Linoleic acid metabolite leads to steroid resistant asthma features partially through NF-κB

Studies have highlighted the role of nutritional and metabolic modulators in asthma pathobiology. Steroid resistance is an important clinical problem in asthma but lacks good experimental models. Linoleic acid, a polyunsaturated fatty acid, has been linked to asthma and glucocorticoid sensitivity. I...

Full description

Saved in:
Bibliographic Details
Published in:Scientific reports 2017-08, Vol.7 (1), p.9565-11, Article 9565
Main Authors: Panda, Lipsa, Gheware, Atish, Rehman, Rakhshinda, Yadav, Manish K, Jayaraj, B S, Madhunapantula, SubbaRao V, Mahesh, Padukudru Anand, Ghosh, Balaram, Agrawal, Anurag, Mabalirajan, Ulaganathan
Format: Article
Language:English
Subjects:
Airway management
Animal models
Animals
Anti-Asthmatic Agents - pharmacology
Asthma
Asthma - drug therapy
Asthma - metabolism
Asthma - pathology
Dexamethasone
Disease Models, Animal
Drug Resistance
Epithelial Cells - drug effects
Epithelial Cells - metabolism
Glucocorticoids
High fat diet
Humans
Hypersensitivity - drug therapy
Hypersensitivity - immunology
Hypersensitivity - metabolism
Hypersensitivity - pathology
Inflammation
Leukocytes (neutrophilic)
Linoleic acid
Linoleic Acid - metabolism
Lipid Metabolism
Lipoxygenase
Metaplasia
Mice
Mitochondria
NF-kappa B - metabolism
NF-κB protein
Receptors, Glucocorticoid - metabolism
Respiratory Mucosa - drug effects
Respiratory Mucosa - metabolism
Respiratory Mucosa - pathology
Respiratory tract
Respiratory tract diseases
Rodents
Steroids - pharmacology
Transcription
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c430t-d1a5b1d94fd4e0c9e482f85afd0cbf5fb41aee653a607bfaf7939fcc7b92727b3
cites cdi_FETCH-LOGICAL-c430t-d1a5b1d94fd4e0c9e482f85afd0cbf5fb41aee653a607bfaf7939fcc7b92727b3
container_end_page 11
container_issue 1
container_start_page 9565
container_title Scientific reports
container_volume 7
creator Panda, Lipsa
Gheware, Atish
Rehman, Rakhshinda
Yadav, Manish K
Jayaraj, B S
Madhunapantula, SubbaRao V
Mahesh, Padukudru Anand
Ghosh, Balaram
Agrawal, Anurag
Mabalirajan, Ulaganathan
description Studies have highlighted the role of nutritional and metabolic modulators in asthma pathobiology. Steroid resistance is an important clinical problem in asthma but lacks good experimental models. Linoleic acid, a polyunsaturated fatty acid, has been linked to asthma and glucocorticoid sensitivity. Its 12/15-lipoxygenase metabolite, 13-S-hydroxyoctadecadienoic acid (HODE) induces mitochondrial dysfunction, with severe airway obstruction and neutrophilic airway inflammation. Here we show that HODE administration leads to steroid unresponsiveness in an otherwise steroid responsive model of allergic airway inflammation (AAI). HODE treatment to allergic mice further increased airway hyperresponsiveness and goblet metaplasia. Treatment with dexamethasone was associated with increased neutrophilic inflammation in HODE treated allergic mice; unlike control allergic mice that showed resolution of inflammation. HODE induced loss of steroid sensitivity was associated with increased p-NFkB in mice and reduced GR-α transcript levels in cultured human bronchial epithelia. In summary, HODE modifies typical AAI to recapitulate many of the phenotypic features seen in severe steroid unresponsive asthma. We speculate that since HODE is a natural metabolite, it may be relevant to the increased asthma severity and steroid insensitivity in patients who are obese or consume high fat diets. Further characterization of HODE induced steroid insensitivity may clarify the mechanisms.
doi_str_mv 10.1038/s41598-017-09869-9
format article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5575291</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1957864268</sourcerecordid><originalsourceid>FETCH-LOGICAL-c430t-d1a5b1d94fd4e0c9e482f85afd0cbf5fb41aee653a607bfaf7939fcc7b92727b3</originalsourceid><addsrcrecordid>eNpdkc9uFSEUhydGY5vaF3BhSNy4GeXvABsTbaya3LSbujMhZxjopWGGKzBN-mo-hM9U6q1NLRsI5zu_cPi67jXB7wlm6kPhRGjVYyJ7rNWge_2sO6SYi54ySp8_Oh90x6Vc4bYE1Zzol90BVUoQLYfD7ucmLCm6YBHYMKHZVRhTDNWh6GAqqCZUqsup1bIroVRYKoJStzMg76Cu7RbtINcAMd6gus1pvdyis9P-z-_Pr7oXHmJxx_f7Uffj9MvFybd-c_71-8mnTW85w7WfCIiRTJr7iTtsteOKeiXAT9iOXviRE3BuEAwGLEcPXmqmvbVy1FRSObKj7uM-d7eOs5usW2qGaHY5zJBvTIJg_q8sYWsu07URQrY_IS3g3X1ATr9WV6qZQ7EuRlhcWoshmjHNqZa8oW-foFdpzUsbr1FCqoHTQTWK7imbUynZ-YfHEGzu_Jm9P9P8mb_-jG5Nbx6P8dDyzxa7BeklmUI</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1957864268</pqid></control><display><type>article</type><title>Linoleic acid metabolite leads to steroid resistant asthma features partially through NF-κB</title><source>Nature Open Access</source><source>Publicly Available Content Database</source><source>Full-Text Journals in Chemistry (Open access)</source><source>PubMed Central</source><creator>Panda, Lipsa ; Gheware, Atish ; Rehman, Rakhshinda ; Yadav, Manish K ; Jayaraj, B S ; Madhunapantula, SubbaRao V ; Mahesh, Padukudru Anand ; Ghosh, Balaram ; Agrawal, Anurag ; Mabalirajan, Ulaganathan</creator><creatorcontrib>Panda, Lipsa ; Gheware, Atish ; Rehman, Rakhshinda ; Yadav, Manish K ; Jayaraj, B S ; Madhunapantula, SubbaRao V ; Mahesh, Padukudru Anand ; Ghosh, Balaram ; Agrawal, Anurag ; Mabalirajan, Ulaganathan</creatorcontrib><description>Studies have highlighted the role of nutritional and metabolic modulators in asthma pathobiology. Steroid resistance is an important clinical problem in asthma but lacks good experimental models. Linoleic acid, a polyunsaturated fatty acid, has been linked to asthma and glucocorticoid sensitivity. Its 12/15-lipoxygenase metabolite, 13-S-hydroxyoctadecadienoic acid (HODE) induces mitochondrial dysfunction, with severe airway obstruction and neutrophilic airway inflammation. Here we show that HODE administration leads to steroid unresponsiveness in an otherwise steroid responsive model of allergic airway inflammation (AAI). HODE treatment to allergic mice further increased airway hyperresponsiveness and goblet metaplasia. Treatment with dexamethasone was associated with increased neutrophilic inflammation in HODE treated allergic mice; unlike control allergic mice that showed resolution of inflammation. HODE induced loss of steroid sensitivity was associated with increased p-NFkB in mice and reduced GR-α transcript levels in cultured human bronchial epithelia. In summary, HODE modifies typical AAI to recapitulate many of the phenotypic features seen in severe steroid unresponsive asthma. We speculate that since HODE is a natural metabolite, it may be relevant to the increased asthma severity and steroid insensitivity in patients who are obese or consume high fat diets. Further characterization of HODE induced steroid insensitivity may clarify the mechanisms.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-017-09869-9</identifier><identifier>PMID: 28851976</identifier><language>eng</language><publisher>England: Nature Publishing Group</publisher><subject>Airway management ; Animal models ; Animals ; Anti-Asthmatic Agents - pharmacology ; Asthma ; Asthma - drug therapy ; Asthma - metabolism ; Asthma - pathology ; Dexamethasone ; Disease Models, Animal ; Drug Resistance ; Epithelial Cells - drug effects ; Epithelial Cells - metabolism ; Glucocorticoids ; High fat diet ; Humans ; Hypersensitivity - drug therapy ; Hypersensitivity - immunology ; Hypersensitivity - metabolism ; Hypersensitivity - pathology ; Inflammation ; Leukocytes (neutrophilic) ; Linoleic acid ; Linoleic Acid - metabolism ; Lipid Metabolism ; Lipoxygenase ; Metaplasia ; Mice ; Mitochondria ; NF-kappa B - metabolism ; NF-κB protein ; Receptors, Glucocorticoid - metabolism ; Respiratory Mucosa - drug effects ; Respiratory Mucosa - metabolism ; Respiratory Mucosa - pathology ; Respiratory tract ; Respiratory tract diseases ; Rodents ; Steroids - pharmacology ; Transcription</subject><ispartof>Scientific reports, 2017-08, Vol.7 (1), p.9565-11, Article 9565</ispartof><rights>2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c430t-d1a5b1d94fd4e0c9e482f85afd0cbf5fb41aee653a607bfaf7939fcc7b92727b3</citedby><cites>FETCH-LOGICAL-c430t-d1a5b1d94fd4e0c9e482f85afd0cbf5fb41aee653a607bfaf7939fcc7b92727b3</cites><orcidid>0000-0002-2547-1023 ; 0000-0001-9167-9271</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1957864268/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1957864268?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,25783,27957,27958,37047,37048,44625,53827,53829,75483</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28851976$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Panda, Lipsa</creatorcontrib><creatorcontrib>Gheware, Atish</creatorcontrib><creatorcontrib>Rehman, Rakhshinda</creatorcontrib><creatorcontrib>Yadav, Manish K</creatorcontrib><creatorcontrib>Jayaraj, B S</creatorcontrib><creatorcontrib>Madhunapantula, SubbaRao V</creatorcontrib><creatorcontrib>Mahesh, Padukudru Anand</creatorcontrib><creatorcontrib>Ghosh, Balaram</creatorcontrib><creatorcontrib>Agrawal, Anurag</creatorcontrib><creatorcontrib>Mabalirajan, Ulaganathan</creatorcontrib><title>Linoleic acid metabolite leads to steroid resistant asthma features partially through NF-κB</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><description>Studies have highlighted the role of nutritional and metabolic modulators in asthma pathobiology. Steroid resistance is an important clinical problem in asthma but lacks good experimental models. Linoleic acid, a polyunsaturated fatty acid, has been linked to asthma and glucocorticoid sensitivity. Its 12/15-lipoxygenase metabolite, 13-S-hydroxyoctadecadienoic acid (HODE) induces mitochondrial dysfunction, with severe airway obstruction and neutrophilic airway inflammation. Here we show that HODE administration leads to steroid unresponsiveness in an otherwise steroid responsive model of allergic airway inflammation (AAI). HODE treatment to allergic mice further increased airway hyperresponsiveness and goblet metaplasia. Treatment with dexamethasone was associated with increased neutrophilic inflammation in HODE treated allergic mice; unlike control allergic mice that showed resolution of inflammation. HODE induced loss of steroid sensitivity was associated with increased p-NFkB in mice and reduced GR-α transcript levels in cultured human bronchial epithelia. In summary, HODE modifies typical AAI to recapitulate many of the phenotypic features seen in severe steroid unresponsive asthma. We speculate that since HODE is a natural metabolite, it may be relevant to the increased asthma severity and steroid insensitivity in patients who are obese or consume high fat diets. Further characterization of HODE induced steroid insensitivity may clarify the mechanisms.</description><subject>Airway management</subject><subject>Animal models</subject><subject>Animals</subject><subject>Anti-Asthmatic Agents - pharmacology</subject><subject>Asthma</subject><subject>Asthma - drug therapy</subject><subject>Asthma - metabolism</subject><subject>Asthma - pathology</subject><subject>Dexamethasone</subject><subject>Disease Models, Animal</subject><subject>Drug Resistance</subject><subject>Epithelial Cells - drug effects</subject><subject>Epithelial Cells - metabolism</subject><subject>Glucocorticoids</subject><subject>High fat diet</subject><subject>Humans</subject><subject>Hypersensitivity - drug therapy</subject><subject>Hypersensitivity - immunology</subject><subject>Hypersensitivity - metabolism</subject><subject>Hypersensitivity - pathology</subject><subject>Inflammation</subject><subject>Leukocytes (neutrophilic)</subject><subject>Linoleic acid</subject><subject>Linoleic Acid - metabolism</subject><subject>Lipid Metabolism</subject><subject>Lipoxygenase</subject><subject>Metaplasia</subject><subject>Mice</subject><subject>Mitochondria</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Receptors, Glucocorticoid - metabolism</subject><subject>Respiratory Mucosa - drug effects</subject><subject>Respiratory Mucosa - metabolism</subject><subject>Respiratory Mucosa - pathology</subject><subject>Respiratory tract</subject><subject>Respiratory tract diseases</subject><subject>Rodents</subject><subject>Steroids - pharmacology</subject><subject>Transcription</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><recordid>eNpdkc9uFSEUhydGY5vaF3BhSNy4GeXvABsTbaya3LSbujMhZxjopWGGKzBN-mo-hM9U6q1NLRsI5zu_cPi67jXB7wlm6kPhRGjVYyJ7rNWge_2sO6SYi54ySp8_Oh90x6Vc4bYE1Zzol90BVUoQLYfD7ucmLCm6YBHYMKHZVRhTDNWh6GAqqCZUqsup1bIroVRYKoJStzMg76Cu7RbtINcAMd6gus1pvdyis9P-z-_Pr7oXHmJxx_f7Uffj9MvFybd-c_71-8mnTW85w7WfCIiRTJr7iTtsteOKeiXAT9iOXviRE3BuEAwGLEcPXmqmvbVy1FRSObKj7uM-d7eOs5usW2qGaHY5zJBvTIJg_q8sYWsu07URQrY_IS3g3X1ATr9WV6qZQ7EuRlhcWoshmjHNqZa8oW-foFdpzUsbr1FCqoHTQTWK7imbUynZ-YfHEGzu_Jm9P9P8mb_-jG5Nbx6P8dDyzxa7BeklmUI</recordid><startdate>20170829</startdate><enddate>20170829</enddate><creator>Panda, Lipsa</creator><creator>Gheware, Atish</creator><creator>Rehman, Rakhshinda</creator><creator>Yadav, Manish K</creator><creator>Jayaraj, B S</creator><creator>Madhunapantula, SubbaRao V</creator><creator>Mahesh, Padukudru Anand</creator><creator>Ghosh, Balaram</creator><creator>Agrawal, Anurag</creator><creator>Mabalirajan, Ulaganathan</creator><general>Nature Publishing Group</general><general>Nature Publishing Group UK</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-2547-1023</orcidid><orcidid>https://orcid.org/0000-0001-9167-9271</orcidid></search><sort><creationdate>20170829</creationdate><title>Linoleic acid metabolite leads to steroid resistant asthma features partially through NF-κB</title><author>Panda, Lipsa ; Gheware, Atish ; Rehman, Rakhshinda ; Yadav, Manish K ; Jayaraj, B S ; Madhunapantula, SubbaRao V ; Mahesh, Padukudru Anand ; Ghosh, Balaram ; Agrawal, Anurag ; Mabalirajan, Ulaganathan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c430t-d1a5b1d94fd4e0c9e482f85afd0cbf5fb41aee653a607bfaf7939fcc7b92727b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Airway management</topic><topic>Animal models</topic><topic>Animals</topic><topic>Anti-Asthmatic Agents - pharmacology</topic><topic>Asthma</topic><topic>Asthma - drug therapy</topic><topic>Asthma - metabolism</topic><topic>Asthma - pathology</topic><topic>Dexamethasone</topic><topic>Disease Models, Animal</topic><topic>Drug Resistance</topic><topic>Epithelial Cells - drug effects</topic><topic>Epithelial Cells - metabolism</topic><topic>Glucocorticoids</topic><topic>High fat diet</topic><topic>Humans</topic><topic>Hypersensitivity - drug therapy</topic><topic>Hypersensitivity - immunology</topic><topic>Hypersensitivity - metabolism</topic><topic>Hypersensitivity - pathology</topic><topic>Inflammation</topic><topic>Leukocytes (neutrophilic)</topic><topic>Linoleic acid</topic><topic>Linoleic Acid - metabolism</topic><topic>Lipid Metabolism</topic><topic>Lipoxygenase</topic><topic>Metaplasia</topic><topic>Mice</topic><topic>Mitochondria</topic><topic>NF-kappa B - metabolism</topic><topic>NF-κB protein</topic><topic>Receptors, Glucocorticoid - metabolism</topic><topic>Respiratory Mucosa - drug effects</topic><topic>Respiratory Mucosa - metabolism</topic><topic>Respiratory Mucosa - pathology</topic><topic>Respiratory tract</topic><topic>Respiratory tract diseases</topic><topic>Rodents</topic><topic>Steroids - pharmacology</topic><topic>Transcription</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Panda, Lipsa</creatorcontrib><creatorcontrib>Gheware, Atish</creatorcontrib><creatorcontrib>Rehman, Rakhshinda</creatorcontrib><creatorcontrib>Yadav, Manish K</creatorcontrib><creatorcontrib>Jayaraj, B S</creatorcontrib><creatorcontrib>Madhunapantula, SubbaRao V</creatorcontrib><creatorcontrib>Mahesh, Padukudru Anand</creatorcontrib><creatorcontrib>Ghosh, Balaram</creatorcontrib><creatorcontrib>Agrawal, Anurag</creatorcontrib><creatorcontrib>Mabalirajan, Ulaganathan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest_Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection (Proquest) (PQ_SDU_P3)</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Biological Sciences</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Journals (ProQuest Database)</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Panda, Lipsa</au><au>Gheware, Atish</au><au>Rehman, Rakhshinda</au><au>Yadav, Manish K</au><au>Jayaraj, B S</au><au>Madhunapantula, SubbaRao V</au><au>Mahesh, Padukudru Anand</au><au>Ghosh, Balaram</au><au>Agrawal, Anurag</au><au>Mabalirajan, Ulaganathan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Linoleic acid metabolite leads to steroid resistant asthma features partially through NF-κB</atitle><jtitle>Scientific reports</jtitle><addtitle>Sci Rep</addtitle><date>2017-08-29</date><risdate>2017</risdate><volume>7</volume><issue>1</issue><spage>9565</spage><epage>11</epage><pages>9565-11</pages><artnum>9565</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Studies have highlighted the role of nutritional and metabolic modulators in asthma pathobiology. Steroid resistance is an important clinical problem in asthma but lacks good experimental models. Linoleic acid, a polyunsaturated fatty acid, has been linked to asthma and glucocorticoid sensitivity. Its 12/15-lipoxygenase metabolite, 13-S-hydroxyoctadecadienoic acid (HODE) induces mitochondrial dysfunction, with severe airway obstruction and neutrophilic airway inflammation. Here we show that HODE administration leads to steroid unresponsiveness in an otherwise steroid responsive model of allergic airway inflammation (AAI). HODE treatment to allergic mice further increased airway hyperresponsiveness and goblet metaplasia. Treatment with dexamethasone was associated with increased neutrophilic inflammation in HODE treated allergic mice; unlike control allergic mice that showed resolution of inflammation. HODE induced loss of steroid sensitivity was associated with increased p-NFkB in mice and reduced GR-α transcript levels in cultured human bronchial epithelia. In summary, HODE modifies typical AAI to recapitulate many of the phenotypic features seen in severe steroid unresponsive asthma. We speculate that since HODE is a natural metabolite, it may be relevant to the increased asthma severity and steroid insensitivity in patients who are obese or consume high fat diets. Further characterization of HODE induced steroid insensitivity may clarify the mechanisms.</abstract><cop>England</cop><pub>Nature Publishing Group</pub><pmid>28851976</pmid><doi>10.1038/s41598-017-09869-9</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-2547-1023</orcidid><orcidid>https://orcid.org/0000-0001-9167-9271</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 2045-2322
ispartof Scientific reports, 2017-08, Vol.7 (1), p.9565-11, Article 9565
issn 2045-2322
2045-2322
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5575291
source Nature Open Access; Publicly Available Content Database; Full-Text Journals in Chemistry (Open access); PubMed Central
subjects Airway management
Animal models
Animals
Anti-Asthmatic Agents - pharmacology
Asthma
Asthma - drug therapy
Asthma - metabolism
Asthma - pathology
Dexamethasone
Disease Models, Animal
Drug Resistance
Epithelial Cells - drug effects
Epithelial Cells - metabolism
Glucocorticoids
High fat diet
Humans
Hypersensitivity - drug therapy
Hypersensitivity - immunology
Hypersensitivity - metabolism
Hypersensitivity - pathology
Inflammation
Leukocytes (neutrophilic)
Linoleic acid
Linoleic Acid - metabolism
Lipid Metabolism
Lipoxygenase
Metaplasia
Mice
Mitochondria
NF-kappa B - metabolism
NF-κB protein
Receptors, Glucocorticoid - metabolism
Respiratory Mucosa - drug effects
Respiratory Mucosa - metabolism
Respiratory Mucosa - pathology
Respiratory tract
Respiratory tract diseases
Rodents
Steroids - pharmacology
Transcription
title Linoleic acid metabolite leads to steroid resistant asthma features partially through NF-κB
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-22T13%3A15%3A59IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Linoleic%20acid%20metabolite%20leads%20to%20steroid%20resistant%20asthma%20features%20partially%20through%20NF-%CE%BAB&rft.jtitle=Scientific%20reports&rft.au=Panda,%20Lipsa&rft.date=2017-08-29&rft.volume=7&rft.issue=1&rft.spage=9565&rft.epage=11&rft.pages=9565-11&rft.artnum=9565&rft.issn=2045-2322&rft.eissn=2045-2322&rft_id=info:doi/10.1038/s41598-017-09869-9&rft_dat=%3Cproquest_pubme%3E1957864268%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c430t-d1a5b1d94fd4e0c9e482f85afd0cbf5fb41aee653a607bfaf7939fcc7b92727b3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1957864268&rft_id=info:pmid/28851976&rfr_iscdi=true