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Ctss\u2212\/\u2212 mice were exposed to long-term cigarette smoke and forced oscillation and expiratory measurements were recorded. Animals were administered chemical modulators of PP2A (protein phosphatase 2A) activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Here we observed enhanced CTSS expression and activity in mouse lungs after exposure to cigarette smoke. Ctss\u2212\/\u2212 mice were resistant to cigarette smoke\u2013induced inflammation, airway hyperresponsiveness, airspace enlargements, and loss of lung function. CTSS expression was negatively regulated by PP2A in human bronchial epithelial cells isolated from healthy nonsmokers and COPD donors and in monocyte-derived macrophages. Modulating PP2A expression or activity, with silencer siRNA or a chemical inhibitor or activator, during acute smoke exposure in mice altered inflammatory responses and CTSS expression and activity in the lung. Enhancement of PP2A activity prevented chronic smoke-induced COPD in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study indicates that the decrease in PP2A activity that occurs in COPD contributes to elevated CTSS expression in the lungs and results in impaired lung function. Enhancing PP2A activity represents a feasible therapeutic approach to reduce CTSS activity and counter smoke-induced lung disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201808-1518oc","type":"journal-article","created":{"date-parts":[[2019,1,14]],"date-time":"2019-01-14T17:51:57Z","timestamp":1547488317000},"page":"51-62","source":"Crossref","is-referenced-by-count":53,"title":["Protein Phosphatase 2A Reduces Cigarette Smoke\u2013induced Cathepsin S and Loss of Lung Function"],"prefix":"10.1093","volume":"200","author":[{"given":"Declan F.","family":"Doherty","sequence":"first","affiliation":[{"name":"Airway Innate Immunity Research Group, Centre for Experimental Medicine, Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen\u2019s University Belfast, Belfast, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7996-8820","authenticated-orcid":false,"given":"Sridesh","family":"Nath","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0411-4665","authenticated-orcid":false,"given":"Justin","family":"Poon","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3964-5335","authenticated-orcid":false,"given":"Robert F.","family":"Foronjy","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, and"},{"name":"Department of Cell Biology, State University of New York Downstate Medical Centre, Brooklyn, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Ohlmeyer","sequence":"additional","affiliation":[{"name":"Icahn School of Medicine at Mount Sinai, New York, New York"},{"name":"Atux Iskay LLC, Plainsboro, New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5127-1498","authenticated-orcid":false,"given":"Abdoulaye J.","family":"Dabo","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, and"},{"name":"Department of Cell Biology, State University of New York Downstate Medical Centre, Brooklyn, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9092-4861","authenticated-orcid":false,"given":"Matthias","family":"Salathe","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas"},{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, University of Miami, Miami, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6392-2086","authenticated-orcid":false,"given":"Mark","family":"Birrell","sequence":"additional","affiliation":[{"name":"Respiratory Pharmacology Group, Airway Disease Section, National Heart and Lung Institute, Imperial College, London, United Kingdom; 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