{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T04:07:54Z","timestamp":1789186074729,"version":"build-2803163510"},"reference-count":67,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T00:00:00Z","timestamp":1777161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T00:00:00Z","timestamp":1777161600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1175134"],"award-info":[{"award-number":["1175134"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["2010287"],"award-info":[{"award-number":["2010287"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["2008937"],"award-info":[{"award-number":["2008937"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["2015613"],"award-info":[{"award-number":["2015613"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000923","name":"Australian Research Council","doi-asserted-by":"publisher","award":["200101058"],"award-info":[{"award-number":["200101058"]}],"id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000923","name":"Australian Research Council","doi-asserted-by":"publisher","award":["230101156"],"award-info":[{"award-number":["230101156"]}],"id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP2002953"],"award-info":[{"award-number":["APP2002953"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Allergy"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>People with severe steroid\u2010resistant asthma are refractory to treatment with the mainstay inhaled corticosteroids (ICS), emphasising the urgent need for alternative therapies. This study aimed to assess the effect of endoplasmic reticulum stress (ERS) on steroid responsiveness and to evaluate the efficacy of 4\u2010phenylebuteric acid (4\u2010PBA) as an add\u2010on treatment to restore steroid responses in severe asthma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The relationship between ERS and steroid response was assessed by treating human airway epithelial cells (AEC) with chemical ERS inducers or TNF, IFN\u2010\u03b3, and IL\u201017, and assessing the effects of dexamethasone (Dex) and 4\u2010PBA. The correlation between genes associated with ERS and GR\u2010signalling was assessed in sputum cells from patients with severe asthma, and the effects of 4\u2010PBA were assessed in two murine models of severe, steroid\u2010resistant asthma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Chemical ERS inducers significantly downregulated the expression of corticosteroid\u2010responsive genes, HSD11B2 and FKBP5 and reduced GR nuclear translocation in basal AECs. Treatment with TNF, IFN\u2010\u03b3 and IL\u201017 upregulated ERS and protein misfolded markers while reducing Dex\u2010induced GR nuclear translocation. In sputum cells from patients with severe asthma, ERS genes negatively correlated with GR\u2010signalling. In differentiated primary bronchial epithelial cells (pBECs), treatment with 4\u2010PBA reversed TNF, IFN\u2010\u03b3 and IL\u201017\u2010induced steroid resistance by upregulating HSD11B2 and FKBP5 gene expression and downregulating inflammatory genes. 4\u2010PBA together with Dex significantly reduced airway inflammation and\/or AHR in experimental models of severe, steroid\u2010resistant asthma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We provide evidence for ERS inducing steroid resistance that underpins severe asthma and demonstrate a therapeutic potential for restoring steroid sensitivity in severe asthma with 4\u2010PBA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/all.70353","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T01:09:05Z","timestamp":1777252145000},"page":"3221-3235","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Resolving Endoplasmic Reticulum\u2010Protein Misfolding Restores Corticosteroid Sensitivity in Experimental Models of Severe Asthma"],"prefix":"10.1111","volume":"81","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4947-5918","authenticated-orcid":false,"given":"Prabuddha S.","family":"Pathinayake","sequence":"first","affiliation":[{"name":"Infection Research Program, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy University of Newcastle  Newcastle New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra C.","family":"Brown","sequence":"additional","affiliation":[{"name":"Immune Health Program Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle  Newcastle New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikhil T.","family":"Awatade","sequence":"additional","affiliation":[{"name":"Immune Health Program Hunter Medical Research Institute and School of Medicine and Public Health, University of Newcastle  Newcastle New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip M.","family":"Hansbro","sequence":"additional","affiliation":[{"name":"Centre for Inflammation, Centenary Institute, and University of Technology Sydney, Faculty of Science, School of Life Sciences  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine J.","family":"Baines","sequence":"additional","affiliation":[{"name":"Immune Health Program Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle  Newcastle New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard Y.","family":"Kim","sequence":"additional","affiliation":[{"name":"Immune Health Program Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle  Newcastle New South Wales Australia"},{"name":"University of Technology Sydney, Faculty of Science, School of Life Sciences  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan W.","family":"Bartlett","sequence":"additional","affiliation":[{"name":"Infection Research Program, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy University of Newcastle  Newcastle New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8526-0631","authenticated-orcid":false,"given":"Jay C.","family":"Horvat","sequence":"additional","affiliation":[{"name":"Immune Health Program Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle  Newcastle New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5676-6126","authenticated-orcid":false,"given":"Peter A. B.","family":"Wark","sequence":"additional","affiliation":[{"name":"Immune Health Program Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle  Newcastle New South Wales Australia"},{"name":"Department of Respiratory and Sleep Medicine John Hunter Hospital  Newcastle New South Wales Australia"},{"name":"School of Translational Medicine Monash University  Melbourne Victoria Australia"},{"name":"Respiratory Medicine Alfred Hospital  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,26]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13223-018-0279-0"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.anai.2021.08.014"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.2147\/JAA.S327659"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12543"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2018.03.004"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3049"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00413-2021"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/resp.14506"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2017.12.1009"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aab3142"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2017.1392425"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.18553\/jmcp.2019.25.5.510"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1704064"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2034975"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2015.03.004"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1210\/edrv.18.3.0303"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.09.007"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1080\/10253890802506409"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.2174\/138945010791591412"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01151-12"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201402-0314OC"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2007-0101"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2020.105189"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201609-1830OC"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2020-215979"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00175"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2014.01.009"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2011.132"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.83"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/1465-9921-14-135"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12931-023-02514-2"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/0091-6749(91)90189-U"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00378.2023"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-15393-2"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0707413104"},{"issue":"3","key":"e_1_2_10_37_1","first-page":"71","article-title":"An Improvement of the 2^(\u2212Delta Delta CT) Method for Quantitative Real\u2010Time Polymerase Chain Reaction Data Analysis","volume":"3","author":"Rao X.","year":"2013","journal-title":"Biostatistics, Bioinformatics and Biomathematics"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.4103\/1947-2714.100998"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2016.04.038"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/resp.13749"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00017911"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00547.2017"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1183\/16000617.0096-2019"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2014-206067"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.7573\/dic.212561"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00703-2018"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/psb.1830"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3786"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vhri.2022.12.007"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jval.2018.04.1593"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00819-2023"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.08.041"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.4168\/aair.2015.7.2.106"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.287.5453.664"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2006.04.055"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep01142"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.16.5651-5663.2003"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.14712\/fb2010056020037"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2099"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2013.09.017"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26058"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40272-015-0159-8"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.psyneuen.2009.05.021"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2014.05.015"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200210-1139OC"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2006-0073OC"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.12.1091"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2020.5089"}],"container-title":["Allergy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/all.70353","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/all.70353","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/all.70353","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T03:22:35Z","timestamp":1789183355000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/all.70353"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,26]]},"references-count":67,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1111\/all.70353"],"URL":"https:\/\/doi.org\/10.1111\/all.70353","archive":["Portico"],"relation":{},"ISSN":["0105-4538","1398-9995"],"issn-type":[{"value":"0105-4538","type":"print"},{"value":"1398-9995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,26]]},"assertion":[{"value":"2025-05-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}