech Co., Ltd., Yantai 264003, China
| | - Chao Liu
- Yantai Jiahui Biotech Co., Ltd., Yantai 264003, China
| | - Song Qin
- Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, China
- Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao 266071, China
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Muacevic A, Adler JR, Mantoo S, Shah T, Rathod SG. The Trend of Arterial Carboxyhemoglobin in Non-smokers as a Prognostic Tool in Severe COVID-19 Patients: A Single-Centre Prospective Study. Cureus 2022; 14:e31955. [PMID: 36582556 PMCID: PMC9795327 DOI: 10.7759/cureus.31955] [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] [Accepted: 11/28/2022] [Indexed: 11/29/2022] Open
Abstract
Introduction Carboxyhemoglobinemia is characterised by decreased oxygen delivery to tissues. In severe and critical coronavirus disease 2019 (COVID-19) illness with hypoxia, this can herald a grave and protracted course of illness. Patients with COVID-19 experience respiratory impairment, lowering the pace at which carbon monoxide (CO) is eliminated and raising the likelihood of carboxyhemoglobinemia. We set out to explore early arterial carboxyhemoglobin (COHb) and COVID-19 patient outcomes in non-smokers and its potential as a predictive tool for mortality. Methods Forty-five patients, non-smokers with severe/critical severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requiring admission in a North Indian 1200-bedded tertiary care hospital, were recruited prospectively from October 2020 to March 2021. Arterial COHb% was evaluated with arterial blood gases using an analyser, which were taken at the time of admission and then every alternate day for the first 10 days. Carboxyhemoglobinemia was defined as COHb% more than 1%. The primary outcome was defined as the patient's hospital outcome (survivor/non-survivor). Results Of the total 45 subjects, 51.1% (n=23) survived. Patients developed carboxyhemoglobinemia with an incidence of 51% during the course of their hospital stay. The mean ± SD of COHb% on admission was 1.0 ± 0.58 and 1.03 ± 0.8 in non-survivors and survivors, respectively (p=0.870). Maximal individual values of 5.3% and 6.1% were seen in survivors and non-survivors, respectively. On serial COHb measurement, non-survivors had significantly higher COHb% on days 6 and 10. No co-relation of COHb% with inflammatory markers was noted. Conclusion Arterial COHb levels in non-survivors were significantly higher than in survivors on days 6 and 10. Our study did not show a prognostic value of serial COHb measurement in patients with severe COVID-19. To establish COHb as a predictive marker in severely ill COVID-19 patients, additional research is required.
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Choi HI, Zeb A, Kim MS, Rana I, Khan N, Qureshi OS, Lim CW, Park JS, Gao Z, Maeng HJ, Kim JK. Controlled therapeutic delivery of CO from carbon monoxide-releasing molecules (CORMs). J Control Release 2022; 350:652-667. [PMID: 36063960 DOI: 10.1016/j.jconrel.2022.08.055] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 08/26/2022] [Accepted: 08/27/2022] [Indexed: 01/06/2023]
Abstract
Carbon monoxide (CO) has been regarded as a "silent killer" for its toxicity toward biological systems. However, a low concentration of endogenously produced CO has shown a number of therapeutic benefits such as anti-inflammatory, anti-proliferative, anti-apoptosis, and cytoprotective activities. Carbon monoxide-releasing molecules (CORMs) have been developed as alternatives to direct CO inhalation, which requires a specialized setting for strict dose control. CORMs are efficient CO donors, with central transition metals (such as ruthenium, iron, cobalt, and manganese) surrounded by CO as a ligand. CORMs can stably store and subsequently release their CO payload in the presence of certain triggers including solvent, light, temperature, and ligand substitution. However, CORMs require appropriate delivery strategies to improve short CO release half-life and target specificity. Herein, we highlighted the therapeutic potential of inhalation and CORMs-delivered CO. The applications of conjugate and nanocarrier systems for controlling CO release and improving therapeutic efficacy of CORMs are also described in detail. The review concludes with some of the hurdles that limit clinical translation of CORMs. Keeping in mind the tremendous potential and growing interest in CORMs, this review would be helpful for designing controlled CO release systems for clinical applications.
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Affiliation(s)
- Ho-Ik Choi
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi, Republic of Korea
| | - Alam Zeb
- College of Pharmacy, Gachon University, 191 Hambakmoe-ro, Yeonsu-gu, Incheon, Republic of Korea; Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Min-Su Kim
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi, Republic of Korea
| | - Isra Rana
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Namrah Khan
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Omer Salman Qureshi
- Department of Pharmacy, Faculty of Natural Sciences, Forman Christian College University, Lahore, Pakistan
| | - Chang-Wan Lim
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi, Republic of Korea
| | - Jeong-Sook Park
- College of Pharmacy, Institute of Drug Research and Development, Chungnam National University, Daejeon, Republic of Korea
| | - Zhonggao Gao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Han-Joo Maeng
- College of Pharmacy, Gachon University, 191 Hambakmoe-ro, Yeonsu-gu, Incheon, Republic of Korea.
| | - Jin-Ki Kim
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi, Republic of Korea.
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Campbell NK, Fitzgerald HK, Dunne A. Regulation of inflammation by the antioxidant haem oxygenase 1. Nat Rev Immunol 2021; 21:411-425. [PMID: 33514947 DOI: 10.1038/s41577-020-00491-x] [Citation(s) in RCA: 264] [Impact Index Per Article: 66.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2020] [Indexed: 01/30/2023]
Abstract
Haem oxygenase 1 (HO-1), an inducible enzyme responsible for the breakdown of haem, is primarily considered an antioxidant, and has long been overlooked by immunologists. However, research over the past two decades in particular has demonstrated that HO-1 also exhibits numerous anti-inflammatory properties. These emerging immunomodulatory functions have made HO-1 an appealing target for treatment of diseases characterized by high levels of chronic inflammation. In this Review, we present an introduction to HO-1 for immunologists, including an overview of its roles in iron metabolism and antioxidant defence, and the factors which regulate its expression. We discuss the impact of HO-1 induction in specific immune cell populations and provide new insights into the immunomodulation that accompanies haem catabolism, including its relationship to immunometabolism. Furthermore, we highlight the therapeutic potential of HO-1 induction to treat chronic inflammatory and autoimmune diseases, and the issues faced when trying to translate such therapies to the clinic. Finally, we examine a number of alternative, safer strategies that are under investigation to harness the therapeutic potential of HO-1, including the use of phytochemicals, novel HO-1 inducers and carbon monoxide-based therapies.
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Affiliation(s)
- Nicole K Campbell
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland. .,Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia. .,Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia.
| | - Hannah K Fitzgerald
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Aisling Dunne
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.,School of Medicine, Trinity College Dublin, Dublin, Ireland
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Photo-Polymerization Damage Protection by Hydrogen Sulfide Donors for 3D-Cell Culture Systems Optimization. Int J Mol Sci 2021; 22:ijms22116095. [PMID: 34198821 PMCID: PMC8201135 DOI: 10.3390/ijms22116095] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 05/26/2021] [Accepted: 05/31/2021] [Indexed: 01/04/2023] Open
Abstract
Photo-polymerized hydrogels are ideally suited for stem-cell based tissue regeneration and three dimensional (3D) bioprinting because they can be highly biocompatible, injectable, easy to use, and their mechanical and physical properties can be controlled. However, photo-polymerization involves the use of potentially toxic photo-initiators, exposure to ultraviolet light radiation, formation of free radicals that trigger the cross-linking reaction, and other events whose effects on cells are not yet fully understood. The purpose of this study was to examine the effects of hydrogen sulfide (H2S) in mitigating cellular toxicity of photo-polymerization caused to resident cells during the process of hydrogel formation. H2S, which is the latest discovered member of the gasotransmitter family of gaseous signalling molecules, has a number of established beneficial properties, including cell protection from oxidative damage both directly (by acting as a scavenger molecule) and indirectly (by inducing the expression of anti-oxidant proteins in the cell). Cells were exposed to slow release H2S treatment using pre-conditioning with glutathione-conjugated-garlic extract in order to mitigate toxicity during the photo-polymerization process of hydrogel formation. The protective effects of the H2S treatment were evaluated in both an enzymatic model and a 3D cell culture system using cell viability as a quantitative indicator. The protective effect of H2S treatment of cells is a promising approach to enhance cell survival in tissue engineering applications requiring photo-polymerized hydrogel scaffolds.
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Ryter SW. Significance of Heme and Heme Degradation in the Pathogenesis of Acute Lung and Inflammatory Disorders. Int J Mol Sci 2021; 22:ijms22115509. [PMID: 34073678 PMCID: PMC8197128 DOI: 10.3390/ijms22115509] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/19/2021] [Accepted: 05/20/2021] [Indexed: 02/07/2023] Open
Abstract
The heme molecule serves as an essential prosthetic group for oxygen transport and storage proteins, as well for cellular metabolic enzyme activities, including those involved in mitochondrial respiration, xenobiotic metabolism, and antioxidant responses. Dysfunction in both heme synthesis and degradation pathways can promote human disease. Heme is a pro-oxidant via iron catalysis that can induce cytotoxicity and injury to the vascular endothelium. Additionally, heme can modulate inflammatory and immune system functions. Thus, the synthesis, utilization and turnover of heme are by necessity tightly regulated. The microsomal heme oxygenase (HO) system degrades heme to carbon monoxide (CO), iron, and biliverdin-IXα, that latter which is converted to bilirubin-IXα by biliverdin reductase. Heme degradation by heme oxygenase-1 (HO-1) is linked to cytoprotection via heme removal, as well as by activity-dependent end-product generation (i.e., bile pigments and CO), and other potential mechanisms. Therapeutic strategies targeting the heme/HO-1 pathway, including therapeutic modulation of heme levels, elevation (or inhibition) of HO-1 protein and activity, and application of CO donor compounds or gas show potential in inflammatory conditions including sepsis and pulmonary diseases.
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Lei L, Guo Y, Lin J, Lin X, He S, Qin Z, Lin Q. Inhibition of endotoxin-induced acute lung injury in rats by bone marrow-derived mesenchymal stem cells: Role of Nrf2/HO-1 signal axis in inhibition of NLRP3 activation. Biochem Biophys Res Commun 2021; 551:7-13. [PMID: 33713981 DOI: 10.1016/j.bbrc.2021.03.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 03/02/2021] [Indexed: 12/29/2022]
Abstract
Both the Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) antioxidant pathway and Nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) pathway are considered essential for the development of acute lung injury (ALI)/ARDS induced by sepsis. Our aim was to study the role of Nrf2/HO-1 pathway on activation of the NLRP3 in the protective effect of marrow mesenchymal stem cells (BMSCs) on LPS-induced ALI. We found that BMSCs ameliorated ALI as evidenced by 1) decreased histopathological injury, wet/dry ratio, and protein permeability index in lung; 2) decreased reactive oxygen species (ROS), malondialdehyde (MDA), and protein carbonyl content and restored the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in lung tissue; 3) reduced LPS-induced increase in inflammatory cell count and promotion of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 levels in bronchoalveolar lavage fluid (BALF); 4) improvement in the four-day survival rate of animals; and 5) enhanced expression of Nrf2 and HO-1 and decreased expression of NOD-like receptor protein 3(NLRP3) and caspase-1 (p20) in lung tissue. Of note, Nrf2 transcription factor inhibitor brusatol and HO-1 inhibitor tin protoporphyrin IX (SnppIX) reversed BMSCs induced down-expression of NLRP3 and caspase-1 (p20), and inhibited the protective effects of BMSCs. These findings demonstrated that the Nrf2-mediated HO-1 signaling pathway plays a critical role in the protective effects of BMSCs on LPS-induced ALI. BMSCs may play an anti-inflammatory effect partly through the Nrf2/HO-1-dependent NLRP3 pathway.
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Affiliation(s)
- Lihua Lei
- Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China; Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, 350001, China
| | - Yiqing Guo
- Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, 350001, China
| | - Jun Lin
- The First Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, 350005, China
| | - Xiaohua Lin
- The First Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, 350005, China
| | - Shiling He
- The First Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, 350005, China
| | - Zaisheng Qin
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, Guangdong, 510515, China.
| | - Qun Lin
- Department of Anesthesiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, 350005, China; Anesthesiology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, 350005, China.
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Ohara Y, Ohara T, Hashimoto K, Hosoya M. Exhaled carbon monoxide levels in infants and toddlers with episodic asthma. Fukushima J Med Sci 2020; 66:78-87. [PMID: 32595177 PMCID: PMC7470756 DOI: 10.5387/fms.2019-02] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Objective: There are few lung function tests available to evaluate bronchial asthma in infants and toddlers. The objective of this study was to test the hypothesis that the measurement of exhaled carbon monoxide (eCO) levels is applicable to evaluate infants and toddlers with stable asthma and during acute asthma attack. Methods: A one-way valve breath sampling bag was developed to collect the exhaled air of infants and toddlers. A total of 483 infants (under 2 years) and toddlers (2-5 years) were studied; 355 had an established diagnosis of asthma (182 suffering mild asthma attacks and 173 without active asthmatic symptoms), 119 had upper respiratory infection (URI) including acute bronchitis, and 9 were healthy. Results: In infants and toddlers, eCO levels of those with asthma attacks [median (interquartile range) = 2.0 (2.0-3.25) ppm, n=182] were significantly higher than those of subjects with asymptomatic asthma [2.0 (1.0-2.0) ppm, n=173, P < 0.0001], URI [2.0 (1.0-3.0) ppm, n=119, P < 0.0001], and healthy children [1.0 (0.0-1.0) ppm, n=9, P < 0.0001]. In 75 children with asthma petit mal, eCO levels during asthma attacks [3.0 (2.0-4.0) ppm] significantly decreased after therapy [1.0 (1.0-2.0) ppm, P < 0.0001]. In infants and toddlers with an established diagnosis of asthma (n=355), eCO cut-off >2 ppm discriminated asthma attack from an asymptomatic state with a sensitivity of 95.6%, a specificity of 43.3%, and an area under the curve (AUC) of 0.71 (95% CI: 0.65-0.76, P < 0.0001). In 401 infants and toddlers with some respiratory symptoms, of which 285 cases were finally diagnosed as asthma [eCO level = 2.0 (2.0-3.0) ppm] and 116 cases were not asthma [eCO level = 2.0 (1.0-3.0) ppm, P < 0.0001], eCO cut-off >3 ppm supported the final diagnosis of asthma with a sensitivity of 38.9%, a specificity of 74.1%, and AUC of 0.63 (95% CI: 0.56-0.69, P < 0.0001). Conclusion: The measurement of eCO by a novel method is applicable to evaluate asthmatic activity and treatment responsiveness, and to diagnose asthma in infants and toddlers.
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Affiliation(s)
| | - Takahiro Ohara
- Division of Community Medicine, Tohoku Medical and Pharmaceutical University
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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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Expression of IL-1β, HMGB1, HO-1, and LDH in malignant and non-malignant pleural effusions. Respir Physiol Neurobiol 2020; 272:103330. [DOI: 10.1016/j.resp.2019.103330] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 10/15/2019] [Accepted: 10/15/2019] [Indexed: 11/22/2022]
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Badshah H, Ikram M, Ali W, Ahmad S, Hahm JR, Kim MO. Caffeine May Abrogate LPS-Induced Oxidative Stress and Neuroinflammation by Regulating Nrf2/TLR4 in Adult Mouse Brains. Biomolecules 2019; 9:biom9110719. [PMID: 31717470 PMCID: PMC6921022 DOI: 10.3390/biom9110719] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 11/06/2019] [Indexed: 12/05/2022] Open
Abstract
Herein, we assayed the antioxidant and anti-inflammatory potential of caffeine in a lipopolysaccharide (LPS)-injected mouse model of neurodegeneration and synaptic impairment. For this purpose, LPS was injected for two weeks on an alternate-day basis (250 µg/kg/i.p. for a total of seven doses), while caffeine was injected daily for four weeks (30 mg/kg/i.p/four weeks). According to our findings, there was a significant increase in the level of reactive oxygen species (ROS), as evaluated from the levels of lipid peroxidation (LPO) and ROS assays. Also, we evaluated the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) and the enzyme hemeoxygenase 1 (HO-1) in the mouse groups and found reduced expression of Nrf2 and HO-1 in the LPS-treated mice brains, but they were markedly upregulated in the LPS + caffeine co-treated group. We also noted enhanced expression of toll-Like Receptor 4 (TLR4), phospho-nuclear factor kappa B (p-NF-kB), and phospho-c-Jun n-terminal kinase (p-JNK) in the LPS-treated mice brains, which was significantly reduced in the LPS + caffeine co-treated group. Moreover, we found enhanced expression of Bcl2-associated X, apoptosis regulator (Bax), and cleaved caspase-3, and reduced expression of B-cell lymphoma 2 (Bcl-2) in the LPS-treated group, which were markedly reversed in the LPS + caffeine co-treated group. Furthermore, we analyzed the expression of synaptic proteins in the treated groups and found a marked reduction in the expression of synaptic markers in the LPS-treated group; these were significantly upregulated in the LPS + caffeine co-treated group. In summary, we conclude that caffeine may inhibit LPS-induced oxidative stress, neuroinflammation, and synaptic dysfunction.
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Affiliation(s)
- Haroon Badshah
- Division of Life Sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea; (H.B.); (M.I.); (W.A.); (S.A.)
| | - Muhammad Ikram
- Division of Life Sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea; (H.B.); (M.I.); (W.A.); (S.A.)
| | - Waqar Ali
- Division of Life Sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea; (H.B.); (M.I.); (W.A.); (S.A.)
| | - Sareer Ahmad
- Division of Life Sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea; (H.B.); (M.I.); (W.A.); (S.A.)
| | - Jong Ryeal Hahm
- Department of Internal Medicine, College of Medicine, and Division of Endocrinology, Gyeongsang National University Hospital and Institute of Health Sciences, Gyeongsang National University, Jinju 52828, Korea;
| | - Myeong Ok Kim
- Division of Life Sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea; (H.B.); (M.I.); (W.A.); (S.A.)
- Correspondence: ; Tel.: +82-55-772-1345; Fax: +82-55-772-2656
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Pereira MLM, Marinho CRF, Epiphanio S. Could Heme Oxygenase-1 Be a New Target for Therapeutic Intervention in Malaria-Associated Acute Lung Injury/Acute Respiratory Distress Syndrome? Front Cell Infect Microbiol 2018; 8:161. [PMID: 29868517 PMCID: PMC5964746 DOI: 10.3389/fcimb.2018.00161] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Accepted: 04/26/2018] [Indexed: 01/17/2023] Open
Abstract
Malaria is a serious disease and was responsible for 429,000 deaths in 2015. Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is one of the main clinical complications of severe malaria; it is characterized by a high mortality rate and can even occur after antimalarial treatment when parasitemia is not detected. Rodent models of ALI/ARDS show similar clinical signs as in humans when the rodents are infected with murine Plasmodium. In these models, it was shown that the induction of the enzyme heme oxygenase 1 (HO-1) is protective against severe malaria complications, including cerebral malaria and ALI/ARDS. Increased lung endothelial permeability and upregulation of VEGF and other pro-inflammatory cytokines were found to be associated with malaria-associated ALI/ARDS (MA-ALI/ARDS), and both were reduced after HO-1 induction. Additionally, mice were protected against MA-ALI/ARDS after treatment with carbon monoxide- releasing molecules or with carbon monoxide, which is also released by the HO-1 activity. However, high HO-1 levels in inflammatory cells were associated with the respiratory burst of neutrophils and with an intensification of inflammation during episodes of severe malaria in humans. Here, we review the main aspects of HO-1 in malaria and ALI/ARDS, presenting the dual role of HO-1 and possibilities for therapeutic intervention by modulating this important enzyme.
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Affiliation(s)
- Marcelo L M Pereira
- Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - Claudio R F Marinho
- Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - Sabrina Epiphanio
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, Brazil
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14
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Vanella L, Barbagallo I, Tibullo D, Forte S, Zappalà A, Li Volti G. The non-canonical functions of the heme oxygenases. Oncotarget 2018; 7:69075-69086. [PMID: 27626166 PMCID: PMC5356613 DOI: 10.18632/oncotarget.11923] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Accepted: 09/05/2016] [Indexed: 11/25/2022] Open
Abstract
Heme oxygenase (HO) isoforms catalyze the conversion of heme to carbon monoxide (CO) and biliverdin with a concurrent release of iron, which can drive the synthesis of ferritin for iron sequestration. Most of the studies so far were directed at evaluating the protective effect of these enzymes because of their ability to generate antioxidant and antiapoptotic molecules such as CO and bilirubin. Recent evidences are suggesting that HO may possess other important physiological functions, which are not related to its enzymatic activity and for which we would like to introduce for the first time the term “non canonical functions”. Recent evidence suggest that both HO isoforms may form protein-protein interactions (i.e. cytochrome P450, adiponectin, CD91) thus serving as chaperone-like protein. In addition, truncated HO-1 isoform was localized in the nuclear compartment under certain experimental conditions (i.e. excitotoxicity, hypoxia) regulating the activity of important nuclear transcription factors (i.e. Nrf2) and DNA repair. In the present review, we discuss three potential signaling mechanisms that we refer to as the non-canonical functions of the HO isoforms: protein-protein interaction, intracellular compartmentalization, and extracellular secretion. The aim of the present review is to describe each of this mechanism and all the aspects warranting additional studies in order to unravel all the functions of the HO system.
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Affiliation(s)
- Luca Vanella
- Department of Drug Sciences, University of Catania, Catania, Italy
| | | | - Daniele Tibullo
- Division of Haematology, AOU "Policlinico - Vittorio Emanuele", University of Catania, Catania, Italy
| | - Stefano Forte
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.,Istituto Oncologico del Mediterraneo Ricerca srl Viagrande, Catania, Italy
| | - Agata Zappalà
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Giovanni Li Volti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.,EuroMediterranean Institute of Science and Technology, Palermo, Italy
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15
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Mahrouf-Yorgov M, Augeul L, Da Silva CC, Jourdan M, Rigolet M, Manin S, Ferrera R, Ovize M, Henry A, Guguin A, Meningaud JP, Dubois-Randé JL, Motterlini R, Foresti R, Rodriguez AM. Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties. Cell Death Differ 2017; 24:1224-1238. [PMID: 28524859 PMCID: PMC5520168 DOI: 10.1038/cdd.2017.51] [Citation(s) in RCA: 202] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 03/05/2017] [Accepted: 03/07/2017] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs) protect tissues against cell death induced by ischemia/reperfusion insults. This therapeutic effect seems to be controlled by physiological cues released by the local microenvironment following injury. Recent lines of evidence indicate that MSC can communicate with their microenvironment through bidirectional exchanges of mitochondria. In particular, in vitro and in vivo studies report that MSCs rescue injured cells through delivery of their own mitochondria. However, the role of mitochondria conveyed from somatic cells to MSC remains unknown. By using a co-culture system consisting of MSC and distressed somatic cells such as cardiomyocytes or endothelial cells, we showed that mitochondria from suffering cells acted as danger-signaling organelles that triggered the anti-apoptotic function of MSC. We demonstrated that foreign somatic-derived mitochondria were engulfed and degraded by MSC, leading to induction of the cytoprotective enzyme heme oxygenase-1 (HO-1) and stimulation of mitochondrial biogenesis. As a result, the capacity of MSC to donate their mitochondria to injured cells to combat oxidative stress injury was enhanced. We found that similar mechanisms - activation of autophagy, HO-1 and mitochondrial biogenesis - occurred after exposure of MSC to exogenous mitochondria isolated from somatic cells, strengthening the idea that somatic mitochondria alert MSC of a danger situation and subsequently promote an adaptive reparative response. In addition, the cascade of events triggered by the transfer of somatic mitochondria into MSC was recapitulated in a model of myocardial infarction in vivo. Specifically, MSC engrafted into infarcted hearts of mice reduced damage, upregulated HO-1 and increased mitochondrial biogenesis, while inhibition of mitophagy or HO-1 failed to protect against cardiac apoptosis. In conclusion, our study reveals a new facet about the role of mitochondria released from dying cells as a key environmental cue that controls the cytoprotective function of MSC and opens novel avenues to improve the effectiveness of MSC-based therapies.
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Affiliation(s)
- Meriem Mahrouf-Yorgov
- Université Paris-Est, UMR-S955, UPEC, Créteil, Paris, France.,INSERM, Unité 955 Team 12, Créteil, Paris, France
| | - Lionel Augeul
- INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de Médecine, Rockefeller, Lyon, France
| | - Claire Crola Da Silva
- INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de Médecine, Rockefeller, Lyon, France
| | - Maud Jourdan
- Université Paris-Est, UMR-S955, UPEC, Créteil, Paris, France.,INSERM, Unité 955 Team 12, Créteil, Paris, France
| | - Muriel Rigolet
- Université Paris-Est, UMR-S955, UPEC, Créteil, Paris, France.,INSERM U955 Team 10, Créteil, Paris, France
| | - Sylvie Manin
- Université Paris-Est, UMR-S955, UPEC, Créteil, Paris, France.,INSERM, Unité 955 Team 12, Créteil, Paris, France
| | - René Ferrera
- INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de Médecine, Rockefeller, Lyon, France
| | - Michel Ovize
- INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de Médecine, Rockefeller, Lyon, France.,Hospices Civils de Lyon, Hôpital Louis Pradel, Service d'Explorations Fonctionnelles, Cardiovasculaires and Centre d'Investigation Clinique, Lyon, France
| | - Adeline Henry
- Université Paris-Est, UMR-S955, UPEC, Créteil, Paris, France.,INSERM U955, Plateforme de Cytométrie en flux, Créteil, Paris, France
| | - Aurélie Guguin
- Université Paris-Est, UMR-S955, UPEC, Créteil, Paris, France.,INSERM U955, Plateforme de Cytométrie en flux, Créteil, Paris, France
| | - Jean-Paul Meningaud
- Service de Chirurgie Plastique et Maxillo-Faciale, AP-HP, Hôpital Henri Mondor-A. Chenevier, Créteil, Paris, France
| | - Jean-Luc Dubois-Randé
- Université Paris-Est, UMR-S955, UPEC, Créteil, Paris, France.,Fédération de Cardiologie, AP-HP, Hôpital Henri Mondor-A. Chenevier, Créteil, Paris, France
| | - Roberto Motterlini
- Université Paris-Est, UMR-S955, UPEC, Créteil, Paris, France.,INSERM, Unité 955 Team 12, Créteil, Paris, France
| | - Roberta Foresti
- Université Paris-Est, UMR-S955, UPEC, Créteil, Paris, France.,INSERM, Unité 955 Team 12, Créteil, Paris, France
| | - Anne-Marie Rodriguez
- Université Paris-Est, UMR-S955, UPEC, Créteil, Paris, France.,INSERM, Unité 955 Team 12, Créteil, Paris, France
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16
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Immenschuh S, Vijayan V, Janciauskiene S, Gueler F. Heme as a Target for Therapeutic Interventions. Front Pharmacol 2017; 8:146. [PMID: 28420988 PMCID: PMC5378770 DOI: 10.3389/fphar.2017.00146] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 03/07/2017] [Indexed: 12/30/2022] Open
Abstract
Heme is a complex of iron and the tetrapyrrole protoporphyrin IX with essential functions in aerobic organisms. Heme is the prosthetic group of hemoproteins such as hemoglobin and myoglobin, which are crucial for reversible oxygen binding and transport. By contrast, high levels of free heme, which may occur in various pathophysiological conditions, are toxic via pro-oxidant, pro-inflammatory and cytotoxic effects. The toxicity of heme plays a major role for the pathogenesis of prototypical hemolytic disorders including sickle cell disease and malaria. Moreover, there is increasing appreciation that detrimental effects of heme may also be critically involved in diseases, which usually are not associated with hemolysis such as severe sepsis and atherosclerosis. In mammalians homeostasis of heme and its potential toxicity are primarily controlled by two physiological systems. First, the scavenger protein hemopexin (Hx) non-covalently binds extracellular free heme with high affinity and attenuates toxicity of heme in plasma. Second, heme oxygenases (HOs), in particular the inducible HO isozyme, HO-1, can provide antioxidant cytoprotection via enzymatic degradation of intracellular heme. This review summarizes current knowledge on the pathophysiological role of heme for various diseases as demonstrated in experimental animal models and in humans. The functional significance of Hx and HOs for the regulation of heme homeostasis is highlighted. Finally, the therapeutic potential of pharmacological strategies that apply Hx and HO-1 in various clinical settings is discussed.
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Affiliation(s)
- Stephan Immenschuh
- Institute for Transfusion Medicine, Hannover Medical SchoolHannover, Germany
| | - Vijith Vijayan
- Institute for Transfusion Medicine, Hannover Medical SchoolHannover, Germany
| | | | - Faikah Gueler
- Department of Nephrology, Hannover Medical SchoolHannover, Germany
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17
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Salifu H, Wilson NO, Liu M, Dickinson-Copeland C, Yatich N, Keenan J, Turpin C, Jolly P, Gyasi R, Adjei AA, Stiles JK. Iron Supplementation Alters Heme and Heme Oxygenase 1 (HO-1) Levels In Pregnant Women in Ghana. SOJ MICROBIOLOGY & INFECTIOUS DISEASES 2016; 4. [PMID: 28124024 DOI: 10.15226/sojmid/4/2/00154] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND Iron supplementation is recommended for pregnant women to meet their iron requirement for a healthy pregnancy. The benefits and risks of universal iron supplementation during pregnancy in malaria endemic countries are currently being debated. As part of a broader study that focused on the effect of heme/HO-1 on pregnancy outcomes in malaria in pregnancy, we determined the association between iron supplementation and free heme levels in blood of pregnant women with and without malaria in Ghana. We hypothesized that pregnant women with malaria who took iron supplements will have higher levels of Heme/HO-1 than those who did not take iron supplements. METHODS A total of 337 women were recruited for this study. Blood samples were collected for malaria diagnosis and heme/HO-1 measurement. Quantification of heme was done using a heme colorimetric assay kit and HO-1 levels were performed using Enzyme-Linked Immunosorbent Assay (ELISA) on plasma samples. RESULTS Malaria positive iron supplemented women, in their third trimester, had significantly higher median levels of heme 59.3(43.1 - 60.4) than non-malaria iron supplemented women 35.7(33.0 - 62.2), p = 0.026. Also, malaria positive iron supplemented women had significant higher median levels of HO-16.2(IQR 4.9 - 8.1) than pregnant women who did not take iron supplements 2.9 (IQR 2.1 - 3.8), p = <0.001. CONCLUSION Although iron supplementation may be highly beneficial and improve pregnancy outcomes for iron deficient or anemic mothers, it is also likely that iron supplementation for pregnant women who are not iron deficient may put this group of women at risk for adverse pregnancy outcomes. Findings from this study sheds light on the effect of iron supplementation on malaria derived heme in pregnancy, which may inform how iron supplementation is recommended for pregnant women who are not iron deficient.
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Affiliation(s)
- Hassana Salifu
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine
| | - Nana O Wilson
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine
| | - Mingli Liu
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine
| | | | - Nelly Yatich
- University of Alabama, Birmingham Alabama, Department of Epidemiology
| | - John Keenan
- University of Alabama, Birmingham Alabama, Department of Epidemiology
| | - Cornelius Turpin
- University of Alabama, Birmingham Alabama, Department of Epidemiology
| | - Pauline Jolly
- University of Alabama, Birmingham Alabama, Department of Epidemiology
| | - Richard Gyasi
- University of Ghana Medical School, Department of Pathology, Korle-Bu Teaching Hospital, Accra, Ghana
| | - Andrew A Adjei
- University of Ghana Medical School, Department of Pathology, Korle-Bu Teaching Hospital, Accra, Ghana
| | - Jonathan K Stiles
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine
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18
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Yuan PQ, Wu SV, Pothoulakis C, Taché Y. Urocortins and CRF receptor type 2 variants in the male rat colon: gene expression and regulation by endotoxin and anti-inflammatory effect. Am J Physiol Gastrointest Liver Physiol 2016; 310:G387-98. [PMID: 26744472 PMCID: PMC4796293 DOI: 10.1152/ajpgi.00337.2015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 12/30/2015] [Indexed: 01/31/2023]
Abstract
Urocortins (Ucns) 1, 2, and 3 and corticotropin-releasing factor receptor 2 (CRF2) mRNA are prominently expressed in various layers of the upper gut. We tested whether Ucns and CRF2 variants are also expressed in the different layers of the rat colon, regulated by LPS (100 μg/kg ip) and play a modulatory role in the colonic immune response to LPS. Transcripts of Ucns and CRF2b, the most common isoform in the periphery, were detected in all laser microdissected layers, including myenteric neurons. LPS increased the mRNA level of Ucn 1, Ucn 2, and Ucn 3 and decreased that of CRF2b in both the colonic mucosa and submucosa + muscle (S+M) layers at 2, 6, and 9 h after injection with a return to basal at 24 h. In addition, CRF2a, another variant more prominent in the brain, and a novel truncated splice variant CRF2a-3 mRNA were detected in all segments of the large intestine. LPS reciprocally regulated the colonic expression of these CRF2 variants by decreasing both CRF2a and CRF2b, while increasing CRF2a-3 in the mucosa and S+M. The CRF2 antagonist astressin2-B further enhanced LPS-induced increase of mRNA level of interleukin (IL)-1β, TNF-α, and inducible nitric oxide synthase in S+M layers and IL-1β in the mucosa and evoked TNF-α expression in the mucosa. These data indicate that Ucns/CRF2 variants are widely expressed in all colonic layers and reciprocally regulated by LPS. CRF2 signaling dampens the CD14/TLR4-mediated acute inflammatory response to Gram-negative bacteria in the colon.
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Affiliation(s)
- Pu-Qing Yuan
- Center for Neurobiology of Stress, Inflammatory Bowel Disease Center, CURE: Digestive Diseases Research Center, Digestive Diseases Division, Veterans Affairs Greater Los Angeles Healthcare System, Department of Medicine and Brain Research Institute, University of California, Los Angeles, California
| | - S Vincent Wu
- Center for Neurobiology of Stress, Inflammatory Bowel Disease Center, CURE: Digestive Diseases Research Center, Digestive Diseases Division, Veterans Affairs Greater Los Angeles Healthcare System, Department of Medicine and Brain Research Institute, University of California, Los Angeles, California
| | - Charalabos Pothoulakis
- Center for Neurobiology of Stress, Inflammatory Bowel Disease Center, CURE: Digestive Diseases Research Center, Digestive Diseases Division, Veterans Affairs Greater Los Angeles Healthcare System, Department of Medicine and Brain Research Institute, University of California, Los Angeles, California
| | - Yvette Taché
- Center for Neurobiology of Stress, Inflammatory Bowel Disease Center, CURE: Digestive Diseases Research Center, Digestive Diseases Division, Veterans Affairs Greater Los Angeles Healthcare System, Department of Medicine and Brain Research Institute, University of California, Los Angeles, California
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19
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Akagi R, Akagi M, Hatori Y, Inouye S. Prevention of Barrier Disruption by Heme Oxygenase-1 in Intestinal Bleeding Model. Biol Pharm Bull 2016; 39:1007-12. [DOI: 10.1248/bpb.b15-01028] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Reiko Akagi
- Department of Pharmacy, Faculty of Pharmacy, Yasuda Women’s University
| | - Masaaki Akagi
- Department of Pharmacology, Faculty of Pharmaceutical Science, Tokushima Bunri University
| | - Yuta Hatori
- Department of Pharmacy, Faculty of Pharmacy, Yasuda Women’s University
| | - Sachiye Inouye
- Department of Pharmacy, Faculty of Pharmacy, Yasuda Women’s University
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20
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Zhu Y, Xie F, Ding L, Fan X, Ding X, Zhang QY. Intestinal epithelium-specific knockout of the cytochrome P450 reductase gene exacerbates dextran sulfate sodium-induced colitis. J Pharmacol Exp Ther 2015; 354:10-7. [PMID: 25926522 PMCID: PMC4468430 DOI: 10.1124/jpet.115.223263] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 04/27/2015] [Indexed: 12/20/2022] Open
Abstract
The potential involvement of intestinal microsomal cytochrome P450 (P450) enzymes in defending against colon inflammation and injury was studied in mice treated with dextran sulfate sodium (DSS) to induce colitis. Wild-type (WT) mice and mice with intestinal epithelium (IE)-specific deletion of the P450 reductase gene (IE-Cpr-null) were compared. IE-Cpr-null mice have little microsomal P450 activity in IE cells. DSS treatment (2.5% in drinking water for 6 days) caused more severe colon inflammation, as evidenced by the presence of higher levels of myeloperoxidase and proinflammatory cytokines [tumor necrosis factor-α, interleukin (IL)-6, and IL-1β], and greater weight loss, colonic tissue damage, and colon shortening, in IE-Cpr-null mice than in WT mice. The IE-Cpr-null mice were deficient in colonic corticosterone (CC) synthesis, as indicated by the inability of ex vivo cultured colonic tissues from DSS-treated IE-Cpr-null mice (in contrast to DSS-treated WT mice) to show increased CC production, compared with vehicle-treated mice, and by the ability of added deoxycorticosterone (DOC), a precursor of CC biosynthesis via mitochondrial CYP11B1, to restore ex vivo CC production by colonic tissues from DSS-treated null mice. Intriguingly, null (but not WT) mice failed to show increased serum CC levels following DSS treatment. Nevertheless, cotreatment of DSS-exposed mice with DOC, which did not restore DSS-induced increase in serum CC, abolished the hypersensitivity of IE-Cpr-null mice to DSS-induced colon injury. Taken together, our results strongly support the notion that microsomal P450 enzymes in the intestine play an important role in protecting colon epithelium from DSS-induced inflammation and injury, possibly through increased local CC synthesis in response to DSS challenge.
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Affiliation(s)
- Yi Zhu
- Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (Y.Z., F.X., L.D., X.F., X.D., Q.-Y.Z.); and College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York (X.D.)
| | - Fang Xie
- Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (Y.Z., F.X., L.D., X.F., X.D., Q.-Y.Z.); and College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York (X.D.)
| | - Liang Ding
- Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (Y.Z., F.X., L.D., X.F., X.D., Q.-Y.Z.); and College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York (X.D.)
| | - Xiaoyu Fan
- Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (Y.Z., F.X., L.D., X.F., X.D., Q.-Y.Z.); and College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York (X.D.)
| | - Xinxin Ding
- Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (Y.Z., F.X., L.D., X.F., X.D., Q.-Y.Z.); and College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York (X.D.)
| | - Qing-Yu Zhang
- Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (Y.Z., F.X., L.D., X.F., X.D., Q.-Y.Z.); and College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York (X.D.)
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21
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Fredenburgh LE, Merz AA, Cheng S. Haeme oxygenase signalling pathway: implications for cardiovascular disease. Eur Heart J 2015; 36:1512-8. [PMID: 25827602 PMCID: PMC4475572 DOI: 10.1093/eurheartj/ehv114] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Revised: 02/25/2015] [Accepted: 03/19/2015] [Indexed: 01/04/2023] Open
Abstract
Evidence now points to the haeme oxygenase (HO) pathway as a possible actor in modulating risk for cardiovascular disease (CVD). In particular, the HO pathway may represent a key endogenous modulator of oxidative, inflammatory, and cytotoxic stress while also exhibiting vasoregulatory properties. In this review, we summarize the accumulating experimental and emerging clinical data indicating how activity of the HO pathway and its products may play a role in mechanisms underlying the development of CVD. We also identify gaps in the literature to date and suggest future directions for investigation. Because HO pathway activity can be influenced not only by genetic traits and environmental stimuli but also by a variety of existing pharmacologic interventions, the pathway could serve as a prime target for reducing the overall burden of CVD. Further work is needed to determine the role of HO pathway products as possible prognostic markers of risk for clinical CVD events and the extent to which therapeutic augmentation or inhibition of HO pathway activity could serve to modify CVD risk.
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Affiliation(s)
- Laura E Fredenburgh
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Allison A Merz
- Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Susan Cheng
- Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Framingham Heart Study, Framingham, MA, USA
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22
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Jancsó Z, Bódi N, Borsos B, Fekete É, Hermesz E. Gut region-specific accumulation of reactive oxygen species leads to regionally distinct activation of antioxidant and apoptotic marker molecules in rats with STZ-induced diabetes. Int J Biochem Cell Biol 2015; 62:125-31. [PMID: 25794426 DOI: 10.1016/j.biocel.2015.03.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Revised: 03/03/2015] [Accepted: 03/09/2015] [Indexed: 02/07/2023]
Abstract
UNLABELLED The aim of this study was to seek possible links between the regionality along the digestive tract and the accumulation of reactive oxygen species, the effectiveness of the antioxidant defense system and the sensitivity to the types of demise in different gut regions of rats with streptozotocin-induced diabetes. Significant changes were observed in the oxidative status and in the activity of the antioxidant defense system in the diabetic colon; the peroxynitrite production was doubled, the level of hemoxygenase-2 protein was increased 11-fold and the expression of anti-apoptotic bcl-2 was also increased. The segment-specific vulnerability of the gastrointestinal tract induced by hyperglycemia was also confirmed by electron microscopy, demonstrating the presence of severe necrosis in the colon of the diabetic rats. No remarkable histopathological alterations were seen in the duodenum of the diabetic animals and there were likewise no significant changes in the production of peroxynitrite in their duodenum, whereas the level of the free radical scavenger metallothionein-2 was increased ∼300-fold. CONCLUSION The spatially restricted vulnerability observed along the digestive tract could originate from a high level of oxidative stress via peroxynitrite production.
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Affiliation(s)
- Zsanett Jancsó
- Department of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary
| | - Nikolett Bódi
- Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary
| | - Barbara Borsos
- Department of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary
| | - Éva Fekete
- Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary
| | - Edit Hermesz
- Department of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary.
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23
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IRG1 induced by heme oxygenase-1/carbon monoxide inhibits LPS-mediated sepsis and pro-inflammatory cytokine production. Cell Mol Immunol 2015; 13:170-9. [PMID: 25640654 PMCID: PMC4786624 DOI: 10.1038/cmi.2015.02] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Revised: 01/03/2015] [Accepted: 01/03/2015] [Indexed: 01/12/2023] Open
Abstract
The immunoresponsive gene 1 (IRG1) protein has crucial functions in embryonic implantation and neurodegeneration. IRG1 promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species (ROS). The cytoprotective protein heme oxygenase-1 (HO-1), which generates endogenous carbon monoxide (CO), is expressed in the lung during Lipopolysaccharide (LPS) tolerance and cross tolerance. However, the detailed molecular mechanisms and functional links between IRG1 and HO-1 in the innate immune system remain unknown. In the present study, we found that the CO releasing molecule-2 (CORM-2) and chemical inducers of HO-1 increased IRG1 expression in a time- and dose-dependent fashion in RAW264.7 cells. Furthermore, inhibition of HO-1 activity by zinc protoporphyrin IX (ZnPP) and HO-1 siRNA significantly reduced expression of IRG1 under these conditions. In addition, treatment with CO and HO-1 induction significantly increased A20 expression, which was reversed by ZnPP and HO-1 siRNA. LPS-stimulated TNF-α was significantly decreased, whereas IRG1 and A20 were increased by CORM-2 application and HO-1 induction, which in turn were abrogated by ZnPP. Interestingly, siRNA against IRG1 and A20 reversed the effects of CO and HO-1 on LPS-stimulated TNF-α production. Additionally, CO and HO-1 inducers significantly increased IRG1 and A20 expression and downregulated TNF-α production in a LPS-stimulated sepsis mice model. Furthermore, the effects of CO and HO-1 on TNF-α production were significantly reversed when ZnPP was administered. In conclusion, CO and HO-1 induction regulates IRG1 and A20 expression, leading to inhibition of inflammation in vitro and in an in vivo mice model.
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Konrad FM, Braun S, Ngamsri KC, Vollmer I, Reutershan J. Heme oxygenase-1 attenuates acute pulmonary inflammation by decreasing the release of segmented neutrophils from the bone marrow. Am J Physiol Lung Cell Mol Physiol 2014; 307:L707-17. [DOI: 10.1152/ajplung.00145.2014] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Recruiting polymorphonuclear neutrophil granulocytes (PMNs) from circulation and bone marrow to the site of inflammation is one of the pivotal mechanisms of the innate immune system. During inflammation, the enzyme heme oxygenase 1 (HO-1) has been shown to reduce PMN migration. Although these effects have been described in various models, underlying mechanisms remain elusive. Recent studies revealed an influence of HO-1 on different cells of the bone marrow. We investigated the particular role of the bone marrow in terms of HO-1-dependent pulmonary inflammation. In a murine model of LPS inhalation, stimulation of HO-1 by cobalt (III) protoporphyrin-IX-chloride (CoPP) resulted in reduced segmented PMN migration into the alveolar space. In the CoPP group, segmented PMNs were also decreased intravascularly, and concordantly, mature and immature PMN populations were higher in the bone marrow. Inhibition of the enzyme by tin protoporphyrin-IX increased segmented and banded PMN migration into the bronchoalveolar lavage fluid with enhanced PMN release from the bone marrow and aggravated parameters of tissue inflammation. Oxidative burst activity was significantly higher in immature compared with mature PMNs. The chemokine stromal-derived factor-1 (SDF-1), which mediates homing of leukocytes into the bone marrow and is decreased in inflammation, was increased by CoPP. When SDF-1 was blocked by the specific antagonist AMD3100, HO-1 activation was no longer effective in curbing PMN trafficking to the inflamed lungs. In conclusion, we show evidence that the anti-inflammatory effects of HO-1 are largely mediated by inhibiting the release of segmented PMNs from the bone marrow rather than direct effects within the lung.
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Affiliation(s)
- Franziska M. Konrad
- Department of Anesthesiology and Intensive Care Medicine, University Hospital of Tübingen, Tübingen, Germany
| | - Stefan Braun
- Department of Anesthesiology and Intensive Care Medicine, University Hospital of Tübingen, Tübingen, Germany
| | - Kristian-Christos Ngamsri
- Department of Anesthesiology and Intensive Care Medicine, University Hospital of Tübingen, Tübingen, Germany
| | - Irene Vollmer
- Department of Anesthesiology and Intensive Care Medicine, University Hospital of Tübingen, Tübingen, Germany
| | - Jörg Reutershan
- Department of Anesthesiology and Intensive Care Medicine, University Hospital of Tübingen, Tübingen, Germany
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Chiabrando D, Vinchi F, Fiorito V, Mercurio S, Tolosano E. Heme in pathophysiology: a matter of scavenging, metabolism and trafficking across cell membranes. Front Pharmacol 2014; 5:61. [PMID: 24782769 PMCID: PMC3986552 DOI: 10.3389/fphar.2014.00061] [Citation(s) in RCA: 308] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 03/18/2014] [Indexed: 01/19/2023] Open
Abstract
Heme (iron-protoporphyrin IX) is an essential co-factor involved in multiple biological processes: oxygen transport and storage, electron transfer, drug and steroid metabolism, signal transduction, and micro RNA processing. However, excess free-heme is highly toxic due to its ability to promote oxidative stress and lipid peroxidation, thus leading to membrane injury and, ultimately, apoptosis. Thus, heme metabolism needs to be finely regulated. Intracellular heme amount is controlled at multiple levels: synthesis, utilization by hemoproteins, degradation and both intracellular and intercellular trafficking. This review focuses on recent findings highlighting the importance of controlling intracellular heme levels to counteract heme-induced oxidative stress. The contributions of heme scavenging from the extracellular environment, heme synthesis and incorporation into hemoproteins, heme catabolism and heme transport in maintaining adequate intracellular heme content are discussed. Particular attention is put on the recently described mechanisms of heme trafficking through the plasma membrane mediated by specific heme importers and exporters. Finally, the involvement of genes orchestrating heme metabolism in several pathological conditions is illustrated and new therapeutic approaches aimed at controlling heme metabolism are discussed.
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Affiliation(s)
- Deborah Chiabrando
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin Turin, Italy
| | - Francesca Vinchi
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin Turin, Italy
| | - Veronica Fiorito
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin Turin, Italy
| | - Sonia Mercurio
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin Turin, Italy
| | - Emanuela Tolosano
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin Turin, Italy
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Heme oxygenase-1 derived carbon monoxide permits maturation of myeloid cells. Cell Death Dis 2014; 5:e1139. [PMID: 24651442 PMCID: PMC3973235 DOI: 10.1038/cddis.2014.97] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Revised: 02/11/2014] [Accepted: 02/12/2014] [Indexed: 02/05/2023]
Abstract
Critical functions of the immune system are maintained by the ability of myeloid progenitors to differentiate and mature into macrophages. We hypothesized that the cytoprotective gas molecule carbon monoxide (CO), generated endogenously by heme oxygenases (HO), promotes differentiation of progenitors into functional macrophages. Deletion of HO-1, specifically in the myeloid lineage (Lyz-Cre:Hmox1flfl), attenuated the ability of myeloid progenitors to differentiate toward macrophages and decreased the expression of macrophage markers, CD14 and macrophage colony-stimulating factor receptor (MCSFR). We showed that HO-1 and CO induced CD14 expression and efficiently increased expansion and differentiation of myeloid cells into macrophages. Further, CO sensitized myeloid cells to treatment with MCSF at low doses by increasing MCSFR expression, mediated partially through a PI3K-Akt-dependent mechanism. Exposure of mice to CO in a model of marginal bone marrow transplantation significantly improved donor myeloid cell engraftment efficiency, expansion and differentiation, which corresponded to increased serum levels of GM-CSF, IL-1α and MCP-1. Collectively, we conclude that HO-1 and CO in part are critical for myeloid cell differentiation. CO may prove to be a novel therapeutic agent to improve functional recovery of bone marrow cells in patients undergoing irradiation, chemotherapy and/or bone marrow transplantation.
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Anyanwu AC, Bentley JK, Popova AP, Malas O, Alghanem H, Goldsmith AM, Hershenson MB, Pinsky DJ. Suppression of inflammatory cell trafficking and alveolar simplification by the heme oxygenase-1 product carbon monoxide. Am J Physiol Lung Cell Mol Physiol 2014; 306:L749-63. [PMID: 24532288 DOI: 10.1152/ajplung.00236.2013] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Bronchopulmonary dysplasia (BPD), a lung disease of prematurely born infants, is characterized in part by arrested development of pulmonary alveolae. We hypothesized that heme oxygenase (HO-1) and its byproduct carbon monoxide (CO), which are thought to be cytoprotective against redox stress, mitigate lung injury and alveolar simplification in hyperoxia-exposed neonatal mice, a model of BPD. Three-day-old C57BL/6J mice were exposed to air or hyperoxia (FiO2, 75%) in the presence or absence of inhaled CO (250 ppm for 1 h twice daily) for 21 days. Hyperoxic exposure increased mean linear intercept, a measure of alveolar simplification, whereas CO treatment attenuated hypoalveolarization, yielding a normal-appearing lung. Conversely, HO-1-null mice showed exaggerated hyperoxia-induced hypoalveolarization. CO also inhibited hyperoxia-induced pulmonary accumulation of F4/80+, CD11c+, and CD11b+ monocytes and Gr-1+ neutrophils. Furthermore, CO attenuated lung mRNA and protein expression of proinflammatory cytokines, including the monocyte chemoattractant CCL2 in vivo, and decreased hyperoxia-induced type I alveolar epithelial cell CCL2 production in vitro. Hyperoxia-exposed CCL2-null mice, like CO-treated mice, showed attenuated alveolar simplification and lung infiltration of CD11b+ monocytes, consistent with the notion that CO blocks lung epithelial cell cytokine production. We conclude that, in hyperoxia-exposed neonatal mice, inhalation of CO suppresses inflammation and alveolar simplification.
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Affiliation(s)
- Anuli C Anyanwu
- Univ. of Michigan, 7220 C, Medical Science Research Bldg. III, 1150 West Medical Center Dr., Ann Arbor, MI 48109-0644 (e-mail address:
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Aung KH, Win-Shwe TT, Kanaya M, Takano H, Tsukahara S. Involvement of hemeoxygenase-1 in di(2-ethylhexyl) phthalate (DEHP)-induced apoptosis of Neuro-2a cells. J Toxicol Sci 2014; 39:217-29. [DOI: 10.2131/jts.39.217] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Affiliation(s)
- Kyaw Htet Aung
- Division of Life Science, Graduate School of Science and Engineering, Saitama University
| | - Tin-Tin Win-Shwe
- Center for Environmental Health Sciences, National Institute for Environmental Studies
| | - Moeko Kanaya
- Division of Life Science, Graduate School of Science and Engineering, Saitama University
| | - Hirohisa Takano
- Department of Environmental Engineering, Graduate School of Engineering, Kyoto University
| | - Shinji Tsukahara
- Division of Life Science, Graduate School of Science and Engineering, Saitama University
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Therapeutic applications of carbon monoxide. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2013; 2013:360815. [PMID: 24648866 PMCID: PMC3932177 DOI: 10.1155/2013/360815] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Revised: 10/21/2013] [Accepted: 11/05/2013] [Indexed: 11/17/2022]
Abstract
Heme oxygenase-1 (HO-1) is a regulated enzyme induced in multiple stress states. Carbon monoxide (CO) is a product of HO catalysis of heme. In many circumstances, CO appears to functionally replace HO-1, and CO is known to have endogenous anti-inflammatory, anti-apoptotic, and antiproliferative effects. CO is well studied in anoxia-reoxygenation and ischemia-reperfusion models and has advanced to phase II trials for treatment of several clinical entities. In alternative injury models, laboratories have used sepsis, acute lung injury, and systemic inflammatory challenges to assess the ability of CO to rescue cells, organs, and organisms. Hopefully, the research supporting the protective effects of CO in animal models will translate into therapeutic benefits for patients. Preclinical studies of CO are now moving towards more complex damage models that reflect polymicrobial sepsis or two-step injuries, such as sepsis complicated by acute respiratory distress syndrome. Furthermore, co-treatment and post-treatment with CO are being explored in which the insult occurs before there is an opportunity to intervene therapeutically. The aim of this review is to discuss the potential therapeutic implications of CO with a focus on lung injury and sepsis-related models.
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Li W, Qiu X, Wang J, Li H, Sun Y, Zhang F, Jin H, Fu J, Xia Z. The therapeutic efficacy of glutamine for rats with smoking inhalation injury. Int Immunopharmacol 2013; 16:248-53. [PMID: 23499678 DOI: 10.1016/j.intimp.2013.02.022] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2012] [Revised: 02/27/2013] [Accepted: 02/27/2013] [Indexed: 11/26/2022]
Abstract
Smoke inhalation injury represents a major cause of mortality in burn patients and is associated with a high incidence of pulmonary complications. Glutamine (GLN) is considered a conditionally essential amino acid during critical illness and injury. However, whether GLN could attenuate lung injury caused by smoke inhalation is still unknown. The purpose of this study is to investigate whether GLN has a beneficial effect on smoke inhalation induced lung injury. In our present work, rats were equally randomized into three groups: Sham group (ambient air inhalation plus GLN treatment), Control group (smoke inhalation plus physiological saline) and GLN treatment group (smoke inhalation injury plus GLN treatment). At sampling, bronchoalveolar lavage fluid was performed to determine total protein concentration and pro-inflammatory cytokine levels. Lung tissues were collected for wet/dry ratio, histopathology, hydroxyproline and Western blotting measurement. Our results exhibited that GLN attenuated the lung histopathological alterations, improved pulmonary oxygenation, and mitigated pulmonary edema. At 28days post-injury, GLN mitigated smoke inhalation-induced excessive collagen deposition as evidence by Masson-Goldner trichrome staining and hydroxyproline content. GLN mitigated smoke inhalation-induced lung inflammatory response, and further prevented the activity of NF-kappa-B. More importantly, results from Western blotting and Immunohistochemistry exhibited that GLN enhanced the expression of HSF-1, HSP-70 and HO-1 in lung tissues. Our data demonstrated that GLN protected rats against smoke inhalation-induced lung injury and its protective mechanism seems to involve in inhibition inflammatory response and enhancing HSP expression.
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Affiliation(s)
- Wuquan Li
- Burn Center, Changhai Hospital, Second Military Medical University, Shanghai, China
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Yukitake H, Kimura H, Tajima Y, Sato Y, Suzuki H, Kajino M, Tanida S, Takizawa M. BTZO-2, an antioxidant response element-activator, provides protection against lethal endotoxic shock in mice. Eur J Pharmacol 2013; 700:80-5. [PMID: 23276667 DOI: 10.1016/j.ejphar.2012.12.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Revised: 12/18/2012] [Accepted: 12/19/2012] [Indexed: 10/27/2022]
Abstract
We recently reported a unique antioxidant response element (ARE)-activator, BTZO-1, which induced expression of cytoprotective proteins such as heme oxygenase-1 (HO-1) and suppressed oxidative stress-induced cardiomyocyte apoptosis via binding to macrophage migration inhibitory factor (MIF). HO-1 induction and apoptosis inhibition have been reported to improve the outcomes following experimental sepsis by protecting the organs. Therefore, we investigated the potential of BTZO-2, an active BTZO-1 derivative, as a drug for sepsis. BTZO-2 significantly protected mice from the endotoxic shock induced by 5mg/kg lipopolysaccharide (LPS); survival rates increased from 42% to 100%. In contrast, BTZO-2 did not provide significant protection to mice from the shock induced by 10 μg/kg LPS together with d-galactosamine (d-GalN, hepatocyte-specific transcription inhibitor) (LPS/d-GalN). Hepatic HO-1 protein was up-regulated by BTZO-2 in mice injected with 5mg/kg LPS, but not in those injected with 10 μg/kg LPS/d-GalN. Interestingly, BTZO-2 showed little or no effect on LPS-induced up-regulation of plasma cytokine levels in mice. Thus, the organ protection mediated by HO-1 may have a pivotal role in the pharmacological effect of BTZO-2. These results suggest that BTZO-2 is a promising compound for a novel drug for sepsis.
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Affiliation(s)
- Hiroshi Yukitake
- Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
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Wegiel B, Hanto DW, Otterbein LE. The social network of carbon monoxide in medicine. Trends Mol Med 2012; 19:3-11. [PMID: 23140858 DOI: 10.1016/j.molmed.2012.10.001] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Accepted: 10/01/2012] [Indexed: 12/22/2022]
Abstract
Networking between cells is critical for proper functioning of the cellular milieu and is mediated by cascades of highly regulated and overlapping signaling molecules. The enzyme heme oxygenase-1 (HO-1) generates three separate signaling molecules through the catalysis of heme - carbon monoxide (CO), biliverdin, and iron - each of which acts via distinct molecular targets to influence cell function, both proximally and distally. This review focuses on state-of-the art developments and insights into the impact of HO-1 and CO on the innate immune response, the effects of which are responsible for an ensemble of functions that help regulate complex immunological responses to bacterial sepsis and ischemia/reperfusion injury. HO-1 exemplifies an evolutionarily conserved system necessary for the cellular milieu to adapt appropriately, function properly, and ensure survival of the organism.
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Affiliation(s)
- Barbara Wegiel
- Transplant Institute, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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Larsen R, Gouveia Z, Soares MP, Gozzelino R. Heme cytotoxicity and the pathogenesis of immune-mediated inflammatory diseases. Front Pharmacol 2012; 3:77. [PMID: 22586395 PMCID: PMC3343703 DOI: 10.3389/fphar.2012.00077] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Accepted: 04/11/2012] [Indexed: 01/01/2023] Open
Abstract
Heme, iron (Fe) protoporphyrin IX, functions as a prosthetic group in a range of hemoproteins essential to support life under aerobic conditions. The Fe contained within the prosthetic heme groups of these hemoproteins can catalyze the production of reactive oxygen species. Presumably for this reason, heme must be sequestered within those hemoproteins, thereby shielding the reactivity of its Fe-heme. However, under pathologic conditions associated with oxidative stress, some hemoproteins can release their prosthetic heme groups. While this heme is not necessarily damaging per se, it becomes highly cytotoxic in the presence of a range of inflammatory mediators such as tumor necrosis factor. This can lead to tissue damage and, as such, exacerbate the pathologic outcome of several immune-mediated inflammatory conditions. Presumably, targeting “free heme” may be used as a therapeutic intervention against these diseases.
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Ohara Y, Ohara T, Ohrui T, Morikawa T, Asamura T, Sasaki H, Arai H. Exhaled carbon monoxide levels in preschool-age children with episodic asthma. Pediatr Int 2012; 54:227-32. [PMID: 22115496 DOI: 10.1111/j.1442-200x.2011.03515.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND The concentration of exhaled carbon monoxide (eCO) in young children with stable asthma and during acute asthma attack is not known. METHODS A sampling bag was developed to collect the exhaled air of preschool children. A total of 257 preschool-age children (≥ 3 years and ≤ 6 years old) were studied; 111 had a diagnosis of asthma (43 suffering a mild asthma attack and 68 without active asthmatic symptom), 99 had upper respiratory infection (URI) and 47 were healthy. RESULTS In preschool-age children, eCO levels of those with asthma attacks (mean ± SE, 2.7 ± 0.3 p.p.m., n= 43) were significantly higher than those of subjects with asymptomatic asthma (0.5 ± 0.1 p.p.m., P < 0.05), URI (0.8 ± 0.1 p.p.m., P < 0.05) and healthy children (0.4 ± 0.1 p.p.m., P < 0.05). A multivariate linear regression model showed that eCO was higher in children with asthma attacks independent of age and gender. In 33 asthmatic children followed before and after treatment, eCO levels during asthma attacks significantly decreased after inhalation therapy with a combination of salbutamol and sodium cromoglycate (before therapy, 2.9 ± 0.4 p.p.m.; after therapy, 0.6 ± 0.1 p.p.m., P < 0.0001). CONCLUSIONS The measurement of eCO using a novel collecting system is useful in the recognition of asthma in preschool children.
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Chung SW, Kwon MY, Kang YH, Chung HT, Lee SJ, Kim HP, Perrella MA. Transforming growth factor-β1 suppression of endotoxin-induced heme oxygenase-1 in macrophages involves activation of Smad2 and downregulation of Ets-2. J Cell Physiol 2012; 227:351-60. [PMID: 21437904 PMCID: PMC3132305 DOI: 10.1002/jcp.22741] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Heme oxygenase (HO)-1 is a cytoprotective molecule that is induced during the response to injury. An increase in HO-1 is an acute indicator of inflammation, and early induction of HO-1 has been suggested to correlate with severity of injury. While a great deal is known about the induction of HO-1 by inflammatory mediators and bacterial lipopolysaccharide (LPS), much less is known about the effects of anti-inflammatory mediators on HO-1 expression. Transforming growth factor (TGF)-β is known to play a critical role in suppressing the immune response, and the TGF-β1 isoform is expressed in inflammatory cells. Thus, we wanted to investigate whether TGF-β1 could inhibit the expression of HO-1 during exposure to an inflammatory stimulus in macrophages. Here we demonstrate that TGF-β1 is able to downregulate LPS-induced HO-1 in mouse macrophages, and this reduction in HO-1 occurred through signaling of TGF-β1 via its type I receptor, and activation of Smad2. This TGF-β1 response is dependent on an intact Ets-binding site (EBS) located 93 base pairs upstream from the mouse HO-1 transcription start site. This EBS is known to be important for Ets-2 transactivation of HO-1 by LPS stimulation, and we show that TGF-β1 is able to suppress LPS-induced Ets-2 mRNA and protein levels in macrophages. Moreover, silencing of Smad2 is able to prevent the suppression of both HO-1 and Ets-2 by TGF-β1 during exposure to LPS. These data suggest that the return of HO-1 to basal levels during the resolution of an inflammatory response may involve its downregulation by anti-inflammatory mediators.
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Affiliation(s)
- Su Wol Chung
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
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Kawano K, Kusunoki T, Ono N, Yao T, Saito T, Yokoi H, Ikeda K. Heme oxygenase-1 expression in chronic rhinosinusitis with eosinophilic infiltration. Auris Nasus Larynx 2011; 39:387-92. [PMID: 22078849 DOI: 10.1016/j.anl.2011.10.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2009] [Revised: 09/28/2011] [Accepted: 10/02/2011] [Indexed: 10/15/2022]
Abstract
OBJECTIVES Chronic rhinosinusitis (CRS) with eosinophilic infiltration is a type of intractable rhinosinusitis often associated with asthma. The oxidants are well known to induce aggravate asthma. Heme oxygenase-1 (HO-1), a cytoprotective enzyme against oxidant, has been extensively studied in airway diseases. However, no study that observed HO-1 in both epithelial and subepithelial tissues of CRS has been reported. METHODS Part of each specimen derived from the nasal polyps of CRS with and without eosinophilic infiltration was promptly fixed for hematoxylin-eosin staining and immunohistochemical analysis for HO-1 and macrophages. RESULTS We found that the expression of HO-1 in the epithelial layers of CRS without eosinophilic infiltration was significantly enhanced as compared with that of CRS with eosinophilic infiltration. On the other hand, the number of macrophages with HO-1 positive reactions was significantly greater in CRS with eosinophilic infiltration compared with CRS without eosinophilic infiltration. CONCLUSIONS Our study suggests that both a reduction of HO-1 expression in epithelial cells and an increase of infiltration of macrophages positive for HO-1 are related to the epithelial damage of CRS with eosinophilic infiltration.
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Affiliation(s)
- Kenji Kawano
- Department of Otorhinolaryngology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
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Gao M, Singh A, Macri K, Reynolds C, Singhal V, Biswal S, Spannhake EW. Antioxidant components of naturally-occurring oils exhibit marked anti-inflammatory activity in epithelial cells of the human upper respiratory system. Respir Res 2011; 12:92. [PMID: 21752292 PMCID: PMC3154159 DOI: 10.1186/1465-9921-12-92] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2011] [Accepted: 07/13/2011] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND The upper respiratory tract functions to protect lower respiratory structures from chemical and biological agents in inspired air. Cellular oxidative stress leading to acute and chronic inflammation contributes to the resultant pathology in many of these exposures and is typical of allergic disease, chronic sinusitis, pollutant exposure, and bacterial and viral infections. Little is known about the effective means by which topical treatment of the nose can strengthen its antioxidant and anti-inflammatory defenses. The present study was undertaken to determine if naturally-occurring plant oils with reported antioxidant activity can provide mechanisms through which upper respiratory protection might occur. METHODS Controlled exposure of the upper respiratory system to ozone and nasal biopsy were carried out in healthy human subjects to assess mitigation of the ozone-induced inflammatory response and to assess gene expression in the nasal mucosa induced by a mixture of five naturally-occurring antioxidant oils--aloe, coconut, orange, peppermint and vitamin E. Cells of the BEAS-2B and NCI-H23 epithelial cell lines were used to investigate the source and potential intracellular mechanisms of action responsible for oil-induced anti-inflammatory activity. RESULTS Aerosolized pretreatment with the mixed oil preparation significantly attenuated ozone-induced nasal inflammation. Although most oil components may reduce oxidant stress by undergoing reduction, orange oil was demonstrated to have the ability to induce long-lasting gene expression of several antioxidant enzymes linked to Nrf2, including HO-1, NQO1, GCLm and GCLc, and to mitigate the pro-inflammatory signaling of endotoxin in cell culture systems. Nrf2 activation was demonstrated. Treatment with the aerosolized oil preparation increased baseline levels of nasal mucosal HO-1 expression in 9 of 12 subjects. CONCLUSIONS These data indicate that selected oil-based antioxidant preparations can effectively reduce inflammation associated with oxidant stress-related challenge to the nasal mucosa. The potential for some oils to activate intracellular antioxidant pathways may provide a powerful mechanism through which effective and persistent cytoprotection against airborne environmental exposures can be provided in the upper respiratory mucosa.
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Affiliation(s)
- Meixia Gao
- Health Effects Assessment Laboratory, Department of Environmental Health Sciences, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205, USA
| | - Anju Singh
- Health Effects Assessment Laboratory, Department of Environmental Health Sciences, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205, USA
| | - Kristin Macri
- Health Effects Assessment Laboratory, Department of Environmental Health Sciences, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205, USA
| | - Curt Reynolds
- Health Effects Assessment Laboratory, Department of Environmental Health Sciences, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205, USA
| | - Vandana Singhal
- Health Effects Assessment Laboratory, Department of Environmental Health Sciences, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205, USA
| | - Shyam Biswal
- Health Effects Assessment Laboratory, Department of Environmental Health Sciences, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205, USA
| | - Ernst W Spannhake
- Health Effects Assessment Laboratory, Department of Environmental Health Sciences, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205, USA
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Ramos EMC, De Toledo AC, Xavier RF, Fosco LC, Vieira RP, Ramos D, Jardim JR. Reversibility of impaired nasal mucociliary clearance in smokers following a smoking cessation programme. Respirology 2011; 16:849-855. [PMID: 21545372 DOI: 10.1111/j.1440-1843.2011.01985.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND AND OBJECTIVE Smoking cessation (SC) is recognized as reducing tobacco-associated mortality and morbidity. The effect of SC on nasal mucociliary clearance (MC) in smokers was evaluated during a 180-day period. METHODS Thirty-three current smokers enrolled in a SC intervention programme were evaluated after they had stopped smoking. Smoking history, Fagerström's test, lung function, exhaled carbon monoxide (eCO), carboxyhaemoglobin (COHb) and nasal MC as assessed by the saccharin transit time (STT) test were evaluated. All parameters were also measured at baseline in 33 matched non-smokers. RESULTS Smokers (mean age 49 ± 12 years, mean pack-year index 44 ± 25) were enrolled in a SC intervention and 27% (n = 9) abstained for 180 days, 30% (n = 11) for 120 days, 49.5% (n = 15) for 90 days or 60 days, 62.7% (n = 19) for 30 days and 75.9% (n = 23) for 15 days. A moderate degree of nicotine dependence, higher education levels and less use of bupropion were associated with the capacity to stop smoking (P < 0.05). The STT was prolonged in smokers compared with non-smokers (P = 0.002) and dysfunction of MC was present at baseline both in smokers who had abstained and those who had not abstained for 180 days. eCO and COHb were also significantly increased in smokers compared with non-smokers. STT values decreased to within the normal range on day 15 after SC (P < 0.01), and remained in the normal range until the end of the study period. Similarly, eCO values were reduced from the seventh day after SC. CONCLUSIONS A SC programme contributed to improvement in MC among smokers from the 15th day after cessation of smoking, and these beneficial effects persisted for 180 days.
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Affiliation(s)
- Ercy Mara Cipulo Ramos
- Department of Physiotherapy, São Paulo State University (UNESP), Presidente Prudente, São Paulo, Brazil.
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Wu M, Huang J, Xu S, Ling T, Xie Y, Shen W. Haem oxygenase delays programmed cell death in wheat aleurone layers by modulation of hydrogen peroxide metabolism. JOURNAL OF EXPERIMENTAL BOTANY 2011; 62:235-48. [PMID: 20797999 PMCID: PMC2993913 DOI: 10.1093/jxb/erq261] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2010] [Revised: 07/31/2010] [Accepted: 08/03/2010] [Indexed: 05/19/2023]
Abstract
Haem oxygenase-1 (HO-1) confers protection against a variety of oxidant-induced cell and tissue injury in animals and plants. In this report, it is confirmed that programmed cell death (PCD) in wheat aleurone layers is stimulated by GA and prevented by ABA. Meanwhile, HO activity and HO-1 protein expression exhibited lower levels in GA-treated layers, whereas the hydrogen peroxide (H(2)O(2)) content was apparently increased. The pharmacology approach illustrated that scavenging or accumulating H(2)O(2) either delayed or accelerated GA-induced PCD. Furthermore, pretreatment with the HO-1 specific inhibitor, zinc protoporphyrin IX (ZnPPIX), before exposure to GA, not only decreased HO activity but also accelerated GA-induced PCD significantly. The application of the HO-1 inducer, haematin, and the enzymatic reaction product of HO, carbon monoxide (CO) aqueous solution, both of which brought about a noticeable induction of HO expression, substantially prevented GA-induced PCD. These effects were reversed when ZnPPIX was added, suggesting that HO in vivo played a role in delaying PCD. Meanwhile, catalase (CAT) and ascorbate peroxidase (APX) activities or transcripts were enhanced by haematin, CO, or bilirubin (BR), the catalytic by-product of HO. This enhancement resulted in a decrease in H(2)O(2) production and a delay in PCD. In addition, the antioxidants butylated hydroxytoluene (BHT), dithiothreitol (DTT), and ascorbic acid (AsA) were able not only to delay PCD but also to mimic the effects of haematin and CO on HO up-regulation. Overall, the above results suggested that up-regulation of HO expression delays PCD through the down-regulation of H(2)O(2) production.
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Affiliation(s)
| | | | | | | | | | - Wenbiao Shen
- College of Life Sciences, Co. Laboratory of Nanjing Agricultural University and Carl Zeiss Far East, Jiangsu Province, Nanjing Agricultural University, Nanjing 210095, PR China
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Mitchell LA, Channell MM, Royer CM, Ryter SW, Choi AMK, McDonald JD. Evaluation of inhaled carbon monoxide as an anti-inflammatory therapy in a nonhuman primate model of lung inflammation. Am J Physiol Lung Cell Mol Physiol 2010; 299:L891-7. [PMID: 20729385 DOI: 10.1152/ajplung.00366.2009] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Carbon monoxide (CO) confers anti-inflammatory protection in rodent models of lung injury when applied at low concentration. Translation of these findings to clinical therapies for pulmonary inflammation requires validation in higher mammals. We have evaluated the efficacy of inhaled CO in reducing LPS-induced lung inflammation in cynomolgus macaques. LPS inhalation resulted in profound neutrophil influx and moderate increases in airway lymphocytes, which returned to baseline levels within 2 wk following exposure. CO exposure (500 ppm, 6 h) following LPS inhalation decreased TNF-α release in bronchoalveolar lavage fluid but did not affect IL-6 or IL-8 release. Lower concentrations of CO (250 ppm, 6 h) did not reduce pulmonary neutrophilia. Pretreatment with budesonide, a currently used inhaled corticosteroid, decreased LPS-induced expression of TNF-α, IL-6, and IL-8, and reduced LPS-induced neutrophilia by ∼84%. In comparison, CO inhalation (500 ppm, for 6 h after LPS exposure) reduced neutrophilia by ∼67%. Thus, inhaled CO was nearly as efficacious as pretreatment with an inhaled corticosteroid at reducing airway neutrophil influx in cynomolgus macaques. However, the therapeutic efficacy of CO required relatively high doses (500 ppm) that resulted in high carboxyhemoglobin (COHb) levels (>30%). Lower CO concentrations (250 ppm), associated with anti-inflammatory protection in rodents, were ineffective in cynomolgus macaques and also yielded relatively high COHb levels. These studies highlight the complexity of interspecies variation of dose-response relationships of CO to COHb levels and to the anti-inflammatory functions of CO. The findings of this study warrant further investigations for assessing the therapeutic application of CO in nonhuman primate models of tissue injury and in human diseases. The study also suggests that akin to many new therapies in human diseases, the translation of CO therapy to human disease will require additional extensive and rigorous proof-of-concept studies in humans in the future.
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Affiliation(s)
- Leah A Mitchell
- Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA
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Xia ZY, Gao J, Ancharaz AK, Liu KX, Xia Z, Luo T. Ischaemic post-conditioning protects lung from ischaemia-reperfusion injury by up-regulation of haeme oxygenase-1. Injury 2010; 41:510-6. [PMID: 19524915 DOI: 10.1016/j.injury.2009.03.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2009] [Accepted: 03/03/2009] [Indexed: 02/02/2023]
Abstract
OBJECTIVE The emergence of ischaemic post-conditioning (IPO) provides a potential method for experimentally and clinically attenuating various types of organ injuries. There has been little work, however, examining its effects in the setting of lung ischaemia reperfusion (IR). The stress protein, haeme oxygenase-1 (HO-1), has been found to exert a potent, protective role in a variety of lung injury models. In this study, we hypothesised that the induction of HO-1 by IPO plays a protective role against the deleterious effects of IR in the lung. METHODS Anaesthetised and mechanically ventilated adult Sprague-Dawley rats were randomly assigned to one of the following groups (n=8 each): the sham-operated control group, the IR group (40 min of left-lung ischaemia and 105 min of reperfusion), the IPO group (three successive cycles of 30-s reperfusion per 30-s occlusion before restoring full perfusion) and the ZnPPIX+IPO group (ZnPPIX, an inhibitor of HO-1, was injected intra-peritoneally at 20 mg kg(-1) 24h prior to the experiment and the rest of the procedures were similar to that of the IPO group). Lung injury was assessed by arterial blood gas analysis, wet-to-dry lung weight ratio and tissue histological changes. The extent of lipid peroxidation was determined by measuring plasma levels of malondialdehyde (MDA) production. Expression of HO-1 was determined by immunohistochemistry. RESULTS Lung IR resulted in a significant reduction of PaO(2) (data in IR, P<0.05 vs. data in sham) and increase of lung wet-to-dry weight ratio, accompanied with increased MDA production and severe lung pathological morphological changes as well as a compensatory increase in HO-1 protein expression, as compared with sham (All P<0.05). IPO markedly attenuated all the above pathological changes seen in the IR group and further increased HO-1 expression. Treatment with ZnPPIX abolished all the protective effects of post-conditioning. CONCLUSION It may be concluded that IPO protects IR-induced lung injury via induction of HO-1.
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Affiliation(s)
- Zhong-yuan Xia
- Anesthesiology Research Laboratory, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, PR China
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Guo Y, Duan W, Li Z, Huang J, Yin Y, Zhang K, Wang Q, Zhang Z, Li C. Decreased GLT-1 and increased SOD1 and HO-1 expression in astrocytes contribute to lumbar spinal cord vulnerability of SOD1-G93A transgenic mice. FEBS Lett 2010; 584:1615-22. [PMID: 20303959 DOI: 10.1016/j.febslet.2010.03.025] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2010] [Revised: 03/04/2010] [Accepted: 03/15/2010] [Indexed: 01/30/2023]
Abstract
The SOD1-G93A transgenic mouse is a widely used ALS model, but the death of lower motor neurons is the hallmark. Here, we show that the SOD1-G93A transgene and HO-1 are preferentially over-expressed in the lumbar spinal cord, particularly in the activated astrocytes of the transgenic mice. We also show down-regulation of GLT-1 in spite of the proliferating astrocytes. However, GLT-1, SOD1-G93A transgene and HO-1 expression were not obviously changed in the motor cortex. Our data link spinal cord vulnerability to relatively decreased expression of GLT-1, and high expression of the transgene and HO-1 in astrocytes in SOD1-G93A transgenic mice.
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Affiliation(s)
- Yansu Guo
- Department of Neurology, The Second Hospital of Hebei Medical University, Hebei, China
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Schober P, Kalmanowicz M, Schwarte LA, Loer SA. Cardiopulmonary Bypass Increases Endogenous Carbon Monoxide Production. J Cardiothorac Vasc Anesth 2009; 23:802-6. [DOI: 10.1053/j.jvca.2009.03.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2008] [Indexed: 11/11/2022]
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Adler KB, Matalon S. Highlights of the October Issue. Am J Respir Cell Mol Biol 2009. [DOI: 10.1165/rcmb.2009-2010ed] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Pogson ZEK, Antoniak MD, Mckeever TM, Lewis SA, Britton JR, Fogarty AW. Exhaled carbon monoxide in asthmatic adults with bronchial reactivity: a prospective study. J Asthma 2009; 46:665-9. [PMID: 19728202 DOI: 10.1080/02770900902963136] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
HYPOTHESIS We hypothesized that eCO may permit non-invasive assessment of disease activity in adults with asthma and bronchial reactivity. METHODS A total of 209 participants 18 to 65 years of age with a diagnosis of asthma and bronchial reactivity provided data for analysis. The association between eCO and bronchial reactivity, forced expiratory volume in one second (FEV(1)), forced vital capacity (FVC), peak expiratory flow rate measurements (PEFR), asthma symptoms score, and bronchodilator use cross-sectionally and within-subject change in eCO were analyzed in relation to change in these variables over 6 weeks. RESULTS There was no difference in eCO in those who were taking inhaled corticosteroids and those who were not (p = 0.33). There was also no cross-sectional or within-in subject association between eCO and bronchial reactivity, FEV(1), FVC, PEFR, symptoms score, or bronchodilator use. CONCLUSIONS In a population of adults with bronchial reactivity, eCO has no or very limited potential as a biomarker of asthma activity.
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Affiliation(s)
- Zara E K Pogson
- Division of Epidemiology and Public Health, University of Nottingham, City Hospital, Nottingham, United Kingdom.
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Donor HO-1 Expression Inhibits Intimal Hyperplasia in Unmanipulated Graft Recipients: A Potential Role for CD8+ T-Cell Modulation by Carbon Monoxide. Transplantation 2009; 88:653-61. [DOI: 10.1097/tp.0b013e3181b2fd83] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Role of Nrf2-mediated heme oxygenase-1 upregulation in adaptive survival response to nitrosative stress. Arch Pharm Res 2009; 32:1163-76. [PMID: 19727608 DOI: 10.1007/s12272-009-1807-8] [Citation(s) in RCA: 107] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2009] [Revised: 03/16/2009] [Accepted: 06/25/2009] [Indexed: 12/21/2022]
Abstract
Nitrosative stress caused by reactive nitrogen species such as nitric oxide and peroxynitrite overproduced during inflammation leads to cell death and has been implicated in the pathogenesis of many human ailments. However, relatively mild nitrosative stress may fortify cellular defense capacities, rendering cells tolerant or adaptive to ongoing and subsequent cytotoxic challenges, a phenomenon known as 'preconditioning' or 'hormesis'. One of the key components of cellular stress response is heme oxygenase-1 (HO-1), the rate limiting enzyme in the process of degrading potentially toxic free heme into biliverdin, free iron and carbon monoxide. HO-1 is upregulated by a wide array of stimuli and has antioxidant, anti-inflammatory and other cytoprotective functions. This review is intended to provide readers with a welldocumented account of the research done in the area of cellular adaptive survival response against nitrosative stress with special focus on the role of HO-1 upregulation, especially through activation of the transcription factor, Nrf2.
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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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Sheu CC, Zhai R, Wang Z, Gong MN, Tejera P, Chen F, Su L, Thompson BT, Christiani DC. Heme oxygenase-1 microsatellite polymorphism and haplotypes are associated with the development of acute respiratory distress syndrome. Intensive Care Med 2009; 35:1343-51. [PMID: 19526221 PMCID: PMC2758618 DOI: 10.1007/s00134-009-1504-6] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2009] [Accepted: 04/22/2009] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Heme oxygenase-1 (HO-1) acts in cytoprotection against acute lung injury. The polymorphic (GT)n repeat in the HO-1 gene (HMOX1) promoter regulates HMOX1 expression. We investigated the associations of HMOX1 polymorphisms with acute respiratory distress syndrome (ARDS) risk and plasma HO-1 levels. DESIGN Unmatched, nested case-control study. SETTING Academic medical center. PATIENTS Consecutive patients with ARDS risk factors upon ICU admission were prospectively enrolled. Cases were 437 Caucasians who developed ARDS and controls were 1,014 Caucasians who did not. MEASUREMENTS AND RESULTS We genotyped the (GT)n polymorphism and three tagging single nucleotide polymorphisms (tSNPs) in 1,451 patients, and measured the plasma HO-1 levels in 106 ARDS patients. We clustered the (GT)n repeats into: S-allele (<24 repeats), M-allele (24-30 repeats) and L-allele (> or = 31 repeats). We found that longer (GT)n repeats were associated with reduced ARDS risk (Ptrend = 0.004 for both alleles and genotypes), but no individual tSNP was associated with ARDS risk. HMOX1 haplotypes were significantly associated with ARDS risk (global test, P = 0.016), and the haplotype S-TAG was associated with increased ARDS risk (OR, 1.75; 95% CI, 1.15-2.68; P = 0.010). Intermediate-phenotype analysis showed longer (GT)n repeats were associated with higher plasma HO-1 levels (Ptrend = 0.019 for alleles and 0.027 for genotypes). CONCLUSIONS Longer (GT)n repeats in the HMOX1 promoter are associated with higher plasma HO-1 levels and reduced ARDS risk. The common haplotype S-TAG is associated with increased ARDS risk. Our results suggest that HMOX1 variation may modulate ARDS risk through the promoter microsatellite polymorphism.
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Affiliation(s)
- Chau-Chyun Sheu
- Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA
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Tsoyi K, Lee TY, Lee YS, Kim HJ, Seo HG, Lee JH, Chang KC. Heme-oxygenase-1 induction and carbon monoxide-releasing molecule inhibit lipopolysaccharide (LPS)-induced high-mobility group box 1 release in vitro and improve survival of mice in LPS- and cecal ligation and puncture-induced sepsis model in vivo. Mol Pharmacol 2009; 76:173-82. [PMID: 19366789 DOI: 10.1124/mol.109.055137] [Citation(s) in RCA: 157] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
We examined our hypothesis that heme-oxygenase-1 (HO-1)-derived carbon monoxide (CO) inhibits the release of high-mobility group box 1 (HMGB1) in RAW264.7 cells activated with lipopolysaccharide (LPS) in vitro and in LPS- or cecal ligation and puncture (CLP)-induced septic mice in vivo, so that HO-1 induction or CO improves survival of sepsis in rodents. We found that pretreatment with HO-1 inducers (hemin, cobalt protoporphyrin IX) or transfection of HO-1 significantly inhibited HMGB1 release, which was blocked by HO-1 small interfering RNA, in cells activated by LPS. Carbon monoxide-releasing molecule 2 (CORM-2) but not bilirubin or deferoxamine inhibited HMGB1 release in LPS-activated macrophages. Oxyhemoglobin reversed the effect of HO-1 inducers on HMGB1 release. Translocation of HMGB1 from nucleus to cytosol was significantly inhibited by HO-1 inducers, CORM-2, or HO-1 transfection. Neutralizing antibodies to tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, interferon-beta, and N(omega)-nitro-L-arginine methyl ester hydrochloride but not N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398) significantly inhibited HMGB1 release in LPS-activated cells. Production of TNF-alpha, IL-1beta, and IFN-beta was significantly reduced by pretreatment of HO-1 inducers, CORM-2, or HO-1 transfection in LPS-activated cells. Plasma levels of HMGB1 in mice challenged with LPS or CLP were significantly reduced by the administration of HO-1 inducers or CORM-2, which was accompanied by either reduction (pretreatment) or no change (delayed administration) of serum TNF-alpha and IL-1beta levels. Regardless of pretreatment or delayed administration, CORM-2 and hemin rescued mice from lethal endotoxemia and sepsis induced by LPS or CLP. Taken together, we concluded that HO-1-derived CO reduces HMGB1 release in LPS-activated cells and LPS- or CLP-induced animal model of sepsis.
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Affiliation(s)
- Konstantin Tsoyi
- Department of Pharmacology, School of Medicine, Gyeongsang National University, Jinju, Republic of Korea
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