{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T17:29:00Z","timestamp":1761672540755,"version":"build-2065373602"},"reference-count":74,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2021,9,23]],"date-time":"2021-09-23T00:00:00Z","timestamp":1632355200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Acute respiratory distress syndrome (ARDS) is a life\u2010threatening illness characterized by decreased alveolar\u2010capillary barrier function, pulmonary edema consisting of proteinaceous fluid, and inhibition of net alveolar fluid transport responsible for resolution of pulmonary edema. There is currently no pharmacotherapy that has proven useful to prevent or treat ARDS, and two trials using beta\u2010agonist therapy to treat ARDS demonstrated no effect. Prior studies indicated that IL\u20108\u2010induced heterologous desensitization of the beta2\u2010adrenergic receptor (\u03b2\n                    <jats:sub>2<\/jats:sub>\n                    \u2010AR) led to decreased beta\u2010agonist\u2010induced mobilization of cyclic adenosine monophosphate (cAMP). Interestingly, phosphodiesterase (PDE) 4 inhibitors have been used in human airway diseases characterized by low intracellular cAMP levels and increases in specific cAMP hydrolyzing activity. Therefore, we hypothesized that PDE4 would mediate IL\u20108\u2010induced heterologous internalization of the \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    \u2010AR and that PDE4 inhibition would restore beta\u2010agonist\u2010induced functions. We determined that CINC\u20101 (a functional IL\u20108 analog in rats) induces internalization of \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    \u2010AR from the cell surface, and arrestin\u20102, PDE4, and \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    \u2010AR form a complex during this process. Furthermore, we determined that cAMP associated with the plasma membrane was adversely affected by \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    \u2010AR heterologous desensitization. Additionally, we determined that rolipram, a PDE4 inhibitor, reversed CINC\u20101\u2010induced derangements of cAMP and also caused \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    \u2010AR to successfully recycle back to the cell surface. Finally, we demonstrated that rolipram could reverse CINC\u20101\u2010mediated inhibition of beta\u2010agonist\u2010induced alveolar fluid clearance in a murine model of trauma\u2010shock. These results indicate that PDE4 plays a role in CINC\u20101\u2010induced heterologous internalization of the \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    \u2010AR; PDE4 inhibition reverses these effects and may be a useful adjunct in particular ARDS patients.\n                  <\/jats:p>","DOI":"10.1096\/fj.202002712rr","type":"journal-article","created":{"date-parts":[[2021,9,23]],"date-time":"2021-09-23T18:57:12Z","timestamp":1632423432000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Phosphodiesterase 4 mediates interleukin\u20108\u2010induced heterologous desensitization of the \u03b2\n                    <sub>2<\/sub>\n                    \u2010adrenergic receptor"],"prefix":"10.1096","volume":"35","author":[{"given":"Thomas C.","family":"Rich","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of South Alabama Mobile Alabama USA"},{"name":"Center for Lung Biology University of South Alabama Mobile Alabama USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silas J.","family":"Leavesley","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of South Alabama Mobile Alabama USA"},{"name":"Center for Lung Biology University of South Alabama Mobile Alabama USA"},{"name":"Department of Chemical and Biomolecular Engineering University of South Alabama Mobile Alabama USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela P.","family":"Brandon","sequence":"additional","affiliation":[{"name":"Division of Molecular and Translational Biomedicine Department of Anesthesiology and Perioperative Medicine University of Alabama at Birmingham Birmingham Alabama USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cilina A.","family":"Evans","sequence":"additional","affiliation":[{"name":"Division of Molecular and Translational Biomedicine Department of Anesthesiology and Perioperative Medicine University of Alabama at Birmingham Birmingham Alabama USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. Vamsee","family":"Raju","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine University of Alabama at Birmingham Birmingham Alabama USA"},{"name":"UAB Lung Health Center University of Alabama at Birmingham Birmingham Alabama USA"},{"name":"Gregory Fleming James Cystic Fibrosis Research Center University of Alabama at Birmingham Birmingham Alabama USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7889-1526","authenticated-orcid":false,"given":"Brant M.","family":"Wagener","sequence":"additional","affiliation":[{"name":"Division of Molecular and Translational Biomedicine Department of Anesthesiology and Perioperative Medicine University of Alabama at Birmingham Birmingham Alabama USA"},{"name":"Division of Critical Care Medicine Department of Anesthesiology and Perioperative Medicine University of Alabama at Birmingham Birmingham Alabama USA"},{"name":"Center for Free Radical Biology University of Alabama at Birmingham Birmingham Alabama USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,9,23]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201609-1767CI"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/17476348.2018.1548280"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0039-1683996"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0039-1685463"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.20411.1"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)61623-1"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201012-2090OC"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00334.2005"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.CCM.0000129489.34416.0E"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117383"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200508-1302OC"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.4187\/respcare.02571"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0039-1684049"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2016-209719"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(14)70097-9"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.14-2454"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.12-219295"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000000595"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.76.060305.150444"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2009.09.007"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M407521200"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e09-01-0019"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200709881"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20051560"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.020388"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.203604"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601968"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0020000"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00163.2011"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2012.01.013"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00079.2009"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2011.01218.x"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-17969-3_18"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1165\/ajrcmb.18.3.2913"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejcts.2004.01.054"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.14985"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfz066"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-018-1712-z"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0063907"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2009.00957.x"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0147442"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0095835"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.058594"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C400505200"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1002522"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3181f4171b"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00458.2006"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00008.2013"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00426.2005"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2017.01.024"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2016.10.007"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.51.5.800"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00125"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvx036"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.283.5402.655"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-41199-1_15"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2005.01.003"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0125803"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ircmb.2018.03.002"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.2174\/1874467211205030004"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2019-0185OC"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201902915R"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201600102R"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-394440-5.00001-2"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.14348\/molcells.2015.2301"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060614-033910"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1074683"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M303772200"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST0311186"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M414316200"},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20060423"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0707936104"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1606267113"},{"key":"e_1_2_9_75_1","doi-asserted-by":"publisher","DOI":"10.3164\/jcbn.38.51"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202002712RR","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.202002712RR","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202002712RR","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T17:12:01Z","timestamp":1761671521000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202002712RR"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,23]]},"references-count":74,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2021,10]]}},"alternative-id":["10.1096\/fj.202002712RR"],"URL":"https:\/\/doi.org\/10.1096\/fj.202002712rr","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"type":"print","value":"0892-6638"},{"type":"electronic","value":"1530-6860"}],"subject":[],"published":{"date-parts":[[2021,9,23]]},"assertion":[{"value":"2020-12-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-09-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-09-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e21946"}}