{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T07:28:29Z","timestamp":1774078109874,"version":"3.50.1"},"reference-count":56,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2015,5,1]],"date-time":"2015-05-01T00:00:00Z","timestamp":1430438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Chronic obstructive pulmonary disease (COPD) and influenza virus infections are major global health issues. Patients with COPD are more susceptible to infection, which exacerbates their condition and increases morbidity and mortality. The mechanisms of increased susceptibility remain poorly understood, and current preventions and treatments have substantial limitations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To characterize the mechanisms of increased susceptibility to influenza virus infection in COPD and the potential for therapeutic targeting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used a combination of primary bronchial epithelial cells (pBECs) from COPD and healthy control subjects, a mouse model of cigarette smoke\u2013induced experimental COPD, and influenza infection. The role of the phosphoinositide-3-kinase (PI3K) pathway was characterized using molecular methods, and its potential for targeting assessed using inhibitors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>COPD pBECs were susceptible to increased viral entry and replication. Infected mice with experimental COPD also had more severe infection (increased viral titer and pulmonary inflammation, and compromised lung function). These processes were associated with impaired antiviral immunity, reduced retinoic acid\u2013inducible gene-I, and IFN\/cytokine and chemokine responses. Increased PI3K-p110\u03b1 levels and activity in COPD pBECs and\/or mice were responsible for increased infection and reduced antiviral responses. Global PI3K, specific therapeutic p110\u03b1 inhibitors, or exogenous IFN-\u03b2 restored protective antiviral responses, suppressed infection, and improved lung function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The increased susceptibility of individuals with COPD to influenza likely results from impaired antiviral responses, which are mediated by increased PI3K-p110\u03b1 activity. This pathway may be targeted therapeutically in COPD, or in healthy individuals, during seasonal or pandemic outbreaks to prevent and\/or treat influenza.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201501-0188oc","type":"journal-article","created":{"date-parts":[[2015,3,9]],"date-time":"2015-03-09T16:51:01Z","timestamp":1425919861000},"page":"1012-1023","source":"Crossref","is-referenced-by-count":135,"title":["Targeting PI3K-p110\u03b1 Suppresses Influenza Virus Infection in Chronic Obstructive Pulmonary Disease"],"prefix":"10.1093","volume":"191","author":[{"given":"Alan","family":"Chen-Yu Hsu","sequence":"first","affiliation":[{"name":"Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute and The University of Newcastle, Newcastle, New South Wales, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malcolm R.","family":"Starkey","sequence":"additional","affiliation":[{"name":"Priority Research 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Jhong","family":"Haw","sequence":"additional","affiliation":[{"name":"Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute and The University of Newcastle, Newcastle, New South Wales, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda J.","family":"Howland","sequence":"additional","affiliation":[{"name":"Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute and The University of Newcastle, Newcastle, New South Wales, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian","family":"Barr","sequence":"additional","affiliation":[{"name":"World Health Organization Collaborating Centre for Reference and Research on Influenza, Melbourne, Victoria, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James B.","family":"Mahony","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, McMaster 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