{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T08:48:43Z","timestamp":1768034923435,"version":"3.49.0"},"reference-count":42,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2012,9,25]],"date-time":"2012-09-25T00:00:00Z","timestamp":1348531200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2012,10]]},"abstract":"<jats:p><jats:bold>BACKGROUND AND PURPOSE<\/jats:bold>Patients with chronic obstructive pulmonary disease (COPD) show a poor response to corticosteroids, which has been linked to oxidative stress. Here we show that the long\u2010acting \u03b2<jats:sub>2<\/jats:sub>\u2010agonist formoterol (FM) reversed corticosteroid insensitivity under oxidative stress via inhibition of phosphoinositide\u20103\u2010kinase (PI3K) signalling.<\/jats:p><jats:p><jats:bold>EXPERIMENTAL APPROACH<\/jats:bold>Responsiveness to corticosteroids dexamethasone (Dex), budesonide (Bud) and fluticasone propionate (FP) was determined, as IC<jats:sub>50<\/jats:sub>values on TNF\u2010\u03b1\u2010induced interleukin 8 release, in U937 monocytic cell line treated with hydrogen peroxide (H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>) or peripheral blood mononuclear cells (PBMCs) from patients with COPD or severe asthma.<\/jats:p><jats:p><jats:bold>KEY RESULTS<\/jats:bold>PBMCs from severe asthma and COPD were less sensitive to Dex compared with those from healthy subjects. Both FM (10<jats:sup>\u22129<\/jats:sup>\u2003M) and salmeterol (SM, 10<jats:sup>\u22128<\/jats:sup>\u2003M) reversed Dex insensitivity in severe asthma, but only FM restored Dex sensitivity in COPD. Although H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>exposure decreased steroid sensitivity in U937 cells, FM restored responsiveness to Bud and FP while the effects of SM were weaker. Additionally, FM, but not SM, partially inhibited H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>\u2010induced PI3K\u03b4\u2010dependent (PKB) phosphorylation. H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>decreased SM\u2010induced cAMP production in U937 cells, but did not significantly affect the response to FM. The reduction of SM effects by H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>was reversed by pretreatment with LY294002, a PI3K inhibitor, or IC87114, a PI3K\u03b4 inhibitor.<\/jats:p><jats:p><jats:bold>CONCLUSION AND IMPLICATIONS<\/jats:bold>FM reversed oxidative stress\u2010induced corticosteroid insensitivity and decreased \u03b2<jats:sub>2<\/jats:sub>adrenoceptor\u2010dependent cAMP production via inhibition of PI3K\u03b4 signalling. FM will be more effective than SM, when combined with corticosteroids, for the treatment of respiratory diseases under conditions of high oxidative stress, such as in COPD.<\/jats:p>","DOI":"10.1111\/j.1476-5381.2012.01864.x","type":"journal-article","created":{"date-parts":[[2012,1,17]],"date-time":"2012-01-17T19:43:02Z","timestamp":1326829382000},"page":"775-786","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Corticosteroid insensitivity is reversed by formoterol via phosphoinositide\u20103\u2010kinase inhibition"],"prefix":"10.1111","volume":"167","author":[{"given":"C","family":"Rossios","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y","family":"To","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G","family":"Osoata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Ito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"PJ","family":"Barnes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K","family":"Ito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2012,9,25]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.109.156224"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2009.03986.x"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2009-0220TR"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)60326-3"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.123.4.1240"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/15412550902724164"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.03.00027003"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa063070"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-009-0682-z"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pupt.2008.11.010"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00158008"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2008.717"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.302.1.111"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/1465-9921-11-63"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2006.10.043"},{"key":"e_1_2_8_17_1","unstructured":"Global Initiative for Asthma(2008).GINA Report Global Strategy for Asthma Management and Prevention.http:\/\/www.ginasthma.com 1\u2013116."},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(06)69288-X"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1067\/mai.2002.122465"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1517\/14728220903078431"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.01.046"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20050466"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.106.111674"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.107.040121"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12272-001-1287-1"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.2147\/COPD.S3671"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200810-1570OC"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.111.071993"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200202113"},{"issue":"17","key":"e_1_2_8_30_1","article-title":"Combined corticosteroid and long\u2010acting beta\u2010agonist in one inhaler versus long\u2010acting beta\u2010agonists for chronic obstructive pulmonary disease","author":"Nannini LJ","year":"2007","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1159\/000237218"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.08-1018"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.2206012"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1177\/1753465809344870"},{"key":"e_1_2_8_35_1","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/S0022-3565(24)37973-X","article-title":"Pharmacological inhibition of protein kinases in intact cells: antagonism of beta adrenergic receptor ligand binding by H\u201089 reveals limitations of usefulness","volume":"288","author":"Penn RB","year":"1999","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(93)90466-U"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2222.2009.03307.x"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1513\/pats.200904-016DS"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.03.00031402"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-200868140-00004"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.2165\/00151829-200605060-00010"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200906-0937OC"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200408-1041OC"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fj.1476-5381.2012.01864.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/j.1476-5381.2012.01864.x","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T22:34:53Z","timestamp":1742337293000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/j.1476-5381.2012.01864.x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,9,25]]},"references-count":42,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2012,10]]}},"alternative-id":["10.1111\/j.1476-5381.2012.01864.x"],"URL":"https:\/\/doi.org\/10.1111\/j.1476-5381.2012.01864.x","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,9,25]]},"assertion":[{"value":"2012-09-25","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}