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Rezk-Hanna M, Rossman MJ, Ludwig K, Sakti P, Cheng CW, Brecht ML, Benowitz NL, Seals DR. Electronic hookah (waterpipe) vaping reduces vascular endothelial function: the role of nicotine. Am J Physiol Heart Circ Physiol 2024; 326:H490-H496. [PMID: 38133618 PMCID: PMC11219048 DOI: 10.1152/ajpheart.00710.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/08/2023] [Accepted: 12/19/2023] [Indexed: 12/23/2023]
Abstract
Vaping has risen substantially in recent years, particularly among young adults. Electronic (e-) hookahs are a newer category of vaping devices touted as safer tobacco alternatives. Although e-hookah vaping acutely reduces endothelial function, the role of nicotine and the mechanisms by which it may impair endothelial function remain understudied. In a randomized crossover study, we investigated the acute effects of vaping e-hookah, with and without nicotine, as compared with sham on endothelial function assessed by brachial artery flow-mediated dilation (FMD), among 18 overtly healthy young adults. To determine the role of changes in circulating factors in plasma on endothelial cell function, human umbilical vein endothelial cells (HUVECs) were cultured with participants' plasma, and acetylcholine-stimulated nitric oxide (NO) production and basal reactive oxygen species (ROS) bioactivity were assessed. Plasma nicotine was measured before and after the sessions. E-hookah vaping with nicotine, which acutely increased heart rate (HR) by 8 ± 3 beats/min and mean arterial pressure (MAP) by 7 ± 2 mmHg (means ± SE; P < 0.05), decreased endothelial-dependent FMD by 1.57 ± 0.19%Δ (P = 0.001), indicating impairment in endothelial function. Vaping e-hookah without nicotine, which mildly increased hemodynamics (HR, 2 ± 2 beats/min and MAP 1 ± 1 mmHg; P = ns), did not significantly impair endothelial function. No changes were observed after sham vaping. HUVECs cultured with participants' plasma after versus before e-hookah vaping with nicotine, but not without nicotine or sham vaping, exhibited reductions in endothelial cell NO bioavailability and increases in ROS bioactivity (P < 0.05). Plasma nicotine concentrations increased after vaping e-hookah with nicotine (6.7 ± 1.8 ng/mL; P = 0.002), whereas no changes were observed after vaping e-hookah without nicotine or sham (P = ns). Acute e-hookah vaping induces endothelial dysfunction by impairing NO bioavailability associated with increased ROS production, and these effects are attributable to nicotine, not to nonnicotine constituents, present in the flavored e-liquid.NEW & NOTEWORTHY Despite safety claims heavily advertised by the hookah tobacco industry, acute e-hookah vaping induces in vivo endothelial dysfunction by impairing ex vivo NO bioavailability associated with increased ROS production. These effects are attributable to nicotine, not to nonnicotine constituents, present in the flavored e-liquid.
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Affiliation(s)
- Mary Rezk-Hanna
- School of Nursing, University of California, Los Angeles, Los Angeles, California, United States
| | - Matthew J Rossman
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
| | - Katelyn Ludwig
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
| | - Primadya Sakti
- School of Nursing, University of California, Los Angeles, Los Angeles, California, United States
| | - Chiao-Wei Cheng
- School of Nursing, University of California, Los Angeles, Los Angeles, California, United States
| | - Mary-Lynn Brecht
- School of Nursing, University of California, Los Angeles, Los Angeles, California, United States
| | - Neal L Benowitz
- Clinical Pharmacology Research Program, Division of Cardiology, Department of Medicine, University of California, San Francisco, San Francisco, California, United States
| | - Douglas R Seals
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
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Yan Q, Chen J, Ren X, Song Y, Xu J, Xuan S, Jiang X, Kuang Z, Tang Z. Vagus Nerve Stimulation Relives Irritable Bowel Syndrome and the Associated Depression via α7nAChR-mediated Anti-inflammatory Pathway. Neuroscience 2023; 530:26-37. [PMID: 37625687 DOI: 10.1016/j.neuroscience.2023.08.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 08/10/2023] [Accepted: 08/18/2023] [Indexed: 08/27/2023]
Abstract
OBJECTIVES The present study is designed to investigate the role of vagus nerve in the treatments of irritable bowel syndrome (IBS) and the associated central nervous system disorders. METHODS An IBS animal model was established by giving acetic acid and chronic-acute stress (AA-CAS) treatment in adult male Wistar rats. Subdiaphragmatic vagotomy (SDV) and vagus nerve stimulation (VNS) were performed to intervene the excitability of vagus nerve. Permeability of blood brain barrier (BBB) was measured and agonist and antagonist of α7 nicotinic acetylcholine receptor (α7nAChR) were used to explore the relevant mechanisms. RESULTS AA-CAS treatment resulted in abnormal fecal output, increased visceral sensitivity, depressive-like behaviors, and overexpression of inflammatory mediators, all of which were reversed by VNS treatment. The effects of VNS could also be observed when α7nAChR agonist was applied. Whereas α7nAChR antagonist (methyllycaconitine, MLA) reversed VNS's effects. Interestingly, VNS also reduced the increased permeability of blood brain barrier (BBB) following AA-CAS treatment in IBS rats. SDV treatment only show temporary efficacy on AA-CAS-induced symptoms and had no effect on the permeability of BBB. CONCLUSION The intestinal abnormalities and depressive symptoms in IBS rats can be improved by VNS treatment. This positive effect of VNS was achieved through α7nAChR-mediated inflammatory pathway and may also be associated with the decreased of BBB permeability.
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Affiliation(s)
- Qizhi Yan
- Shaoxing People's Hospital, Shaoxing 312000, China
| | - Jiawei Chen
- Shaoxing People's Hospital, Shaoxing 312000, China
| | - Xiuying Ren
- Shaoxing People's Hospital, Shaoxing 312000, China
| | - Yibo Song
- Shaoxing People's Hospital, Shaoxing 312000, China
| | - Jian Xu
- Shaoxing People's Hospital, Shaoxing 312000, China
| | - Shaoyan Xuan
- Shaoxing People's Hospital, Shaoxing 312000, China
| | - Xi Jiang
- Zhejiang University Mingzhou Hospital, Ningbo 315000, China
| | - Zhijian Kuang
- Zhejiang University Mingzhou Hospital, Ningbo 315000, China
| | - Zhihua Tang
- Shaoxing People's Hospital, Shaoxing 312000, China.
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Mahmoudzadeh L, Abtahi Froushani SM, Ajami M, Mahmoudzadeh M. Effect of Nicotine on Immune System Function. Adv Pharm Bull 2023; 13:69-78. [PMID: 36721811 PMCID: PMC9871277 DOI: 10.34172/apb.2023.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 09/30/2021] [Accepted: 12/31/2021] [Indexed: 02/03/2023] Open
Abstract
As a parasympathetic alkaloid and the main substance in cigarette smoke, nicotine modulates the immune system, inhibits innate and acquired immunity and is used in treating many autoimmune diseases. It often stimulates the α7 receptor and causes an anti-inflammatory state in the body. This study is designed to evaluate the role of nicotine treatment on immune system. The results showed that nicotine affects many cells in immune system, alters the downstream intracellular mechanisms and changes lymphocytes polarization. This substance alters TLRs and STATs gene expression and thus changes in the innate immune system. All these events inhibit the secretion of pro-inflammatory cytokines and chemokines which increase angiogenesis and metastasis and exacerbates tumors due to increasing survival and cell growth. Nicotine can aggravate tumors in cancer patients, with many positive effects observed in the treating autoimmune disease, Nicotine treatment function in different conditions depends on factors such as concentration, how it is employed, treatment duration and other conditions such as body conditions affecting the immune system, hence, further studies and review of all conditions are required.
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Affiliation(s)
- leila Mahmoudzadeh
- Division of Immunology, Department of Microbiology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | | | - Marjan Ajami
- Department of Food and Nutrition Policy and Planning Research, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Mahmoudzadeh
- Nutrition Research Center and Department of Food Science and Technology, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Corresponding Author: Maryam Mahmoudzadeh, Fax:+98 41 33363231,
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Zhang W, Lin H, Zou M, Yuan Q, Huang Z, Pan X, Zhang W. Nicotine in Inflammatory Diseases: Anti-Inflammatory and Pro-Inflammatory Effects. Front Immunol 2022; 13:826889. [PMID: 35251010 PMCID: PMC8895249 DOI: 10.3389/fimmu.2022.826889] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 01/21/2022] [Indexed: 11/13/2022] Open
Abstract
As an anti-inflammatory alkaloid, nicotine plays dual roles in treating diseases. Here we reviewed the anti-inflammatory and pro-inflammatory effects of nicotine on inflammatory diseases, including inflammatory bowel disease, arthritis, multiple sclerosis, sepsis, endotoxemia, myocarditis, oral/skin/muscle inflammation, etc., mainly concerning the administration methods, different models, therapeutic concentration and duration, and relevant organs and tissues. According to the data analysis from recent studies in the past 20 years, nicotine exerts much more anti-inflammatory effects than pro-inflammatory ones, especially in ulcerative colitis, arthritis, sepsis, and endotoxemia. On the other hand, in oral inflammation, nicotine promotes and aggravates some diseases such as periodontitis and gingivitis, especially when there are harmful microorganisms in the oral cavity. We also carefully analyzed the nicotine dosage to determine its safe and effective range. Furthermore, we summarized the molecular mechanism of nicotine in these inflammatory diseases through regulating immune cells, immune factors, and the vagus and acetylcholinergic anti-inflammatory pathways. By balancing the “beneficial” and “harmful” effects of nicotine, it is meaningful to explore the effective medical value of nicotine and open up new horizons for remedying acute and chronic inflammation in humans.
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Affiliation(s)
- Wenji Zhang
- Guangdong Provincial Engineering & Technology Research Center for Tobacco Breeding and Comprehensive Utilization, Key Laboratory of Crop Genetic Improvement of Guangdong Province, Crops Research Institute, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Hui Lin
- Department of Radiation Oncology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Mingmin Zou
- Guangdong Provincial Engineering & Technology Research Center for Tobacco Breeding and Comprehensive Utilization, Key Laboratory of Crop Genetic Improvement of Guangdong Province, Crops Research Institute, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Qinghua Yuan
- Guangdong Provincial Engineering & Technology Research Center for Tobacco Breeding and Comprehensive Utilization, Key Laboratory of Crop Genetic Improvement of Guangdong Province, Crops Research Institute, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Zhenrui Huang
- Guangdong Provincial Engineering & Technology Research Center for Tobacco Breeding and Comprehensive Utilization, Key Laboratory of Crop Genetic Improvement of Guangdong Province, Crops Research Institute, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Xiaoying Pan
- Guangdong Provincial Engineering & Technology Research Center for Tobacco Breeding and Comprehensive Utilization, Key Laboratory of Crop Genetic Improvement of Guangdong Province, Crops Research Institute, Guangdong Academy of Agricultural Sciences, Guangzhou, China
- *Correspondence: Xiaoying Pan, ; Wenjuan Zhang,
| | - Wenjuan Zhang
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, China
- *Correspondence: Xiaoying Pan, ; Wenjuan Zhang,
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Sharma A, Lee J, Fonseca AG, Moshensky A, Kothari T, Sayed IM, Ibeawuchi SR, Pranadinata RF, Ear J, Sahoo D, Crotty-Alexander LE, Ghosh P, Das S. E-cigarettes compromise the gut barrier and trigger inflammation. iScience 2021. [PMID: 33537654 DOI: 10.1101/2020.07.29.227348] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/11/2023] Open
Abstract
E-cigarette usage continues to rise, yet the safety of e-cigarette aerosols is questioned. Using murine models of acute and chronic e-cigarette aerosol inhalation, murine colon transcriptomics, and murine and human gut-derived organoids in co-culture models, we assessed the effects of e-cigarette use on the gut barrier. Histologic and transcriptome analyses revealed that chronic, but not acute, nicotine-free e-cigarette use increased inflammation and reduced expression of tight junction (TJ) markers. Exposure of murine and human enteroid-derived monolayers (EDMs) to nicotine-free e-cigarette aerosols alone or in co-culture with bacteria also causes barrier disruption, downregulation of TJ protein, and enhanced inflammation in response to infection. These data highlight the harmful effects of "non-nicotine" component of e-cigarettes on the gut barrier. Considering the importance of an intact gut barrier for host fitness and the impact of gut mucosal inflammation on a multitude of chronic diseases, these findings are broadly relevant to both medicine and public health.
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Affiliation(s)
- Aditi Sharma
- Department of Pathology, University of California, San Diego, CA 92093, USA
| | - Jasper Lee
- Department of Pathology, University of California, San Diego, CA 92093, USA
| | - Ayden G Fonseca
- Department of Cellular and Molecular Medicine, University of California, San Diego, CA 92093, USA
| | - Alex Moshensky
- Department of Medicine, University of California, San Diego, CA 92093, USA
| | - Taha Kothari
- Department of Pathology, University of California, San Diego, CA 92093, USA
| | - Ibrahim M Sayed
- Department of Pathology, University of California, San Diego, CA 92093, USA
| | | | - Rama F Pranadinata
- Department of Cellular and Molecular Medicine, University of California, San Diego, CA 92093, USA
| | - Jason Ear
- Department of Cellular and Molecular Medicine, University of California, San Diego, CA 92093, USA
- Department of Medicine, University of California, San Diego, CA 92093, USA
| | - Debashis Sahoo
- Department of Pediatrics, University of California, San Diego, CA 92093, USA
- Department of Computer Science and Engineering, Jacobs School of Engineering, University of California, San Diego, CA 92093, USA
- Rebecca and John Moore Comprehensive Cancer Center, University of California, San Diego, CA 92093, USA
| | - Laura E Crotty-Alexander
- Department of Medicine, University of California, San Diego, CA 92093, USA
- Veterans Affairs Medical Center, VA San Diego Healthcare System, La Jolla, San Diego, CA 92093, USA
| | - Pradipta Ghosh
- Department of Cellular and Molecular Medicine, University of California, San Diego, CA 92093, USA
- Department of Medicine, University of California, San Diego, CA 92093, USA
- Rebecca and John Moore Comprehensive Cancer Center, University of California, San Diego, CA 92093, USA
- Veterans Affairs Medical Center, VA San Diego Healthcare System, La Jolla, San Diego, CA 92093, USA
| | - Soumita Das
- Department of Pathology, University of California, San Diego, CA 92093, USA
- Rebecca and John Moore Comprehensive Cancer Center, University of California, San Diego, CA 92093, USA
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Sharma A, Lee J, Fonseca AG, Moshensky A, Kothari T, Sayed IM, Ibeawuchi SR, Pranadinata RF, Ear J, Sahoo D, Crotty-Alexander LE, Ghosh P, Das S. E-cigarettes compromise the gut barrier and trigger inflammation. iScience 2021; 24:102035. [PMID: 33537654 PMCID: PMC7841355 DOI: 10.1016/j.isci.2021.102035] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/15/2020] [Accepted: 12/31/2020] [Indexed: 12/13/2022] Open
Abstract
E-cigarette usage continues to rise, yet the safety of e-cigarette aerosols is questioned. Using murine models of acute and chronic e-cigarette aerosol inhalation, murine colon transcriptomics, and murine and human gut-derived organoids in co-culture models, we assessed the effects of e-cigarette use on the gut barrier. Histologic and transcriptome analyses revealed that chronic, but not acute, nicotine-free e-cigarette use increased inflammation and reduced expression of tight junction (TJ) markers. Exposure of murine and human enteroid-derived monolayers (EDMs) to nicotine-free e-cigarette aerosols alone or in co-culture with bacteria also causes barrier disruption, downregulation of TJ protein, and enhanced inflammation in response to infection. These data highlight the harmful effects of "non-nicotine" component of e-cigarettes on the gut barrier. Considering the importance of an intact gut barrier for host fitness and the impact of gut mucosal inflammation on a multitude of chronic diseases, these findings are broadly relevant to both medicine and public health.
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Affiliation(s)
- Aditi Sharma
- Department of Pathology, University of California, San Diego, CA 92093, USA
| | - Jasper Lee
- Department of Pathology, University of California, San Diego, CA 92093, USA
| | - Ayden G. Fonseca
- Department of Cellular and Molecular Medicine, University of California, San Diego, CA 92093, USA
| | - Alex Moshensky
- Department of Medicine, University of California, San Diego, CA 92093, USA
| | - Taha Kothari
- Department of Pathology, University of California, San Diego, CA 92093, USA
| | - Ibrahim M. Sayed
- Department of Pathology, University of California, San Diego, CA 92093, USA
| | | | - Rama F. Pranadinata
- Department of Cellular and Molecular Medicine, University of California, San Diego, CA 92093, USA
| | - Jason Ear
- Department of Cellular and Molecular Medicine, University of California, San Diego, CA 92093, USA
- Department of Medicine, University of California, San Diego, CA 92093, USA
| | - Debashis Sahoo
- Department of Pediatrics, University of California, San Diego, CA 92093, USA
- Department of Computer Science and Engineering, Jacobs School of Engineering, University of California, San Diego, CA 92093, USA
- Rebecca and John Moore Comprehensive Cancer Center, University of California, San Diego, CA 92093, USA
| | - Laura E. Crotty-Alexander
- Department of Medicine, University of California, San Diego, CA 92093, USA
- Veterans Affairs Medical Center, VA San Diego Healthcare System, La Jolla, San Diego, CA 92093, USA
| | - Pradipta Ghosh
- Department of Cellular and Molecular Medicine, University of California, San Diego, CA 92093, USA
- Department of Medicine, University of California, San Diego, CA 92093, USA
- Rebecca and John Moore Comprehensive Cancer Center, University of California, San Diego, CA 92093, USA
- Veterans Affairs Medical Center, VA San Diego Healthcare System, La Jolla, San Diego, CA 92093, USA
| | - Soumita Das
- Department of Pathology, University of California, San Diego, CA 92093, USA
- Rebecca and John Moore Comprehensive Cancer Center, University of California, San Diego, CA 92093, USA
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Heldt NA, Reichenbach N, McGary HM, Persidsky Y. Effects of Electronic Nicotine Delivery Systems and Cigarettes on Systemic Circulation and Blood-Brain Barrier: Implications for Cognitive Decline. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 191:243-255. [PMID: 33285126 DOI: 10.1016/j.ajpath.2020.11.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 10/23/2020] [Accepted: 11/06/2020] [Indexed: 12/17/2022]
Abstract
Electronic nicotine delivery systems (often known as e-cigarettes) are a novel tobacco product with growing popularity, particularly among younger demographics. The implications for public health are twofold, as these products may represent a novel source of tobacco-associated disease but may also provide a harm reduction strategy for current tobacco users. There is increasing recognition that e-cigarettes impact vascular function across multiple organ systems. Herein, we provide a comparison of evidence regarding the role of e-cigarettes versus combustible tobacco in vascular disease and implications for blood-brain barrier dysfunction and cognitive decline. Multiple non-nicotinic components of tobacco smoke have been identified in e-cigarette aerosol, and their involvement in vascular disease is discussed. In addition, nicotine and nicotinic signaling may modulate peripheral immune and endothelial cell populations in a highly context-dependent manner. Direct preclinical evidence for electronic nicotine delivery system-associated neurovascular impairment is provided, and a model is proposed in which non-nicotinic elements exert a proinflammatory effect that is functionally antagonized by the presence of nicotine.
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Affiliation(s)
- Nathan A Heldt
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania.
| | - Nancy Reichenbach
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Hannah M McGary
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Yuri Persidsky
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania.
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Translational research into the effects of cigarette smoke on inflammatory mediators and epithelial TRPV1 in Crohn's disease. PLoS One 2020; 15:e0236657. [PMID: 32760089 PMCID: PMC7410291 DOI: 10.1371/journal.pone.0236657] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 07/09/2020] [Indexed: 01/08/2023] Open
Abstract
Crohn's disease is a pathological condition of the gastro-intestinal tract, causing severe transmural inflammation in the ileum and/or colon. Cigarette smoking is one of the best known environmental risk factors for the development of Crohn's disease. Nevertheless, very little is known about the effect of prolonged cigarette smoke exposure on inflammatory modulators in the gut. We examined the effect of cigarette smoke on cytokine profiles in the healthy and inflamed gut of human subjects and in the trinitrobenzene sulphonic acid mouse model, which mimics distal Crohn-like colitis. In addition, the effect of cigarette smoke on epithelial expression of transient receptor potential channels and their concurrent increase with cigarette smoke-augmented cytokine production was investigated. Active smoking was associated with increased IL-8 transcription in ileum of controls (p < 0,001; n = 18-20/group). In the ileum, TRPV1 mRNA levels were decreased in never smoking Crohn's disease patients compared to healthy subjects (p <0,001; n = 20/group). In the colon, TRPV1 mRNA levels were decreased (p = 0,046) in smoking healthy controls (n = 20/group). Likewise, healthy mice chronically exposed to cigarette smoke (n = 10/group) showed elevated ileal Cxcl2 (p = 0,0075) and colonic Kc mRNA levels (p = 0,0186), whereas TRPV1 mRNA and protein levels were elevated in the ileum (p = 0,0315). Although cigarette smoke exposure prior to trinitrobenzene sulphonic acid administration did not alter disease activity, increased pro-inflammatory cytokine production was observed in the distal colon (Kc: p = 0,0273; Cxcl2: p = 0,104; Il1-β: p = 0,0796), in parallel with the increase of Trpv1 mRNA (p < 0,001). We infer that CS affects pro-inflammatory cytokine expression in healthy and inflamed gut, and that the simultaneous modulation of TRPV1 may point to a potential involvement of TRPV1 in cigarette smoke-induced production of inflammatory mediators.
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Kamalian A, Sohrabi Asl M, Dolatshahi M, Afshari K, Shamshiri S, Momeni Roudsari N, Momtaz S, Rahimi R, Abdollahi M, Abdolghaffari AH. Interventions of natural and synthetic agents in inflammatory bowel disease, modulation of nitric oxide pathways. World J Gastroenterol 2020; 26:3365-3400. [PMID: 32655263 PMCID: PMC7327787 DOI: 10.3748/wjg.v26.i24.3365] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/09/2020] [Accepted: 06/04/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) refers to a group of disorders characterized by chronic inflammation of the gastrointestinal (GI) tract. The elevated levels of nitric oxide (NO) in serum and affected tissues; mainly synthesized by the inducible nitric oxide synthase (iNOS) enzyme; can exacerbate GI inflammation and is one of the major biomarkers of GI inflammation. Various natural and synthetic agents are able to ameliorate GI inflammation and decrease iNOS expression to the extent comparable with some IBD drugs. Thereby, the purpose of this study was to gather a list of natural or synthetic mediators capable of modulating IBD through the NO pathway. Electronic databases including Google Scholar and PubMed were searched from 1980 to May 2018. We found that polyphenols and particularly flavonoids are able to markedly attenuate NO production and iNOS expression through the nuclear factor κB (NF-κB) and JAK/STAT signaling pathways. Prebiotics and probiotics can also alter the GI microbiota and reduce NO expression in IBD models through a broad array of mechanisms. A number of synthetic molecules have been found to suppress NO expression either dependent on the NF-κB signaling pathway (i.e., dexamethasone, pioglitazone, tropisetron) or independent from this pathway (i.e., nicotine, prednisolone, celecoxib, β-adrenoceptor antagonists). Co-administration of natural and synthetic agents can affect the tissue level of NO and may improve IBD symptoms mainly by modulating the Toll like receptor-4 and NF-κB signaling pathways.
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Affiliation(s)
- Aida Kamalian
- Department of Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Masoud Sohrabi Asl
- Department of Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Mahsa Dolatshahi
- Department of Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Khashayar Afshari
- Department of Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Shiva Shamshiri
- Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Nazanin Momeni Roudsari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran 1941933111, Iran
| | - Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran 1417614411, Iran
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran
- Gastrointestinal Pharmacology Interest Group, Universal Scientific Education and Research Network, Tehran 1417614411, Iran
| | - Roja Rahimi
- Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Mohammad Abdollahi
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Amir Hossein Abdolghaffari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran 1941933111, Iran
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran 1417614411, Iran
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran
- Gastrointestinal Pharmacology Interest Group, Universal Scientific Education and Research Network, Tehran 1417614411, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran
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Michael OS, Dibia CL, Adeyanju OA, Olaniyi KS, Areola ED, Olatunji LA. Estrogen-progestin oral contraceptive and nicotine exposure synergistically confers cardio-renoprotection in female Wistar rats. Biomed Pharmacother 2020; 129:110387. [PMID: 32540646 DOI: 10.1016/j.biopha.2020.110387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 06/04/2020] [Accepted: 06/07/2020] [Indexed: 10/24/2022] Open
Abstract
Approximately fifty percent of premenopausal women who smoke cigarettes or on nicotine replacement therapy are also on hormonal contraceptives, especially oral estrogen-progestin. Oral estrogen-progestin therapy has been reported to promote insulin resistance (IR) which causes lipid influx into non-adipose tissue and impairs Na+/K+ -ATPase activity, especially in the heart and kidney. However, the effects of nicotine on excess lipid and altered Na+/K+ -ATPase activity associated with the use of estrogen-progestin therapy have not been fully elucidated. This study therefore aimed at investigating the effect of nicotine on cardiac and renal lipid influx and Na+/K+ -ATPase activity during estrogen-progestin therapy. Twenty-four female Wistar rats grouped into 4 (n = 6/group) received (p.o.) vehicle, nicotine (1.0 mg/kg) with or without estrogen-progestin steroids (1.0 μg ethinyl estradiol and 5.0 μg levonorgestrel) and estrogen-progestin only daily for 6 weeks. Data showed that estrogen-progestin treatment or nicotine exposure caused IR, hyperinsulinemia, increased cardiac and renal uric acid, malondialdehyde, triglyceride, glycogen synthase kinase-3, plasminogen activator inhibitor-1, reduced bilirubin and circulating estradiol. Estrogen-progestin treatment led to decreased cardiac Na+/K+-ATPase activity while nicotine did not alter Na+/K+-ATPase activity but increased plasma and tissue cotinine. Renal Na+/K+-ATPase activity was not altered by the treatments. However, all these alterations were reversed following combined administration of oral estrogen-progestin therapy and nicotine. The present study therefore demonstrates that oral estrogen-progestin therapy and nicotine exposure synergistically prevents IR-linked cardio-renotoxicity with corresponding improvement in cardiac and renal lipid accumulation, oxidative stress, inflammation and Na+/K+-ATPase activity.
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Affiliation(s)
- O S Michael
- Cardiometabolic Research Unit, Department of Physiology, College of Health Sciences, Bowen University, Iwo, Nigeria; HOPE Cardiometabolic Research Team, Department of Physiology, University of Ilorin, Ilorin, Nigeria.
| | - C L Dibia
- HOPE Cardiometabolic Research Team, Department of Physiology, University of Ilorin, Ilorin, Nigeria; Department of Physiology, Nnamdi Azikiwe University, Awka, Anambra State, Nigeria
| | - O A Adeyanju
- HOPE Cardiometabolic Research Team, Department of Physiology, University of Ilorin, Ilorin, Nigeria; Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, 360101, Nigeria
| | - K S Olaniyi
- HOPE Cardiometabolic Research Team, Department of Physiology, University of Ilorin, Ilorin, Nigeria; Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, 360101, Nigeria
| | - E D Areola
- HOPE Cardiometabolic Research Team, Department of Physiology, University of Ilorin, Ilorin, Nigeria
| | - L A Olatunji
- HOPE Cardiometabolic Research Team, Department of Physiology, University of Ilorin, Ilorin, Nigeria
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12
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Garg BK, Loring RH. GTS-21 has cell-specific anti-inflammatory effects independent of α7 nicotinic acetylcholine receptors. PLoS One 2019; 14:e0214942. [PMID: 30947238 PMCID: PMC6448884 DOI: 10.1371/journal.pone.0214942] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 03/22/2019] [Indexed: 12/15/2022] Open
Abstract
α7 Nicotinic acetylcholine receptors (nAChRs) reportedly reduce inflammation by blocking effects of the important pro-inflammatory transcription factor, nuclear factor kappa-light chain-enhancer of B cells (NFκB). The α7 nAChR partial agonist GTS-21 reduces secretion of pro-inflammatory cytokines including interleukin-6 (IL6) and tumor-necrosis factor (TNF) in models of endotoxemia and sepsis, and its anti-inflammatory effects are widely ascribed to α7 nAChR activation. However, mechanistic details of α7 nAChR involvement in GTS-21 effects on inflammatory pathways remain unclear. Here, we investigate how GTS-21 acts in two cell systems including the non-immune rat pituitary cell line GH4C1 expressing an NFκB-driven reporter gene and cytokine secretion by ex vivo cultures of primary mouse macrophages activated by lipopolysaccharide (LPS). GTS-21 does not change TNF-stimulated NFκB signaling in GH4C1 cells expressing rat α7 nAChRs, suggesting that GTS-21 requires additional unidentified factors besides α7 nAChR expression to allow anti-inflammatory effects in these cells. In contrast, GTS-21 dose-dependently suppresses LPS-induced IL6 and TNF secretion in primary mouse macrophages endogenously expressing α7 nAChRs. GTS-21 also blocks TNF-induced phosphorylation of NFκB inhibitor alpha (IκBα), an important intermediary in NFκB signaling. However, α7 antagonists methyllycaconitine and α-bungarotoxin only partially reverse GTS-21 blockade of IL6 and TNF secretion. Further, GTS-21 significantly inhibited LPS-induced IL6 and TNF secretion in macrophages isolated from knockout mice lacking α7 nAChRs. These data indicate that even though a discrete component of the anti-inflammatory effects of GTS-21 requires expression of α7 nAChRs in macrophages, GTS-21 also has anti-inflammatory effects independent of these receptors depending on the cellular context.
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Affiliation(s)
- Brijesh K. Garg
- Department of Pharmaceutical Science, Northeastern University, Boston, Massachusetts, United States of America
| | - Ralph H. Loring
- Department of Pharmaceutical Science, Northeastern University, Boston, Massachusetts, United States of America
- * E-mail:
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Eduardo CRC, Alejandra TIG, Guadalupe DRKJ, Herminia VRG, Lenin P, Enrique BV, Evandro BM, Oscar B, Iván GPM. Modulation of the extraneuronal cholinergic system on main innate response leukocytes. J Neuroimmunol 2019; 327:22-35. [PMID: 30683425 DOI: 10.1016/j.jneuroim.2019.01.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 01/15/2019] [Accepted: 01/15/2019] [Indexed: 12/17/2022]
Abstract
The expression of elements of the cholinergic system has been demonstrated in non-neuronal cells, such as immune cells, where acetylcholine modulates innate and adaptive responses. However, the study of the non-neuronal cholinergic system has focused on lymphocyte cholinergic mechanisms, with less attention to its role of innate cells. Considering this background, the aims of this review are 1) to review information regarding the cholinergic components of innate immune system cells; 2) to discuss the effect of cholinergic stimuli on cell functions; 3) and to describe the importance of cholinergic stimuli on host immunocompetence, in order to set the base for the design of intervention strategies in the biomedical field.
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Affiliation(s)
- Covantes-Rosales Carlos Eduardo
- Universidad Autónoma de Nayarit, Secretaría de Investigación y Posgrado, Laboratorio de Inmunotoxicología, Boulevard Tepic-Xalisco s/n, Cd de la Cultura Amado Nervo, C.P. 63000 Tepic, Nayarit, Mexico
| | - Toledo-Ibarra Gladys Alejandra
- Universidad Autónoma de Nayarit, Secretaría de Investigación y Posgrado, Laboratorio de Inmunotoxicología, Boulevard Tepic-Xalisco s/n, Cd de la Cultura Amado Nervo, C.P. 63000 Tepic, Nayarit, Mexico; Centro Nayarita de Innovación y Transferencia de Tecnología A.C. Laboratorio Nacional para la Investigación en Inocuidad Alimentaria-Unidad Nayarit, Calle Tres s/n. Cd Industrial, Tepic, Nayarit, Mexico
| | - Díaz-Resendiz Karina Janice Guadalupe
- Universidad Autónoma de Nayarit, Secretaría de Investigación y Posgrado, Laboratorio de Inmunotoxicología, Boulevard Tepic-Xalisco s/n, Cd de la Cultura Amado Nervo, C.P. 63000 Tepic, Nayarit, Mexico
| | - Ventura-Ramón Guadalupe Herminia
- Universidad Autónoma de Nayarit, Secretaría de Investigación y Posgrado, Laboratorio de Inmunotoxicología, Boulevard Tepic-Xalisco s/n, Cd de la Cultura Amado Nervo, C.P. 63000 Tepic, Nayarit, Mexico; Centro Nayarita de Innovación y Transferencia de Tecnología A.C. Laboratorio Nacional para la Investigación en Inocuidad Alimentaria-Unidad Nayarit, Calle Tres s/n. Cd Industrial, Tepic, Nayarit, Mexico
| | - Pavón Lenin
- Instituto Nacional de Psiquiatría "Ramón de la Fuente", Laboratorio de Psicoinmunología, Calzada México-Xochimilco 101, Col. San Lorenzo Huipulco, Tlalpan, 14370 México City, DF, Mexico
| | - Becerril-Villanueva Enrique
- Instituto Nacional de Psiquiatría "Ramón de la Fuente", Laboratorio de Psicoinmunología, Calzada México-Xochimilco 101, Col. San Lorenzo Huipulco, Tlalpan, 14370 México City, DF, Mexico
| | - Bauer Moisés Evandro
- Pontifícia Universidade Católica do Rio Grande do Sul, Instituto de Pesquisas Biomédicas, Laboratório de Imunologia do Envelhecimento, 90610-000 Porto Alegre, RS, Brazil
| | - Bottaso Oscar
- Universidad Nacional de Rosario-Consejo Nacional de Investigaciones Científicas y Técnicas (UNR-CONICET), Instituto de Inmunología Clínica y Experimental de Rosario, Rosario, Argentina
| | - Girón-Pérez Manuel Iván
- Universidad Autónoma de Nayarit, Secretaría de Investigación y Posgrado, Laboratorio de Inmunotoxicología, Boulevard Tepic-Xalisco s/n, Cd de la Cultura Amado Nervo, C.P. 63000 Tepic, Nayarit, Mexico; Centro Nayarita de Innovación y Transferencia de Tecnología A.C. Laboratorio Nacional para la Investigación en Inocuidad Alimentaria-Unidad Nayarit, Calle Tres s/n. Cd Industrial, Tepic, Nayarit, Mexico.
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Dangana EO, Michael OS, Omolekulo TE, Areola ED, Olatunji LA. Enhanced hepatic glycogen synthesis and suppressed adenosine deaminase activity by lithium attenuates hepatic triglyceride accumulation in nicotine-exposed rats. Biomed Pharmacother 2018; 109:1417-1427. [PMID: 30551393 DOI: 10.1016/j.biopha.2018.10.067] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 10/05/2018] [Accepted: 10/12/2018] [Indexed: 01/08/2023] Open
Abstract
Reduced liver glycogen synthesis might signify increased glucose flux towards fat synthesis and triggers hepatic triglyceride accumulation and dysmetabolism. Adenosine deaminase (ADA) reduces adenosine content which increases glycogenolysis. In the present study, we evaluate the effect of modulating glycogen synthesis and ADA by lithium chloride (LiCl) on nicotine-induced dysmetabolism. Twenty four male Wistar rats (n = 6/group) were allotted into four groups namely; vehicle-treated (po), nicotine-treated (1.0 mg/kg; po), LiCl-treated (5.0 mg/kg; po) and nicotine + LiCl-treated groups. The treatments lasted for 8 weeks. Nicotine exposure resulted in reduced body weight gain, liver weight, visceral adiposity, glycogen content and synthase. Along with increased insulin resistance (IR), fasting plasma glucose, lactate, plasma and hepatic ADA, XO, UA, and triglyceride (TG), total cholesterol (TC), free fatty acid, lipid peroxidation and liver injury markers. However, plasma and hepatic glucose-6-phosphate dehydrogenase-dependent antioxidant defenses were not affected by nicotine exposure. Concurrent treatment with LiCl normalizes all alterations with exception of hepatic TC. This result shows that enhancement of hepatic glycogen synthesis and suppression of ADA/XO/uric acid pathway by lithium can salvage the liver from nicotine-induced TG accumulation.
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Affiliation(s)
- Elizabeth O Dangana
- HOPE Cardiometabolic Research Team, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
| | - Olugbenga S Michael
- HOPE Cardiometabolic Research Team, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria; Cardiometabolic Research Unit, Department of Physiology, College of Health Sciences, Bowen University Iwo, Nigeria
| | - Tolulope E Omolekulo
- HOPE Cardiometabolic Research Team, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
| | - Emmanuel D Areola
- HOPE Cardiometabolic Research Team, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
| | - Lawrence A Olatunji
- HOPE Cardiometabolic Research Team, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria.
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Kim SE, Lee JY, Shim KS, Lee S, Min K, Bae JH, Kim HJ, Park K, Song HR. Attenuation of inflammation and cartilage degradation by sulfasalazine-containing hyaluronic acid on osteoarthritis rat model. Int J Biol Macromol 2018; 114:341-348. [PMID: 29548914 DOI: 10.1016/j.ijbiomac.2018.03.059] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 03/05/2018] [Accepted: 03/12/2018] [Indexed: 01/16/2023]
Abstract
The aim of this study was to investigate the effects of a sulfasalazine-containing hyaluronic acid (SASP/HA) systems on in vitro anti-inflammation and the alleviation of cartilage degradation in both lipopolysaccharide (LPS)-stimulated synoviocytes and a rat model of monosodium iodoacetate (MIA)-induced osteoarthritis (OA). The SASP/HA resulted in long-term release of SASP from the SASP/HA for up to 60 days in a sustained manner. In vitro studies performed using real-time polymerase chain reaction (PCR) assay revealed that the SASP/HA was able to effectively and dose-dependently inhibit the mRNA expression levels of pro-inflammatory cytokines such as matrix metalloproteinases-3 (MMP-3), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in LPS-stimulated synoviocytes. In vivo studies showed that intra articular injection of SASP/HA greatly reduced the MIA-stimulated mRNA expression of MMP-3, COX-2, IL-6, and TNF-α in blood. Furthermore, these significant anti-inflammatory effects of SASP/HA contributed markedly to the alleviation of progression of MIA-induced OA and cartilage degradation, as demonstrated by X-ray, micro-computed tomography (micro-CT), gross findings, and histological evaluations. Therefore, our findings indicated that the long-term and sustained delivery of SASP using HA can play a therapeutic role in alleviating inflammation as well as protecting against cartilage damage in OA.
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Affiliation(s)
- Sung Eun Kim
- Department of Orthopedic Surgery and Rare Diseases Institute, Korea University Guro Hospital, Korea University College of Medicine, #148, Guro-dong, Guro-gu, Seoul 08308, Republic of Korea
| | - Jae Yong Lee
- Department of Biomedical Science, Korea University College of Medicine, Korea University, Anam-dong, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Kyu-Sik Shim
- Department of Biomedical Science, Korea University College of Medicine, Korea University, Anam-dong, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Sunghee Lee
- BMI Korea R&D Center, Plant 11, Cheomdanro 7 Gil, Jeju City, Jeju-do 63309, Republic of Korea
| | - Kyoengwoo Min
- BMI Korea R&D Center, Plant 11, Cheomdanro 7 Gil, Jeju City, Jeju-do 63309, Republic of Korea
| | - Ji-Hoon Bae
- Department of Orthopedic Surgery and Rare Diseases Institute, Korea University Guro Hospital, Korea University College of Medicine, #148, Guro-dong, Guro-gu, Seoul 08308, Republic of Korea
| | - Hak-Jun Kim
- Department of Orthopedic Surgery and Rare Diseases Institute, Korea University Guro Hospital, Korea University College of Medicine, #148, Guro-dong, Guro-gu, Seoul 08308, Republic of Korea
| | - Kyeongsoon Park
- Department of Systems Biotechnology, Chung-Ang University, Anseong, Gyeonggi-do 17546, Republic of Korea.
| | - Hae-Ryong Song
- Department of Orthopedic Surgery and Rare Diseases Institute, Korea University Guro Hospital, Korea University College of Medicine, #148, Guro-dong, Guro-gu, Seoul 08308, Republic of Korea.
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16
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Gomes JP, Watad A, Shoenfeld Y. Nicotine and autoimmunity: The lotus' flower in tobacco. Pharmacol Res 2018; 128:101-109. [PMID: 29051105 DOI: 10.1016/j.phrs.2017.10.005] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 10/13/2017] [Accepted: 10/15/2017] [Indexed: 12/14/2022]
Abstract
Nicotine, the major component of cigarettes, has demonstrated conflicting impact on the immune system: some authors suggest that increases pro-inflammatory cytokines and provokes cellular apoptosis of neutrophils, releasing intracellular components that act as auto-antigens; others claimed that nicotine has a protective and anti-inflammatory effects, especially by binding to α7 subunit of nicotinic acetylcholine receptors. The cholinergic pathway contributes to an anti-inflammatory environment characterized by increasing T regulatory cells response, down-regulating of pro-inflammatory cytokines and a pro-inflammatory cells apoptosis. The effects of nicotine were studied in different autoimmune disease, as multiple sclerosis, type 1 diabetes, rheumatoid arthritis, sarcoidosis, Behçet's disease and inflammatory bowel diseases. The major problems about nicotine are the addiction and the adverse effects of related to each commercialized formulation. We sought in this review to summarize the knowledge accumulated to date concerning the relationship between nicotine and autoimmunity.
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Affiliation(s)
- João Pedro Gomes
- Department A of Internal Medicine, Hospital and University Centre of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Portugal
| | - Abdulla Watad
- Zabludowicz Center for Autoimmune Disease, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Israel
| | - Yehuda Shoenfeld
- Zabludowicz Center for Autoimmune Disease, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Israel.
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17
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Özdemir-Kumral ZN, Özbeyli D, Özdemir AF, Karaaslan BM, Kaytaz K, Kara MF, Tok OE, Ercan F, Yegen BÇ. Protective Effect of Nicotine on Sepsis-Induced Oxidative Multiorgan Damage: Role of Neutrophils. Nicotine Tob Res 2018; 19:859-864. [PMID: 27613897 DOI: 10.1093/ntr/ntw198] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 07/20/2016] [Indexed: 12/15/2022]
Abstract
Introduction Despite its adverse health consequences, tobacco smoking is associated with lower incidence of several neurodegenerative and inflammatory diseases. The present study is aimed to show the effects of nicotine, major tobacco constituent, on five organs targeted by sepsis. Methods Male Wistar albino rats received tap water with (5mg/kg) or without nicotine for 14 days. Under ketamine anesthesia, sepsis (n = 50) was induced by ligation and puncture of the cecum, while sham group (n = 8) had only laparotomy. In other rats, nicotine drink was withdrawn for 5 days before sepsis induction, while in acute nicotine group, rats were injected with nicotine (30mg/kg, i.p.) before sepsis, but had no oral intake. Rats were decapitated 24 hours after surgery to obtain lung, liver, ileum, heart, and kidney tissues to determine malondialdehyde (MDA) and glutathione (GSH) levels and myeloperoxidase (MPO) activities. Data were analyzed by one-way analysis of variance and Tukey multiple comparison tests or Student's t test. Results Chronic nicotine administration or its withdrawal reduced lipid peroxidation and MPO activity and prevented GSH depletion with some varying results in different target tissues. Nicotine injection prior to sepsis depressed MPO activity in all tissues and reduced MDA levels except for the lung, while GSH levels were elevated only in the hepatic and ileal tissues. Histologically observed injury was ameliorated by all nicotine treatments at varying degrees. Conclusions The findings of the present study indicate that long-term nicotine administration reduces sepsis-induced oxidative damage in several tissues, which appears to involve inhibition of neutrophil activity in the inflamed tissues. Implications Nicotine administration or its withdrawal reduced lipid peroxidation and neutrophil content and prevented GSH depletion with some varying results in different target tissues. A single injection prior to sepsis induction depressed MPO activity in all the tissues and reduced all tissue MDA levels except for the lung. When nicotine was withdrawn for 5 days, its inhibitory effect on MPO activity was still present in all the tissues except for the liver. Microscopically an improved inflammatory response was observed in all the tissues of rats that have received different nicotine pretreatment regimens.
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Affiliation(s)
| | - Dilek Özbeyli
- Department of Physiology, Marmara University School of Medicine, Istanbul, Turkey
| | - Ahmet F Özdemir
- Department of Physiology, Marmara University School of Medicine, Istanbul, Turkey
| | - Bugra M Karaaslan
- Department of Physiology, Marmara University School of Medicine, Istanbul, Turkey
| | - Kübra Kaytaz
- Department of Physiology, Marmara University School of Medicine, Istanbul, Turkey
| | - Mustafa F Kara
- Department of Physiology, Marmara University School of Medicine, Istanbul, Turkey
| | - Olgu E Tok
- Department of Histology & Embryology, Marmara University School of Medicine, Istanbul, Turkey
| | - Feriha Ercan
- Department of Histology & Embryology, Marmara University School of Medicine, Istanbul, Turkey
| | - Berrak Ç Yegen
- Department of Physiology, Marmara University School of Medicine, Istanbul, Turkey
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Seyedabadi M, Rahimian R, Ghia JE. The role of alpha7 nicotinic acetylcholine receptors in inflammatory bowel disease: involvement of different cellular pathways. Expert Opin Ther Targets 2018; 22:161-176. [PMID: 29298542 DOI: 10.1080/14728222.2018.1420166] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Autonomic imbalance plays a pivotal role in the pathophysiology of inflammatory bowel diseases (IBD). The central nervous system (CNS) cooperates dynamically with the immune system to regulate inflammation through humoral and neural pathways. In particular, acetylcholine (Ach), the main neurotransmitter in the vagus nerve, decreases the production of pro-inflammatory cytokines through a mechanism dependent on the α7 nicotinic Ach receptors (α7nAChRs). Areas covered: Here, we review the evidence for involvement of the cholinergic anti-inflammatory pathway (CAP) in IBD. We also elaborate the role of α7nAChRs and subsequent cellular pathways in CAP. Finally, we review potential therapeutic implications of modulators of these receptors. Expert opinion: Alpha7nAChR modulators possess both cognitive improving and anti-inflammatory properties. Although, these agents demonstrated therapeutic benefits in experimental models, their efficacy has not always been translated in clinical trials. Thus, development of more specific α7nAChR ligands as well as more experimental studies and better controlled trials, especially in the field of IBD, are encouraged for a progress in this field.
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Affiliation(s)
- Mohammad Seyedabadi
- a Department of Pharmacology, School of Medicine , Bushehr University of Medical Sciences , Bushehr , Iran.,b The Persian Gulf Biomedical Sciences Research Institute , Bushehr University of Medical Sciences , Bushehr , Iran.,c Education Development Center , Bushehr University of Medical Sciences , Bushehr , Iran
| | - Reza Rahimian
- d Department of Psychiatry and Neuroscience, Faculty of Medicine , CERVO Brain Research Center, Laval University , Quebec , Quebec , Canada
| | - Jean-Eric Ghia
- e Department of Immunology , University of Manitoba , Winnipeg , Manitoba , Canada.,f Department of Internal Medicine Section of Gastroenterology, and Inflammatory Bowel Disease Clinical & Research Center , University of Manitoba , Winnipeg , Manitoba , Canada
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Anti-inflammatory and antithrombotic effects of nicotine exposure in oral contraceptive-induced insulin resistance are glucocorticoid-independent. Pharmacol Rep 2016; 69:512-519. [PMID: 28349880 DOI: 10.1016/j.pharep.2016.12.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 11/30/2016] [Accepted: 12/16/2016] [Indexed: 12/27/2022]
Abstract
BACKGROUND Reports showed that estrogen-progestin oral contraceptive (COC) or tobacco smoking causes increased risk of cardiovascular diseases (CVD) in premenopausal women. Studies also suggest that nicotine, a major tobacco alkaloid, may worsen or improve atherothrombotic CVD. Altered hemorheology, prothrombotic and pro-inflammatory biomarkers, have been implicated in the development of atherothrombotic CVD events. However, the effect of non-smoking nicotine exposure on these biomarkers during COC treatment is not yet established. We therefore sought to determine the effects of nicotine exposure during COC treatment on these biomarkers, and also tested the hypothesis that the nicotine effects would be glucocorticoid-dependent. METHODS Female Sprague-Dawley rats aged 10 weeks were given (po) vehicle, low-dose nicotine (0.1mg/kg) or high-dose nicotine (1.0mg/kg) with or without COC steroids (5.0μg/kg ethinylestradiol and 25.0μg/kg levonorgestrel) daily for 6 weeks. RESULTS COC treatment or nicotine exposure led to increased insulin resistance (IR), hemorheological (blood viscosity, hematocrit and plasma viscosity), prothrombotic (plasminogen activator inhibitor-1), pro-inflammatory (uric acid, C-reactive protein, neutrophil/lymphocyte and platelet/lymphocyte ratios) biomarkers and corticosterone. However, these effects except that on corticosterone were abrogated by nicotine exposure during COC treatment. CONCLUSIONS Our study indicates that nicotine- or COC-induced IR may be mediated via inflammatory/thrombotic pathway. The results imply that nicotine exposure could impact negatively on atherothrombotic biomarkers in COC non-users, whereas the impact in COC users could be positive. The results also suggest that the anti-inflammatory, antithrombotic and blood viscosity-lowering effects of nicotine exposure during COC use is circulating glucocorticoid-independent.
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Nicotine Inhibits Clostridium difficile Toxin A-Induced Colitis but Not Ileitis in Rats. Int J Inflam 2016; 2016:4705065. [PMID: 26881175 PMCID: PMC4737023 DOI: 10.1155/2016/4705065] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 12/16/2015] [Indexed: 11/17/2022] Open
Abstract
Nicotine is protective in ulcerative colitis but not Crohn's disease of the small intestine, but little is known about the effects of nicotine on Clostridium difficile toxin A-induced enteritis. Isolated ileal or colonic segments in anesthetized rats were pretreated with nicotine bitartrate or other pharmacological agents before intraluminal injection of toxin A. After 3 hours, the treated segments were removed and inflammation was assessed. Nicotine biphasically inhibited toxin A colitis but not ileitis. Pretreatment with the nicotinic receptor antagonist, hexamethonium, blocked the effects of nicotine. Pretreating the colonic segments with hexamethonium before toxin A administration resulted in more inflammation than seen with toxin A alone, suggesting that a tonic nicotinic anti-inflammatory condition exists in the colon. Nicotine also inhibited toxin A-induced increased colonic concentrations of the TRPV1 (transient receptor potential vanilloid subtype 1) agonist, leukotriene B4 (LTB4), and release of the proinflammatory neuropeptide, substance P. Pretreatment with nicotine did not protect against direct TRPV1-mediated colitis caused by intraluminal capsaicin. Nicotinic cholinergic receptors tonically protect the colon against inflammation and nicotine inhibits toxin A colitis but not toxin A ileitis in rats in part by inhibition of toxin A-induced activation of TRPV1 by endogenous TRPV1 agonists such as LTB4.
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Levine YA, Koopman F, Faltys M, Zitnik R, Tak PP. Neurostimulation of the Cholinergic Antiinflammatory Pathway in Rheumatoid Arthritis and Inflammatory Bowel Disease. Bioelectron Med 2014. [DOI: 10.15424/bioelectronmed.2014.00008] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
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Jiang X, Alfredsson L, Klareskog L, Bengtsson C. Smokeless Tobacco (Moist Snuff) Use and the Risk of Developing Rheumatoid Arthritis: Results From a Case-Control Study. Arthritis Care Res (Hoboken) 2014; 66:1582-6. [DOI: 10.1002/acr.22325] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Revised: 03/13/2014] [Accepted: 03/18/2014] [Indexed: 11/08/2022]
Affiliation(s)
- Xia Jiang
- Institute of Environmental Medicine, Karolinska Institute; Stockholm Sweden
| | - Lars Alfredsson
- Institute of Environmental Medicine, Karolinska Institute, and Centre for Occupational and Environmental Medicine, Stockholm County Council; Stockholm Sweden
| | - Lars Klareskog
- Karolinska Institutet and Karolinska University Hospital; Stockholm Sweden
| | - Camilla Bengtsson
- Institute of Environmental Medicine, Karolinska Institute; Stockholm Sweden
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Pelissier-Rota M, Lainé M, Ducarouge B, Bonaz B, Jacquier-Sarlin M. Role of Cholinergic Receptors in Colorectal Cancer: Potential Therapeutic Implications of Vagus Nerve Stimulation? ACTA ACUST UNITED AC 2013. [DOI: 10.4236/jct.2013.46128] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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AlSharari SD, Akbarali HI, Abdullah RA, Shahab O, Auttachoat W, Ferreira GA, White KL, Lichtman AH, Cabral GA, Damaj MI. Novel insights on the effect of nicotine in a murine colitis model. J Pharmacol Exp Ther 2013; 344:207-17. [PMID: 23115221 PMCID: PMC3533410 DOI: 10.1124/jpet.112.198796] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2012] [Accepted: 10/29/2012] [Indexed: 12/11/2022] Open
Abstract
Studies showed that nicotine has a positive influence on symptoms of ulcerative colitis. In the present study, we explored the effect of nicotine treatment using different routes of administration in the dextran sodium sulfate (DSS) colitis mouse model. We also investigated the effects of cotinine, a major metabolite of nicotine, in the model. C57BL6 adult male mice were given DSS solution freely in the drinking water for seven consecutive days, and tap water was given thereafter. Disease severity, length of the colon, colon tissue histology, and inflammatory markers, including colonic myeloperoxidase activity and colonic tumor necrosis factor-α levels, were evaluated. The effect of nicotine and cotinine treatments via various different routes of administration were examined the DSS model. In addition, we measured the plasma levels of nicotine and cotinine in our treatment protocols. Administration of low, but not high, doses of oral nicotine in DSS-treated mice resulted in a significant decrease in disease severity, histologic damage scores, as well as colonic level of tumor necrosis factor-α. However, the anti-inflammatory effect of nicotine was not seen after chronic s.c. or minipump infusion of the drug. Differences in plasma levels of nicotine and cotinine do not seem to account for this lack of effect. Finally, oral cotinine alone failed to show a significant effect in the DSS model of colitis. These results highlight that dose and route of administration play a critical role in the protective effect of nicotine in the DSS mouse colitis model.
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Affiliation(s)
- Shakir D AlSharari
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Box 980613, Richmond, VA 23298-0613, USA
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25
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Verschuere S, De Smet R, Allais L, Cuvelier CA. The effect of smoking on intestinal inflammation: what can be learned from animal models? J Crohns Colitis 2012; 6:1-12. [PMID: 22261522 DOI: 10.1016/j.crohns.2011.09.006] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2011] [Revised: 09/11/2011] [Accepted: 09/12/2011] [Indexed: 12/11/2022]
Abstract
Epidemiological evidence demonstrates that smoking is the most important environmental risk factor in Crohn's disease while it positively interferes with the disease course of ulcerative colitis. However, the underlying mechanisms through which smoking exerts this divergent effect and affects pathogenesis of inflammatory bowel disease are largely unknown. Animal smoke models are good models to investigate the impact of cigarette smoke on intestinal physiology and inflammation. They enable one to explore the interaction of smoke components and the gut on cellular and molecular level, clarifying how smoking interferes with normal gut function and with disease course in inflammatory conditions. This review describes the currently used animal models for studying the impact of cigarette smoke on the intestinal tract. We first discuss the different methods for simulation of smoking. Furthermore, we focus on the effect of smoke exposure on normal gut physiology and immunology, on experimental (entero)colitis, and on inflammation-induced neoplasia. Based on this current knowledge, a hypothesis is formulated about the mechanisms through which cigarette smoke interferes with the gut in normal and pathological conditions.
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26
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Agarwal PK, van den Born J, van Goor H, Navis G, Gans ROB, Bakker SJL. Renoprotective effects of long-term oral nicotine in a rat model of spontaneous proteinuria. Am J Physiol Renal Physiol 2012; 302:F895-904. [PMID: 22218593 DOI: 10.1152/ajprenal.00507.2011] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Many proteinuric renal conditions are accompanied by renal inflammation. Nicotine is known to have anti-inflammatory properties and is used in oral form to help subjects quit smoking. A potential anti-inflammatory role of nicotine in proteinuric renal diseases has not been investigated to date. We therefore evaluated the effects of oral nicotine in a rat model of proteinuria-induced renal inflammation. We used a well-established model of adult (24 wk of age) male Munich-Wistar-Frömter rats. Animals were given three different physiological doses of nicotine in drinking water for 28 wk until 52 wk of age (long term). A group without nicotine served as a parallel control. At 52 wk of age, the control group had a 2.1 times reduction in creatinine clearance, 3.2 times increase in urinary protein excretion, an increased focal glomerulosclerosis (FGS) score, increased glomerular desmin deposition, decreased glomerular podocin, and a higher accumulation of macrophages and myofibroblasts compared with 24-wk-old animals. Oral treatment with nicotine dose dependently preserved renal function and halted proteinuria progression, which were independent of blood pressure reduction. It also reduced FGS, desmin deposition, podocin loss, and density of renal macrophages and myofibroblasts. Nicotine also reduced the level of gene expression of the renal inflammatory markers monocyte chemoattractant protein and vascular cell adhesion molecule-1. In conclusion, long-term oral nicotine preserved kidney function, reduced proteinuria, reduced renal inflammation, and protected progression of renal structural damage in a rat model of proteinuria. We further suggest evaluating nicotine as a potential additional therapeutic option for treating proteinuric kidney diseases.
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Affiliation(s)
- Pramod K Agarwal
- Dept. of Internal Medicine, Experimental Nephrology, University Medical Center Groningen, Antonius Deusinglaan 1, Groningen, The Netherlands.
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van der Zanden EP, Hilbers FW, Verseijden C, van den Wijngaard RM, Skynner M, Lee K, Ulloa L, Boeckxstaens GE, de Jonge WJ. Nicotinic acetylcholine receptor expression and susceptibility to cholinergic immunomodulation in human monocytes of smoking individuals. Neuroimmunomodulation 2012; 19:255-65. [PMID: 22441542 PMCID: PMC7068785 DOI: 10.1159/000335185] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2011] [Accepted: 11/14/2011] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE Smoking is generally accepted as a factor that affects the disease course in inflammatory bowel disease patients. Whether these effects can be contributed to the immunomodulatory effects of nicotine via nicotinic acetylcholine receptor (nAChR) activation is unclear. As previous data suggest that the α7 nicotinic acetylcholine receptor (CHRNA7) and its duplicated variant CHRFAM7A may specifically participate in the inflammatory response of monocytes, we evaluated whether repeated nicotine exposure or smoking affects monocyte CHRNA7 and CHRFAM7A expression and cholinergic immunomodulation. METHODS The human monocyte cell line THP-I was incubated with nicotine for different time points before endotoxin exposure. In a pilot volunteer study using smoking (n = 4) and nonsmoking (n = 7) individuals, vagal output was stimulated by olive oil administration after which monocytes were analyzed for nicotinic receptor expression. Serum tumor necrosis factor (TNF) levels were determined using ELISA and expression levels of the nAChR subunits CHRNA7, CHRNB2 or CHRFAM7A were analyzed using QPCR. RESULTS Repeated nicotine exposure upregulated CHRNA7 expression on THP-I monocytes and led to an enhanced potential of α7 nAChR agonist GSK1345038A to reduce TNF levels. Furthermore, CHRNA7 was only detectable in isolated blood monocytes of smokers. On the other hand, the expression of CHRFAM7A and CHRNB2 was not affected by nicotine exposure. Lipopolysaccharides-induced TNF secretion was inhibited by nicotinic receptor activation in THP-I monocytes, but this response was not consistently seen in blood monocytes from smoking individuals. CONCLUSIONS We conclude that CHRNA7 expression on blood monocytes is upregulated in smoking individuals, which may contribute to cholinergic immunomodulation.
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Affiliation(s)
| | - Francisca W. Hilbers
- Tytgat Institute for GI and Liver Research, Academic Medical Center, Amsterdam, The Netherlands
| | - Caroline Verseijden
- Tytgat Institute for GI and Liver Research, Academic Medical Center, Amsterdam, The Netherlands
| | | | - Mike Skynner
- Immuno-Inflammation CEDD, GlaxoSmithKline, Stevenage, UK
| | - Kevin Lee
- Immuno-Inflammation CEDD, GlaxoSmithKline, Stevenage, UK
| | - Luis Ulloa
- New Jersey Medical School, UMDNJ, Newark, N.J., USA
| | - Guy E. Boeckxstaens
- Tytgat Institute for GI and Liver Research, Academic Medical Center, Amsterdam, The Netherlands
- Department of Gastroenterology, University Hospital of Leuven, Catholic University of Leuven, Leuven, Belgium
| | - Wouter J. de Jonge
- Tytgat Institute for GI and Liver Research, Academic Medical Center, Amsterdam, The Netherlands
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Aldhous MC, Soo K, Stark LA, Ulanicka AA, Easterbrook JE, Dunlop MG, Satsangi J. Cigarette smoke extract (CSE) delays NOD2 expression and affects NOD2/RIPK2 interactions in intestinal epithelial cells. PLoS One 2011; 6:e24715. [PMID: 21931826 PMCID: PMC3171477 DOI: 10.1371/journal.pone.0024715] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2010] [Accepted: 08/19/2011] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Genetic and environmental factors influence susceptibility to Crohn's disease (CD): NOD2 is the strongest individual genetic determinant and smoking the best-characterised environmental factor. Carriage of NOD2 mutations predispose to small-intestinal, stricturing CD, a phenotype also associated with smoking. We hypothesised that cigarette smoke extract (CSE) altered NOD2 expression and function in intestinal epithelial cells. METHODS AND FINDINGS Intestinal epithelial cell-lines (SW480, HT29, HCT116) were stimulated with CSE and nicotine (to mimic smoking) ±TNFα (to mimic inflammation). NOD2 expression was measured by qRT-PCR and western blotting; NOD2-RIPK2 interactions by co-immunoprecipitation (CoIP); nuclear NFκB-p65 by ELISA; NFκB activity by luciferase reporter assays and chemokines (CCL20, IL8) in culture supernatants by ELISA. In SW480 and HT29 cells the TNFα-induced NOD2 expression at 4 hours was reduced by CSE (p = 0.0226), a response that was dose-dependent (p = 0.003) and time-dependent (p = 0.0004). Similar effects of CSE on NOD2 expression were seen in cultured ileal biopsies from healthy individuals. In SW480 cells CSE reduced TNFα-induced NFκB-p65 translocation at 15 minutes post-stimulation, upstream of NOD2. Levels of the NOD2-RIPK2 complex were no different at 8 hours post-stimulation with combinations of CSE, nicotine and TNFα, but at 18 hours it was increased in cells stimulated with TNFα+CSE but decreased with TNFα alone (p = 0.0330); CSE reduced TNFα-induced NFκB activity (p = 0.0014) at the same time-point. At 24 hours, basal CCL20 and IL8 (p<0.001 for both) and TNFα-induced CCL20 (p = 0.0330) production were decreased by CSE. CSE also reduced NOD2 expression, CCL20 and IL8 production seen with MDP-stimulation of SW480 cells pre-treated with combinations of TNFα and CSE. CONCLUSIONS CSE delayed TNFα-induced NOD2 mRNA expression and was associated with abnormal NOD2/RIPK2 interaction, reduced NFκB activity and decreased chemokine production. These effects may be involved in the pathogenesis of small-intestinal CD and may have wider implications for the effects of smoking in NOD2-mediated responses.
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Affiliation(s)
- Marian C Aldhous
- Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
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Brégeon F, Xeridat F, Andreotti N, Lepidi H, Delpierre S, Roch A, Ravailhe S, Jammes Y, Steinberg JG. Activation of nicotinic cholinergic receptors prevents ventilator-induced lung injury in rats. PLoS One 2011; 6:e22386. [PMID: 21857926 PMCID: PMC3152549 DOI: 10.1371/journal.pone.0022386] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2011] [Accepted: 06/20/2011] [Indexed: 01/14/2023] Open
Abstract
Respiratory distress syndrome is responsible for 40 to 60 percent mortality. An over mortality of about 10 percent could result from additional lung injury and inflammation due to the life-support mechanical ventilation, which stretches the lung. It has been recently demonstrated, in vitro, that pharmacological activation of the alpha 7 nicotinic receptors (α7-nAChR) could down regulate intracellular mediators involved in lung cell inflammatory response to stretch. Our aim was to test in vivo the protective effect of the pharmacological activation of the α7-nAChR against ventilator-induced lung injury (VILI). Anesthetized rats were ventilated for two hours with a high stretch ventilation mode delivering a stroke volume large enough to generate 25-cmH2O airway pressure, and randomly assigned to four groups: pretreated with parenteral injection of saline or specific agonist of the α7-nAChR (PNU-282987), or submitted to bilateral vagus nerve electrostimulation while pre-treated or not with the α7-nAChR antagonist methyllycaconitine (MLA). Controls ventilated with a conventional stroke volume of 10 mL/kg gave reference data. Physiological indices (compliance of the respiratory system, lung weight, blood oxygenation, arterial blood pressure) and lung contents of inflammatory mediators (IL-6 measured by ELISA, substance P assessed using HPLC) were severely impaired after two hours of high stretch ventilation (sham group). Vagal stimulation was able to maintain the respiratory parameters close to those obtained in Controls and reduced lung inflammation except when associated to nicotinic receptor blockade (MLA), suggesting the involvement of α7-nAChR in vagally-mediated protection against VILI. Pharmacological pre-treatment with PNU-282987 strongly decreased lung injury and lung IL-6 and substance P contents, and nearly abolished the increase in plasmatic IL-6 levels. Pathological examination of the lungs confirmed the physiological differences observed between the groups. In conclusion, these data suggest that the stimulation of α7-nAChR is able to attenuate VILI in rats.
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Affiliation(s)
- Fabienne Brégeon
- UMR MD2 P2COE, Institut Fédératif de Recherche Jean-Roche, Faculté de Médecine, Université de la Méditerranée Aix-Marseille II and Explorations Fonctionnelles Respiratoires de l' Hôpital Nord, Assistance Publique-Hôpitaux de Marseille, Marseille, France.
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Yasuda M, Kawahara R, Hashimura H, Yamanaka N, Iimori M, Amagase K, Kato S, Takeuchi K. Dopamine D₂-receptor antagonists ameliorate indomethacin-induced small intestinal ulceration in mice by activating α7 nicotinic acetylcholine receptors. J Pharmacol Sci 2011; 116:274-82. [PMID: 21691039 DOI: 10.1254/jphs.11037fp] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
We have reported that nicotine and the specific α7AChR agonist ameliorate indomethacin-induced intestinal lesions in mice by activating α7 nicotinic acetylcholine receptors (α7nAChR). Dopamine D₂-receptor antagonists, such as domperidone and metoclopramide, enhance the release of ACh from vagal efferent nerves. The present study examined the effects of domperidone and metoclopramide on indomethacin-induced small intestinal ulceration in mice, focusing on the α7AChR. Male C57BL/6 mice were administered indomethacin (10 mg/kg, s.c.) and sacrificed 24 h later. Domperidone (0.1-10 mg/kg) and metoclopramide (0.03-0.3 mg/kg) were administered i.p. twice, at 0.5 h before and 8 h after indomethacin treatment, while methyllycaconitine (a selective antagonist of α7nAChR, 30 mg/kg) was administered twice, at 0.5 h before each domperidone treatment. Indomethacin caused severe hemorrhagic lesions in the small intestine, mostly to the jejunum and ileum, with a concomitant increase in myeloperoxidase (MPO) activity. Domperidone suppressed the severity of lesions and the increase in MPO activity at low doses (0.1-3 mg/kg), but not at a high dose (10 mg/kg). Similar effects were also observed by metoclopramide. The protective effects of domperidone and metoclopramide were totally abolished by prior administration of methyllycaconitine. Indomethacin treatment markedly enhanced inducible nitric oxide synthase and chemokine mRNA expression in the small intestine, but these responses were all significantly attenuated by either domperidone or metoclopramide. These findings suggest that dopamine D₂-receptor antagonists ameliorate indomethacin-induced small intestinal ulceration through the activation of endogenous anti-inflammatory pathways mediated by α7nAChR.
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Affiliation(s)
- Masashi Yasuda
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
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Onat A, Hergenç G. Low-grade inflammation, and dysfunction of high-density lipoprotein and its apolipoproteins as a major driver of cardiometabolic risk. Metabolism 2011; 60:499-512. [PMID: 20580781 DOI: 10.1016/j.metabol.2010.04.018] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2010] [Revised: 04/12/2010] [Accepted: 04/19/2010] [Indexed: 12/30/2022]
Abstract
Dysfunction of high-density lipoprotein (HDL) particles that even become proinflammatory or lose atheroprotective properties is known through analyses of HDL isolated from diabetic subjects. Recently, high concentrations of HDL or apolipoprotein (apo) A-I in individuals with diabetes or coronary heart disease were found to reveal dysfunction in some population-based studies. Such dysfunction of HDL and its apos A-I, A-II, and C-III has been observed in a general population for the first time among Turkish adults. Functional defectiveness manifested itself by unexpected correlations with inflammatory biomarkers and, in long-term follow-up, by lack of protection against diabetes and coronary heart disease, accounting for the excess incidences in Turks. Female sex was more pronouncedly affected by this process that presumably exists in other ethnicities in South Asia, East Europe, and the Middle East. In contradistinction, in Western and East Asian population, only individuals with glucose intolerance or those at risk for cardiometabolic disease are considered to be or were documented in a review of clinical trials to have been affected by impaired function of HDL. High-density lipoprotein dysfunctionality is closely linked to obesity and low-grade inflammation yet seems to act partly independently of them. Cigarette smoking in overweight women with low-grade inflammation appears to offer limited protection against cardiometabolic risk. The great impact in public health of the dysfunction of protective serum proteins requires individual clinical recognition, appropriate preventive measures, and delineation of management, including with anti-inflammatory drugs.
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Affiliation(s)
- Altan Onat
- Turkish Society of Cardiology, Istanbul University, Istanbul 34098, Turkey.
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Kawahara R, Yasuda M, Hashimura H, Amagase K, Kato S, Takeuchi K. Activation of α7 nicotinic acetylcholine receptors ameliorates indomethacin-induced small intestinal ulceration in mice. Eur J Pharmacol 2010; 650:411-7. [PMID: 20969854 DOI: 10.1016/j.ejphar.2010.10.031] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2010] [Revised: 09/24/2010] [Accepted: 10/06/2010] [Indexed: 02/06/2023]
Abstract
Cholinergic anti-inflammatory actions have been shown to result mainly from the activation of α7 nicotinic acetylcholine receptors. Here, we investigated the possible role of α7 nicotinic acetylcholine receptors in the pathogenesis of indomethacin-induced small intestinal ulceration in mice. Male C57BL/6 mice were given indomethacin (10mg/kg, s.c.), and sacrificed 24h later. Nicotine (0.3-3mg/kg) and PNU-282987 (a selective agonist of α7 nicotinic acetylcholine receptors; 1-10mg/kg) were administered i.p. twice, at 0.5h before and 8h after indomethacin treatment, while methyllycaconitine (a selective antagonist of α7 nicotinic acetylcholine receptors; 10mg/kg was administered twice, at 0.5h before each nicotine treatment. Indomethacin caused severe hemorrhagic lesions in the small intestine with marked increases in myeloperoxidase (MPO) activity and inducible nitric oxide synthase (iNOS) expression in the mucosa. Pretreatment with nicotine reduced the severity of intestinal lesions in a dose-dependent manner. The protective effect of nicotine was mimicked by PNU-282987 and significantly attenuated by methyllycaconitine. The increases in MPO activity and iNOS expression induced by indomethacin were also significantly suppressed by nicotine and PNU-282987. Immunohistochemical study showed that the expression of α7 nicotinic acetylcholine receptors was clearly enhanced in the submucosa of the damaged area following indomethacin treatment. These results suggest that the activation of α7 nicotinic acetylcholine receptors ameliorates indomethacin-induced small intestinal ulceration, and that this effect may result from the inhibition of iNOS expression and neutrophil migration.
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Affiliation(s)
- Ryoji Kawahara
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan
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Snoek SA, Verstege MI, Boeckxstaens GE, van den Wijngaard RM, de Jonge WJ. The enteric nervous system as a regulator of intestinal epithelial barrier function in health and disease. Expert Rev Gastroenterol Hepatol 2010; 4:637-51. [PMID: 20932148 DOI: 10.1586/egh.10.51] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The intestinal epithelia proliferate and differentiate along the crypt villus axis to constitute a barrier cell layer separating some 10¹³ potentially harmful bacteria from a sterile mucosal compartment. Strict regulatory mechanisms are required to maintain a balance between the appropriate uptake of luminal food components and proteins, while constraining the exposure of the mucosal compartment to luminal antigens and microbes. The enteric nervous system is increasingly recognized as such a regulatory housekeeper of the epithelial barrier integrity, in addition to its ascribed immunomodulatory potential. Inflammation affects both epithelial integrity and barrier function and, in turn, loss of barrier function perpetuates inflammatory conditions. The observation that inflammatory conditions affect enteric neurons may add to the dysregulated barrier function in chronic disease. Here, we review the current understanding of the regulatory role of the nervous system in the maintenance of barrier function in healthy state, or during pathological conditions of, for instance, stress-induced colitis, surgical trauma or inflammation. We will discuss the clinical potential for advances in understanding the role of the enteric nervous system in this important phenomenon.
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Affiliation(s)
- Susanne A Snoek
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
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Zhou Y, Zuo X, Li Y, Wang Y, Zhao H, Xiao X. Nicotine inhibits tumor necrosis factor-α induced IL-6 and IL-8 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Rheumatol Int 2010; 32:97-104. [DOI: 10.1007/s00296-010-1549-4] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2010] [Accepted: 07/11/2010] [Indexed: 10/19/2022]
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Snoek SA, Verstege MI, van der Zanden EP, Deeks N, Bulmer DC, Skynner M, Lee K, Te Velde AA, Boeckxstaens GE, de Jonge WJ. Selective alpha7 nicotinic acetylcholine receptor agonists worsen disease in experimental colitis. Br J Pharmacol 2010; 160:322-33. [PMID: 20423343 DOI: 10.1111/j.1476-5381.2010.00699.x] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND AND PURPOSE In various models vagus nerve activation has been shown to ameliorate intestinal inflammation, via nicotinic acetylcholine receptors (nAChRs) expressed on immune cells. As the alpha7 nAChR has been put forward to mediate this effect, we studied the effect of nicotine and two selective alpha7 nAChR agonists (AR-R17779, (-)-spiro[1-azabicyclo[2.2.2] octane-3,5'-oxazolidin-2'-one and GSK1345038A) on disease severity in two mouse models of experimental colitis. EXPERIMENTAL APPROACH Colitis was induced by administration of 1.5% dextran sodium sulphate (DSS) in drinking water or 2 mg 2,4,6-trinitrobenzene sulphonic acid (TNBS) intrarectally. Nicotine (0.25 and 2.50 micromol.kg(-1)), AR-R17779 (0.6-30 micromol.kg(-1)) or GSK1345038A (6-120 micromol.kg(-1)) was administered daily by i.p. injection. After 7 (DSS) or 5 (TNBS) days clinical parameters and colonic inflammation were scored. KEY RESULTS Nicotine and both alpha7 nAChR agonists reduced the activation of NF-kappaB and pro-inflammatory cytokines in whole blood and macrophage cultures. In DSS colitis, nicotine treatment reduced colonic cytokine production, but failed to reduce disease parameters. Reciprocally, treatment with AR-R17779 or GSK1345038A worsened disease and led to increased colonic pro-inflammatory cytokine levels in DSS colitis. The highest doses of GSK1345038A (120 micromol.kg(-1)) and AR-R17779 (30 micromol.kg(-1)) ameliorated clinical parameters, without affecting colonic inflammation. Neither agonist ameliorated TNBS-induced colitis. CONCLUSIONS AND IMPLICATIONS Although nicotine reduced cytokine responses in vitro, both selective alpha7 nAChR agonists worsened the effects of DSS-induced colitis or were ineffective in those of TNBS-induced colitis. Our data indicate the need for caution in evaluating alpha7 nAChR as a drug target in colitis.
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Affiliation(s)
- Susanne A Snoek
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, the Netherlands
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Chernyavsky AI, Arredondo J, Skok M, Grando SA. Auto/paracrine control of inflammatory cytokines by acetylcholine in macrophage-like U937 cells through nicotinic receptors. Int Immunopharmacol 2009; 10:308-15. [PMID: 20004742 DOI: 10.1016/j.intimp.2009.12.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2009] [Revised: 11/20/2009] [Accepted: 12/01/2009] [Indexed: 01/16/2023]
Abstract
Although acetylcholine (ACh) is well known for its neurotransmitter function, recent studies have indicated that it also functions as an immune cytokine that prevents macrophage activation through a 'cholinergic (nicotinic) anti-inflammatory pathway'. In this study, we used the macrophage-like U937 cells to elucidate the mechanisms of the physiologic control of cytokine production by auto/paracrine ACh through the nicotinic class of ACh receptors (nAChRs) expressed in these cells. Stimulation of cells with lipopolysaccharide up-regulated expression of alpha1, alpha4, alpha5, alpha7, alpha10, beta1 and beta3 subunits, down-regulated alpha6 and beta2 subunits, and did not alter the relative quantity of alpha9 and beta4 mRNAs. Distinct nAChR subtypes showed differential regulation of the production of pro- and anti-inflammatory cytokines. While inhibition of the expression of the TNF-alpha gene was mediated predominantly by the alpha-bungarotoxin sensitive nAChRs, that of the IL-6 and IL-18 genes-by the mecamylamine-sensitive nAChRs. Both the Mec- and alphaBtx-sensitive nAChRs regulated expression of the IL-1beta gene equally efficiently. Upregulation of IL-10 production by auto/paracrine ACh was mediated predominantly through alpha7 nAChR. These findings offer a new insight on how nicotinic agonists control inflammation, thus laying a groundwork for the development of novel immunomodulatory therapies based on the nAChR subtype selectivity of nicotinic agonists.
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Chatterjee PK, Al-Abed Y, Sherry B, Metz CN. Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation. Am J Physiol Cell Physiol 2009; 297:C1294-306. [PMID: 19741199 DOI: 10.1152/ajpcell.00160.2009] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The cholinergic anti-inflammatory pathway is a physiological mechanism that inhibits cytokine production and minimizes tissue injury during inflammation. Previous investigations revealed that cholinergic stimulation (via cholinergic agonists and vagus nerve stimulation) suppresses endothelial cell activation and leukocyte recruitment. The purpose of this study was to investigate the mechanisms by which cholinergic agonists (e.g., nicotine and GTS-21) regulate endothelial cell activation. Specifically, we examined the effects of cholinergic agonists on IL-6-mediated endothelial cell activation through the JAK2/STAT3 signaling pathway. Treatment of macrovascular human umbilical vein endothelial cells (HUVECs) and microvascular endothelial cells (MVECs) with the cholinergic agonists nicotine and GTS-21 significantly reduced IL-6-mediated monocyte chemoattractant protein-1 (MCP-1) production and ICAM-1 expression which are regulated through the JAK2/STAT3 pathway. We found that treatment of endothelial cells with cholinergic agonists significantly reduced STAT3 activation by phosphorylation and DNA binding. The inhibition of STAT3 phosphorylation was reversed by sodium orthovanadate, an inhibitor of tyrosine phosphatases, as well as by NSC-87877 suggesting a SHP1/2-dependent mechanism. Further investigations showed that cholinergic agonists reduced the phosphorylation of JAK2, an upstream component of the JAK2/STAT3 pathway. Finally, we observed that nicotine and GTS-21 treatment decreased levels of SOCS3 (suppressor of cytokine signaling; a regulator of the inflammatory activity of IL-6) in activated endothelial cells. These data demonstrate that cholinergic agonists suppress IL-6-mediated endothelial cell activation through the JAK2/STAT3 pathway. Our results have significant implications for better understanding the therapeutic potential of cholinergic agonists for treating IL-6 mediated inflammatory conditions.
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Affiliation(s)
- Prodyot K Chatterjee
- The Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, New York, USA
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Lindblad SS, Mydel P, Jonsson IM, Senior RM, Tarkowski A, Bokarewa M. Smoking and nicotine exposure delay development of collagen-induced arthritis in mice. Arthritis Res Ther 2009; 11:R88. [PMID: 19519907 PMCID: PMC2714144 DOI: 10.1186/ar2728] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2009] [Revised: 06/08/2009] [Accepted: 06/11/2009] [Indexed: 11/24/2022] Open
Abstract
Introduction Recent epidemiologic studies have implicated smoking as an environmental risk factor for the development of rheumatoid arthritis (RA). The aim of the present study is the evaluation of the role of cigarette smoke (CS) in the pathogenesis of collagen-induced arthritis in mice. Methods DBA/1 mice exposed to CS for 16 weeks (n = 25) and mice exposed to nicotine in drinking water (n = 10) were immunized with collagen type II (CII). Severity of arthritis was evaluated clinically and morphologically and compared with control mice (n = 35). Intensity of inflammation was evaluated by serum IL-6 and TNF-α levels. Additionally, antibody response to CII (anti-CII) and citrullinated peptides (aCCP) was measured. Results Clinical evaluation of arthritis showed a delayed onset of arthritis in CS-exposed mice compared with non-smoking controls (P < 0.05). Histologic index and weight changes were comparable between the groups; however, smoking mice presented less weight loss during the acute phase of the disease and gained weight significantly faster in the recovery phase (P < 0.05). Similar results were obtained in the mice exposed to nicotine. Nicotine also showed a direct anti-inflammatory effect diminishing IL-6 production by stimulated splenocytes in vitro (P < 0.001). Additionally, smoking mice had lower levels of aCCP and anti-CII antibodies compared with non-smoking (P < 0.05). Conclusions Neither smoking nor nicotine exposure aggravates development of CII-induced arthritis in mouse model. Moreover, CS exposure was associated with a lower level of anti-CII antibodies, providing a possible explanation for a delay of arthritis onset in this group.
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Affiliation(s)
- Sofia S Lindblad
- Department of Rheumatology and Inflammation Research, University of Gothenburg, Sahlgrenska University Hospital, Guldhedsgatan 10, Göteborg S-41346, Sweden.
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Huang H, Lavoie-Lamoureux A, Lavoie JP. Cholinergic stimulation attenuates the IL-4 induced expression of E-selectin and vascular endothelial growth factor by equine pulmonary artery endothelial cells. Vet Immunol Immunopathol 2009; 132:116-21. [PMID: 19501920 DOI: 10.1016/j.vetimm.2009.05.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2008] [Revised: 03/30/2009] [Accepted: 05/11/2009] [Indexed: 10/20/2022]
Abstract
The endothelium plays a critical role in regulating leukocyte recruitment and migration during inflammation. Recent studies provide evidence that acetylcholine (ACh) and other cholinergic mediators block endothelial cells activation and leukocyte recruitment during inflammation. We thus postulated that the non-neuronal cholinergic system might modulate the recruitment of neutrophils during allergic pulmonary inflammation. In the present study, we examined the effects of cholinergic stimulation on the expression of neutrophil chemokines and adhesion molecules by endothelial cells stimulated by recombinant equine (re) IL-4. Using primary equine pulmonary artery endothelial cells culture and real-time RT-PCR method, we observed that ACh, nicotine, and muscarine inhibit the expression of E-selectin and vascular endothelial growth factor by endothelial cells stimulated by reIL-4. The expression of CXCL-8, a potent neutrophil chemotactic cytokine, remained unaffected however. These findings suggest that the cholinergic anti-inflammatory pathway may modulate pulmonary allergic inflammation and remodeling by the inhibition of selected adhesion molecules and growth factors.
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Affiliation(s)
- H Huang
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Université de Montréal, C.P. 5000, 3200 Sicotte, Saint-Hyacinthe, Québec, Canada, J2S 7C6.
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Van Der Zanden EP, Boeckxstaens GE, de Jonge WJ. The vagus nerve as a modulator of intestinal inflammation. Neurogastroenterol Motil 2009; 21:6-17. [PMID: 19140954 DOI: 10.1111/j.1365-2982.2008.01252.x] [Citation(s) in RCA: 107] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The cholinergic nervous system attenuates the production of pro-inflammatory cytokines and inhibits inflammatory processes. Hence, in animal models of intestinal inflammation, such as postoperative ileus and dextran sulfate sodium-induced colitis, vagus nerve stimulation ameliorates disease activity. On the other hand, in infectious models of microbial peritonitis, vagus nerve activation seemingly acts counteractive; it impairs bacterial clearance and increases mortality. It is originally indicated that the key mediator of the cholinergic anti-inflammatory pathway, acetylcholine (ACh), inhibits cytokine release directly via the alpha7 nicotinic ACh receptor (nAChR) expressed on macrophages. However, more recent data also point towards the vagus nerve as an indirect modulator of innate inflammatory processes, exerting its anti-inflammatory effects via postganglionic modulation of immune cells in primary immune organs. This review discusses advances in the possible mechanisms by which the vagus nerve can mediate the immune response, and the role of nAChR activation and signalling on macrophages and other immune cells.
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Affiliation(s)
- E P Van Der Zanden
- Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands
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Aldhous MC, Prescott RJ, Roberts S, Samuel K, Waterfall M, Satsangi J. Does nicotine influence cytokine profile and subsequent cell cycling/apoptotic responses in inflammatory bowel disease? Inflamm Bowel Dis 2008; 14:1469-82. [PMID: 18618634 DOI: 10.1002/ibd.20523] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Smoking differentially influences susceptibility to the inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis (UC). We investigated the effects of nicotine on cytokine, cell cycle, and apoptotic responses in peripheral blood mononuclear cells (PBMCs) from IBD patients and healthy controls (HCs). METHODS PBMCs from IBD patients and HC were stimulated with lipopolysaccharide (LPS; 1 microg/mL) or phytohemagglutinin (PHA, 5 or 0.5 microg/mL), +/- nicotine (1, 10, 100 microg/mL). Cytokines (IL1beta, IL2, IL10, IL12/IL23p40, TGFbeta, TNFalpha) were measured in supernatants at 24 hours. After 72 hours cells were analyzed by flow cytometry for cell cycle and apoptosis. Statistical modeling was used to identify interactions between cytokines and cell cycle / apoptosis and minimize confounding effects. RESULTS Stimulation by LPS and PHA (5 microg/mL) increased IL12/IL23p40 production from CD and UC versus HC (P < 0.05); PHA (0.5 microg/mL) increased IL1beta in UC and decreased TGFbeta from CD and UC (P < 0.01). In all groups, nicotine reduced LPS- and PHA (0.5 microg/mL)-stimulated production of IL1beta, IL10, TGFbeta, and TNFalpha (P < 0.001). Cell cycle analysis showed that PHA, but not LPS, induced proliferation and decreased G(0)/G(1) resting cells in CD and UC versus HC (P < 0.001). Nicotine decreased PHA-stimulated S-phase proliferation and increased G(0)/G(1) resting cells (P < 0.01). Modeling showed independent associations between IL12/IL23p40 and apoptosis (P = 0.01), IL1beta and resting cells (P = 0.006), TNFalpha and proliferating cells (P < 0.001). Disease activity and smoking habit had no effect. CONCLUSIONS Dysregulated cytokine profiles in UC and CD are associated with specific alterations in cell cycle responses; these effects may be modified by nicotine, and potentially by anticytokine therapies.
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Affiliation(s)
- Marian C Aldhous
- Gastrointestinal Unit, School of Clinical and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland, UK.
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Cheng PY, Lee YM, Law KK, Lin CW, Yen MH. The involvement of AMP-activated protein kinases in the anti-inflammatory effect of nicotine in vivo and in vitro. Biochem Pharmacol 2007; 74:1758-65. [PMID: 17869227 DOI: 10.1016/j.bcp.2007.08.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2007] [Revised: 08/03/2007] [Accepted: 08/03/2007] [Indexed: 12/31/2022]
Abstract
AMP-activated protein kinase (AMPK) is the downstream component of a kinase cascade that plays a pivotal role in energy homeostasis. AMPK has recently emerged as an attractive and novel target for inflammatory disorders. Thus, the aim of this study was to assess the role of AMPKalpha in the anti-inflammatory effect of nicotine in carrageenan-induced rat paw edema model and to evaluate the mechanism of nicotine-induced AMPKalpha phosphorylation in RAW 264.7 cells. The results indicate that nicotine alleviated paw edema and the activation of AMPKalpha involved in the anti-inflammatory effect of nicotine in vivo. In addition, nicotine was able to activate AMPKalpha phosphorylation in macrophages and this effect was mediated through nicotinic acetylcholine receptors. Furthermore, nicotine significantly induced the phosphorylation of Akt and the Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK) protein expression in macrophages. Wortmannin, a specific inhibitor of phosphotidylinositol 3-kinase (PI3K), suppressed nicotine-induced Akt and AMPKalpha phosphorylation. STO-609, a CaMKK inhibitor, not only inhibited the activation of AMPKalpha but also suppressed the phosphorylation of Akt induced by nicotine. In conclusion, both of CaMKK and PI3K/Akt pathways are involved in the nicotine-induced AMPKalpha phosphorylation in macrophages, and the interaction of CaMKK and Akt may exist. AMPKalpha is a novel and critical component of anti-inflammatory effect of nicotine.
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Affiliation(s)
- Pao-Yun Cheng
- Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan
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Dowling O, Rochelson B, Way K, Al-Abed Y, Metz CN. Nicotine inhibits cytokine production by placenta cells via NFkappaB: potential role in pregnancy-induced hypertension. Mol Med 2007; 13:576-83. [PMID: 17878927 PMCID: PMC1978252 DOI: 10.2119/2007-00067.dowling] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2007] [Accepted: 09/04/2007] [Indexed: 01/23/2023] Open
Abstract
Pregnancy-induced hypertension (PIH), also known as preeclampsia, is one of the major causes of maternal and fetal death. While the precise cause of PIH is not known, aberrant cytokine production and placenta participation are considered to be important factors. Gestational cigarette smoking, which is widely accepted to be harmful to both the mother and fetus, is protective against PIH. Based on the antiinflammatory activity of nicotine, the major component of cigarettes, we examined the effect of nicotine and other cholinergic agonists on placental inflammatory responses ex vivo. We observed that nicotine and other cholinergic agonists significantly suppress placenta cytokine production following stimulation. Placenta cells express the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), and using cholinergic antagonists, we demonstrated that the antiinflammatory effect of nicotine and other cholinergic agonists is, in part, mediated through the nAChR pathway. By contrast, cholinergic stimulation had no effect on the expression of soluble fms-like tyrosine kinase (sFlt), an antiangiogenic substance implicated in maternal vascular dysfunction during PIH. Mechanistic studies reveal that cholinergic agonists exert their antiinflammatory effects through the NFkappaB pathway. Taken together, our results suggest that cholinergic agonists, including nicotine, may reduce cytokine production by placenta cells via NFkappaB to protect against PIH.
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Affiliation(s)
- Oonagh Dowling
- The Susan and Herman Merinoff Center for Patient-Oriented Research, The Feinstein Institute for Medical Research, North Shore-LIJ Health System
| | - Burton Rochelson
- Division of Maternal-Fetal Medicine, North Shore University Hospital, Manhasset, New York, USA
| | - Kathleen Way
- The Susan and Herman Merinoff Center for Patient-Oriented Research, The Feinstein Institute for Medical Research, North Shore-LIJ Health System
| | - Yousef Al-Abed
- The Susan and Herman Merinoff Center for Patient-Oriented Research, The Feinstein Institute for Medical Research, North Shore-LIJ Health System
| | - Christine N Metz
- The Susan and Herman Merinoff Center for Patient-Oriented Research, The Feinstein Institute for Medical Research, North Shore-LIJ Health System
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McGilligan VE, Wallace JMW, Heavey PM, Ridley DL, Rowland IR. Hypothesis about mechanisms through which nicotine might exert its effect on the interdependence of inflammation and gut barrier function in ulcerative colitis. Inflamm Bowel Dis 2007; 13:108-15. [PMID: 17206646 DOI: 10.1002/ibd.20020] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Ulcerative colitis (UC) is characterized by impairment of the epithelial barrier and the formation of ulcer-type lesions, which result in local leaks and generalized alterations of mucosal tight junctions. Ultimately, this results in increased basal permeability. Although disruption of the epithelial barrier in the gut is a hallmark of inflammatory bowel disease and intestinal infections, it remains unclear whether barrier breakdown is an initiating event of UC or rather a consequence of an underlying inflammation, evidenced by increased production of proinflammatory cytokines. UC is less common in smokers, suggesting that the nicotine in cigarettes may ameliorate disease severity. The mechanism behind this therapeutic effect is still not fully understood, and indeed it remains unclear if nicotine is the true protective agent in cigarettes. Nicotine is metabolized in the body into a variety of metabolites and can also be degraded to form various breakdown products. It is possible these metabolites or degradation products may be the true protective or curative agents. A greater understanding of the pharmacodynamics and kinetics of nicotine in relation to the immune system and enhanced knowledge of gut permeability defects in UC are required to establish the exact protective nature of nicotine and its metabolites in UC. This review suggests possible hypotheses for the protective mechanism of nicotine in UC, highlighting the relationship between gut permeability and inflammation, and indicates where in the pathogenesis of the disease nicotine may mediate its effect.
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Affiliation(s)
- Victoria E McGilligan
- Northern Ireland Centre for Food and Health (NICHE), Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
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Yoshikawa H, Kurokawa M, Ozaki N, Nara K, Atou K, Takada E, Kamochi H, Suzuki N. Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppression of I-kappaB phosphorylation and nuclear factor-kappaB transcriptional activity through nicotinic acetylcholine receptor alpha7. Clin Exp Immunol 2006; 146:116-23. [PMID: 16968406 PMCID: PMC1809735 DOI: 10.1111/j.1365-2249.2006.03169.x] [Citation(s) in RCA: 228] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Macrophages/monocytes and the proinflammatory mediators, such as tumour necrosis factor (TNF)-alpha, prostaglandin E(2) (PGE(2)), macrophage inflammatory protein (MIP)-1alpha and MIP-1alpha, play a critical role in the progression of immunological disorders including rheumatoid arthritis, Behçet's disease and Crohn's disease. In addition, the nicotinic acetylcholine receptor-alpha7 (alpha7nAChR) subunit is an essential regulator of inflammation. In this study, we evaluated the expression of the alpha7nAChR subunit on human peripheral monocytes and the effect of nicotine on the production of these proinflammatory mediators by activated monocytes. Fluorescein isothiocyanate (FITC)-labelled alpha-bungarotoxin demonstrated the cell surface expression of the alpha7nAchR subunit. Pretreatment with low-dose nicotine caused inhibition of TNF-alpha, PGE(2), MIP-1alpha and MIP-1alpha production, and mRNA expression of TNF-alpha, MIP-1alpha and MIP-1alpha and COX-2 in lipopolysaccharide (LPS)-activated monocytes. These suppressive effects of nicotine were caused at the transcriptional level and were mediated through alpha7nAChR. Nicotine suppressed the phosphorylation of I-kappaB, and then inhibited the transcriptional activity of nuclear factor-kappaB. These immunosuppressive effects of nicotine may contribute to the regulation of some immune diseases.
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Affiliation(s)
- H Yoshikawa
- Department of Immunology and Medicine, Institute of Advanced Medical Science, St Marianna Graduate School of Medicine, Kawasaki, Japan
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Kwon JY, Kim YH, Kim SH, Kang MH, Maeng YS, Lee KY, Park YW. Difference in the expression of alpha 7 nicotinic receptors in the placenta in normal versus severe preeclampsia pregnancies. Eur J Obstet Gynecol Reprod Biol 2006; 132:35-9. [PMID: 16837119 DOI: 10.1016/j.ejogrb.2006.05.034] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2005] [Revised: 04/16/2006] [Accepted: 05/26/2006] [Indexed: 10/24/2022]
Abstract
OBJECTIVE The prevalence of preeclampsia is low in smokers, suggesting a possible role of nicotinic receptor in the pathophysiology of the disease. Alpha 7 nicotinic acetylcholine receptor (alpha7 nAChR) was recently found in non-neuronal tissue with various mediating functions. Therefore, we investigated the difference in the placental expression of the alpha7 nAChR in normal versus severe preeclampsia placentas. STUDY DESIGN Central portions of placenta were obtained from 9 severe preeclampsia women and 11 gestational-age-matched normal pregnant women delivered between the gestational ages of 33 and 40 weeks following elective or emergency cesarean section. RT-PCR, western blotting, and immunohistochemical staining were performed to evaluate the alpha7 nAChR expression difference. RESULTS In all the placentas, the alpha7 nAChR was expressed in endothelial cells, vascular smooth muscle cells, and stromal cells, but not in trophoblasts. The vascular staining was more intense in the severe preeclampsia placenta (p=0.02). Although the gene expression did not differ between the two groups, protein expression was greater in 7 of 9 placenta samples from the severe preeclampsia group. CONCLUSION Placental expression of alpha7 nAChR differs between normal and severe preeclampsia placentas, suggesting that it may be involved in the pathogenesis of preeclampsia.
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Affiliation(s)
- Ja-Young Kwon
- Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynecology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemoon-gu, Seoul 120-752, South Korea
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Baker JA, Odunuga OO, Rodabaugh KJ, Reid ME, Menezes RJ, Moysich KB. Active and passive smoking and risk of ovarian cancer. Int J Gynecol Cancer 2006; 16 Suppl 1:211-8. [PMID: 16515593 DOI: 10.1111/j.1525-1438.2006.00473.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
It is unclear whether smoking is a risk factor for epithelial ovarian cancer, although some studies have suggested that it may be associated with an increased risk of mucinous tumors. This study investigated the effect of smoking and environmental tobacco smoke (ETS) on ovarian cancer risk among 434 women with primary epithelial ovarian, peritoneal, or fallopian cancers and 868 age- and region-matched hospital controls with nonneoplastic conditions. All participants completed a comprehensive epidemiologic questionnaire. Results indicate that decreased risk of ovarian cancer was associated with being a nonsmoker exposed to ETS (adjusted odds ratio [aOR] 0.68, 95% confidence interval [CI] 0.46-0.99), a former smoker (aOR 0.76, 95% CI 0.53-1.10), or a current smoker (aOR 0.53, 95% CI 0.32-0.88). A similar protective effect was noted for smokers with moderate or high exposure based on smoking intensity, duration, and cumulative exposure, as well as for never smokers exposed to ETS. Results did not differ substantially by histologic subtype. Although prevailing theories of ovarian cancer etiology implicate incessant ovulation, characteristics of the study population suggest that anovulation was not the protective mechanism in this study. Immunosuppression by nicotine or upregulation of enzymes that metabolize carcinogens may be responsible for the effects observed.
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Affiliation(s)
- J A Baker
- Department of Epidemiology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA
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Robbins CS, Pouladi MA, Fattouh R, Dawe DE, Vujicic N, Richards CD, Jordana M, Inman MD, Stampfli MR. Mainstream cigarette smoke exposure attenuates airway immune inflammatory responses to surrogate and common environmental allergens in mice, despite evidence of increased systemic sensitization. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2005; 175:2834-42. [PMID: 16116169 DOI: 10.4049/jimmunol.175.5.2834] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The purpose of this study was to investigate the impact of mainstream cigarette smoke exposure (MTS) on allergic sensitization and the development of allergic inflammatory processes. Using two different experimental murine models of allergic airways inflammation, we present evidence that MTS increased cytokine production by splenocytes in response to OVA and ragweed challenge. Paradoxically, MTS exposure resulted in an overall attenuation of the immune inflammatory response, including a dramatic reduction in the number of eosinophils and activated (CD69+) and Th2-associated (T1ST2+) CD4 T lymphocytes in the lung. Although MTS did not impact circulating levels of OVA-specific IgE and IgG1, we observed a striking reduction in OVA-specific IgG2a production and significantly diminished airway hyperresponsiveness. MTS, therefore, plays a disparate role in the development of allergic responses, inducing a heightened state of allergen-specific sensitization, but dampening local immune inflammatory processes in the lung.
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Affiliation(s)
- Clinton S Robbins
- Department of Pathology, Center for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada
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Saeed RW, Varma S, Peng-Nemeroff T, Sherry B, Balakhaneh D, Huston J, Tracey KJ, Al-Abed Y, Metz CN. Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation. ACTA ACUST UNITED AC 2005; 201:1113-23. [PMID: 15809354 PMCID: PMC2213139 DOI: 10.1084/jem.20040463] [Citation(s) in RCA: 390] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Endothelial cell activation plays a critical role in regulating leukocyte recruitment during inflammation and infection. Based on recent studies showing that acetylcholine and other cholinergic mediators suppress the production of proinflammatory cytokines via the α7 nicotinic acetylcholine receptor (α7 nAChR) expressed by macrophages and our observations that human microvascular endothelial cells express the α7 nAChR, we examined the effect of cholinergic stimulation on endothelial cell activation in vitro and in vivo. Using the Shwartzman reaction, we observed that nicotine (2 mg/kg) and the novel cholinergic agent CAP55 (12 mg/kg) inhibit endothelial cell adhesion molecule expression. Using endothelial cell cultures, we observed the direct inhibitory effects of acetylcholine and cholinergic agents on tumor necrosis factor (TNF)-induced endothelial cell activation. Mecamylamine, an nAChR antagonist, reversed the inhibition of endothelial cell activation by both cholinergic agonists, confirming the antiinflammatory role of the nAChR cholinergic pathway. In vitro mechanistic studies revealed that nicotine blocked TNF-induced nuclear factor–κB nuclear entry in an inhibitor κB (IκB)α- and IκBɛ-dependent manner. Finally, with the carrageenan air pouch model, both vagus nerve stimulation and cholinergic agonists significantly blocked leukocyte migration in vivo. These findings identify the endothelium, a key regulator of leukocyte trafficking during inflammation, as a target of anti-inflammatory cholinergic mediators.
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Affiliation(s)
- Rubina W Saeed
- Laboratory of Medicinal Biochemistry, Institute for Medical Research at North Shore-LIJ, Manhasset, NY 11030, USA
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Abstract
The 'cytokine theory of disease' states that an overproduction of cytokines can cause the clinical manifestations of disease. Much effort has been expended to determine how cytokines are regulated in normal health. Transcriptional, translational and other molecular control mechanisms protect the host from excessive cytokine production. A recent discovery revealed an unexpected pathway that inhibits macrophage cytokine production. The inflammatory reflex is a physiological pathway in which the autonomic nervous system detects the presence of inflammatory stimuli and modulates cytokine production. Afferent signals to the brain are transmitted via the vagus nerve, which activates a reflex response that culminates in efferent vagus nerve signalling. Termed the 'cholinergic anti-inflammatory pathway', efferent activity in the vagus nerve releases acetylcholine (ACh) in the vicinity of macrophages within the reticuloendothelial system. ACh can interact specifically with macrophage alpha7 subunits of nicotinic ACh receptors, leading to cellular deactivation and inhibition of cytokine release. This 'hard-wired' connection between the nervous and immune systems can be harnessed therapeutically in animal models of inflammatory disease, via direct electrical stimulation of the vagus nerve, or through the use of cholinergic agonists that specifically activate the macrophage alpha7 subunit of the ACh receptor. Autonomic dysfunction has been associated with human inflammatory diseases including rheumatoid arthritis, diabetes and sepsis; whether this dysfunction results from the inflammatory component of these diseases, or is actually an underlying cause, is now less clear. The description of the cholinergic anti-inflammatory now brings to the fore several new therapeutic strategies for inflammatory disease, and suggests that many of these diseases may actually be diseases of autonomic dysfunction.
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Affiliation(s)
- C J Czura
- North Shore-LIJ Research Institute, Center for Patient Oriented Research, Manhasset, NY, USA.
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