P2X7 receptor and caspase 1 activation are central to airway inflammation observed after exposure to tobacco smoke
Chronic Obstructive Pulmonary Disease (COPD) is a cigarette smoke (CS)-driven inflammatory airway disease with an increasing global prevalence. Currently there is no effective medication to stop the relentless progression of this disease. It has recently been shown that an activator of the P2X7/infl...
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| description | Chronic Obstructive Pulmonary Disease (COPD) is a cigarette smoke (CS)-driven inflammatory airway disease with an increasing global prevalence. Currently there is no effective medication to stop the relentless progression of this disease. It has recently been shown that an activator of the P2X7/inflammasome pathway, ATP, and the resultant products (IL-1β/IL-18) are increased in COPD patients. The aim of this study was to determine whether activation of the P2X7/caspase 1 pathway has a functional role in CS-induced airway inflammation. Mice were exposed to CS twice a day to induce COPD-like inflammation and the role of the P2X7 receptor was investigated. We have demonstrated that CS-induced neutrophilia in a pre-clinical model is temporally associated with markers of inflammasome activation, (increased caspase 1 activity and release of IL-1β/IL-18) in the lungs. A selective P2X7 receptor antagonist and mice genetically modified so that the P2X7 receptors were non-functional attenuated caspase 1 activation, IL-1β release and airway neutrophilia. Furthermore, we demonstrated that the role of this pathway was not restricted to early stages of disease development by showing increased caspase 1 activation in lungs from a more chronic exposure to CS and from patients with COPD. This translational data suggests the P2X7/Inflammasome pathway plays an ongoing role in disease pathogenesis. These results advocate the critical role of the P2X7/caspase 1 axis in CS-induced inflammation, highlighting this as a possible therapeutic target in combating COPD. |
| doi_str_mv | 10.1371/journal.pone.0024097 |
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Currently there is no effective medication to stop the relentless progression of this disease. It has recently been shown that an activator of the P2X7/inflammasome pathway, ATP, and the resultant products (IL-1β/IL-18) are increased in COPD patients. The aim of this study was to determine whether activation of the P2X7/caspase 1 pathway has a functional role in CS-induced airway inflammation. Mice were exposed to CS twice a day to induce COPD-like inflammation and the role of the P2X7 receptor was investigated. We have demonstrated that CS-induced neutrophilia in a pre-clinical model is temporally associated with markers of inflammasome activation, (increased caspase 1 activity and release of IL-1β/IL-18) in the lungs. A selective P2X7 receptor antagonist and mice genetically modified so that the P2X7 receptors were non-functional attenuated caspase 1 activation, IL-1β release and airway neutrophilia. Furthermore, we demonstrated that the role of this pathway was not restricted to early stages of disease development by showing increased caspase 1 activation in lungs from a more chronic exposure to CS and from patients with COPD. This translational data suggests the P2X7/Inflammasome pathway plays an ongoing role in disease pathogenesis. These results advocate the critical role of the P2X7/caspase 1 axis in CS-induced inflammation, highlighting this as a possible therapeutic target in combating COPD.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0024097</identifier><identifier>PMID: 21915284</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Adenosine ; Animals ; Biology ; Caspase ; Caspase 1 - metabolism ; Caspase-1 ; Cell activation ; Chronic exposure ; Chronic obstructive pulmonary disease ; Cigarette smoke ; Cigarettes ; Conditioned stimulus ; Cytokines ; Development and progression ; Developmental stages ; Drugs ; Emphysema ; Exposure ; Genetic modification ; Genetically modified organisms ; Heart ; Humans ; Hypotheses ; In Vitro Techniques ; Inflammasomes ; Inflammation ; Inflammation - chemically induced ; Inflammation - metabolism ; Interleukin 18 ; Interleukin-18 - metabolism ; Interleukin-1beta - metabolism ; Laboratories ; Lipopolysaccharides - toxicity ; Lung diseases ; Lungs ; Male ; Medical research ; Medicine ; Mice ; Neutrophilia ; Neutrophils ; Obstructive lung disease ; Pathogenesis ; Patients ; Pharmacology ; Physiology ; Receptors ; Receptors, Purinergic P2X7 - metabolism ; Respiratory System - drug effects ; Respiratory System - metabolism ; Respiratory tract diseases ; Rodents ; Smoke ; Smoking ; Smoking - adverse effects ; Tobacco ; Tobacco smoke ; Tumor necrosis factor-TNF</subject><ispartof>PloS one, 2011-09, Vol.6 (9), p.e24097</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Eltom et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Eltom et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c757t-f39c5384534469c26966db73455bd5430adefaa2538bcf45ed2888b9872d33893</citedby><cites>FETCH-LOGICAL-c757t-f39c5384534469c26966db73455bd5430adefaa2538bcf45ed2888b9872d33893</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3167831/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3167831/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21915284$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Eltom, Suffwan</creatorcontrib><creatorcontrib>Stevenson, Christopher S</creatorcontrib><creatorcontrib>Rastrick, Joseph</creatorcontrib><creatorcontrib>Dale, Nicole</creatorcontrib><creatorcontrib>Raemdonck, Kristof</creatorcontrib><creatorcontrib>Wong, Sissie</creatorcontrib><creatorcontrib>Catley, Matthew C</creatorcontrib><creatorcontrib>Belvisi, Maria G</creatorcontrib><creatorcontrib>Birrell, Mark A</creatorcontrib><title>P2X7 receptor and caspase 1 activation are central to airway inflammation observed after exposure to tobacco smoke</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Chronic Obstructive Pulmonary Disease (COPD) is a cigarette smoke (CS)-driven inflammatory airway disease with an increasing global prevalence. Currently there is no effective medication to stop the relentless progression of this disease. It has recently been shown that an activator of the P2X7/inflammasome pathway, ATP, and the resultant products (IL-1β/IL-18) are increased in COPD patients. The aim of this study was to determine whether activation of the P2X7/caspase 1 pathway has a functional role in CS-induced airway inflammation. Mice were exposed to CS twice a day to induce COPD-like inflammation and the role of the P2X7 receptor was investigated. We have demonstrated that CS-induced neutrophilia in a pre-clinical model is temporally associated with markers of inflammasome activation, (increased caspase 1 activity and release of IL-1β/IL-18) in the lungs. A selective P2X7 receptor antagonist and mice genetically modified so that the P2X7 receptors were non-functional attenuated caspase 1 activation, IL-1β release and airway neutrophilia. Furthermore, we demonstrated that the role of this pathway was not restricted to early stages of disease development by showing increased caspase 1 activation in lungs from a more chronic exposure to CS and from patients with COPD. This translational data suggests the P2X7/Inflammasome pathway plays an ongoing role in disease pathogenesis. These results advocate the critical role of the P2X7/caspase 1 axis in CS-induced inflammation, highlighting this as a possible therapeutic target in combating COPD.</description><subject>Activation</subject><subject>Adenosine</subject><subject>Animals</subject><subject>Biology</subject><subject>Caspase</subject><subject>Caspase 1 - metabolism</subject><subject>Caspase-1</subject><subject>Cell activation</subject><subject>Chronic exposure</subject><subject>Chronic obstructive pulmonary disease</subject><subject>Cigarette smoke</subject><subject>Cigarettes</subject><subject>Conditioned stimulus</subject><subject>Cytokines</subject><subject>Development and progression</subject><subject>Developmental stages</subject><subject>Drugs</subject><subject>Emphysema</subject><subject>Exposure</subject><subject>Genetic modification</subject><subject>Genetically modified organisms</subject><subject>Heart</subject><subject>Humans</subject><subject>Hypotheses</subject><subject>In Vitro Techniques</subject><subject>Inflammasomes</subject><subject>Inflammation</subject><subject>Inflammation - 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metabolism</topic><topic>Caspase-1</topic><topic>Cell activation</topic><topic>Chronic exposure</topic><topic>Chronic obstructive pulmonary disease</topic><topic>Cigarette smoke</topic><topic>Cigarettes</topic><topic>Conditioned stimulus</topic><topic>Cytokines</topic><topic>Development and progression</topic><topic>Developmental stages</topic><topic>Drugs</topic><topic>Emphysema</topic><topic>Exposure</topic><topic>Genetic modification</topic><topic>Genetically modified organisms</topic><topic>Heart</topic><topic>Humans</topic><topic>Hypotheses</topic><topic>In Vitro Techniques</topic><topic>Inflammasomes</topic><topic>Inflammation</topic><topic>Inflammation - chemically induced</topic><topic>Inflammation - metabolism</topic><topic>Interleukin 18</topic><topic>Interleukin-18 - metabolism</topic><topic>Interleukin-1beta - metabolism</topic><topic>Laboratories</topic><topic>Lipopolysaccharides - toxicity</topic><topic>Lung diseases</topic><topic>Lungs</topic><topic>Male</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Mice</topic><topic>Neutrophilia</topic><topic>Neutrophils</topic><topic>Obstructive lung disease</topic><topic>Pathogenesis</topic><topic>Patients</topic><topic>Pharmacology</topic><topic>Physiology</topic><topic>Receptors</topic><topic>Receptors, Purinergic P2X7 - 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Currently there is no effective medication to stop the relentless progression of this disease. It has recently been shown that an activator of the P2X7/inflammasome pathway, ATP, and the resultant products (IL-1β/IL-18) are increased in COPD patients. The aim of this study was to determine whether activation of the P2X7/caspase 1 pathway has a functional role in CS-induced airway inflammation. Mice were exposed to CS twice a day to induce COPD-like inflammation and the role of the P2X7 receptor was investigated. We have demonstrated that CS-induced neutrophilia in a pre-clinical model is temporally associated with markers of inflammasome activation, (increased caspase 1 activity and release of IL-1β/IL-18) in the lungs. A selective P2X7 receptor antagonist and mice genetically modified so that the P2X7 receptors were non-functional attenuated caspase 1 activation, IL-1β release and airway neutrophilia. Furthermore, we demonstrated that the role of this pathway was not restricted to early stages of disease development by showing increased caspase 1 activation in lungs from a more chronic exposure to CS and from patients with COPD. This translational data suggests the P2X7/Inflammasome pathway plays an ongoing role in disease pathogenesis. These results advocate the critical role of the P2X7/caspase 1 axis in CS-induced inflammation, highlighting this as a possible therapeutic target in combating COPD.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21915284</pmid><doi>10.1371/journal.pone.0024097</doi><tpages>e24097</tpages><oa>free_for_read</oa></addata></record> |
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| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Activation Adenosine Animals Biology Caspase Caspase 1 - metabolism Caspase-1 Cell activation Chronic exposure Chronic obstructive pulmonary disease Cigarette smoke Cigarettes Conditioned stimulus Cytokines Development and progression Developmental stages Drugs Emphysema Exposure Genetic modification Genetically modified organisms Heart Humans Hypotheses In Vitro Techniques Inflammasomes Inflammation Inflammation - chemically induced Inflammation - metabolism Interleukin 18 Interleukin-18 - metabolism Interleukin-1beta - metabolism Laboratories Lipopolysaccharides - toxicity Lung diseases Lungs Male Medical research Medicine Mice Neutrophilia Neutrophils Obstructive lung disease Pathogenesis Patients Pharmacology Physiology Receptors Receptors, Purinergic P2X7 - metabolism Respiratory System - drug effects Respiratory System - metabolism Respiratory tract diseases Rodents Smoke Smoking Smoking - adverse effects Tobacco Tobacco smoke Tumor necrosis factor-TNF |
| title | P2X7 receptor and caspase 1 activation are central to airway inflammation observed after exposure to tobacco smoke |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T13%3A30%3A31IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=P2X7%20receptor%20and%20caspase%201%20activation%20are%20central%20to%20airway%20inflammation%20observed%20after%20exposure%20to%20tobacco%20smoke&rft.jtitle=PloS%20one&rft.au=Eltom,%20Suffwan&rft.date=2011-09-06&rft.volume=6&rft.issue=9&rft.spage=e24097&rft.pages=e24097-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0024097&rft_dat=%3Cgale_plos_%3EA476880823%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1308406592&rft_id=info:pmid/21915284&rft_galeid=A476880823&rft_doaj_id=oai_doaj_org_article_f89eb3440113435898d0242cf8b1bd40&rfr_iscdi=true |