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Phosphodiesterases (PDEs) hydrolyze cAMP and\/or cGMP and, thus, play crucial roles in cyclic nucleotide homeostasis. Abnormal alterations of PDE expression have been implicated in several diseases. To understand the function of PDEs in macrophages, we screened for all PDE genes in both peritoneal and alveolar macrophages from C57BL\/6J mice and found that PDE4B and PDE10A are highly induced by LPS. A number of PDE4 inhibitors have been used clinically for the treatment of inflammatory lung diseases. However, the role of PDE10A in inflammation is still poorly understood. We therefore investigated the role of PDE10A in macrophage inflammatory response in vitro and acute lung inflammation in vivo. We found that LPS induces a sustained PDE10A expression in macrophages, which is different from a transient induction by PDE4B. PDE10A inhibition blocked LPS-induced MCP-1 expression, but not TNF-\u03b1, whereas PDE4B inhibition blocked LPS-induced TNF-\u03b1 expression, but not MCP-1. In addition, PDE10A inhibition or deficiency decreased LPS-induced HIF-1\u03b1 protein expression and subsequently suppressed MCP-1 expression. In vivo, PDE10A expression was also elevated in lung tissue after LPS exposure. Global PDE10A knockout or systemic administration of the PDE10A inhibitor TP-10 in mice significantly suppressed inflammatory molecule levels in the lung tissue and bronchoalveolar lavage fluid as well as inflammatory cell infiltration. These findings show that PDE10A plays a critical role in lung inflammation by promoting the activation of resident macrophages and infiltration of neutrophils.<\/jats:p>","DOI":"10.4049\/jimmunol.2001026","type":"journal-article","created":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T17:50:29Z","timestamp":1623433829000},"page":"3010-3020","source":"Crossref","is-referenced-by-count":23,"title":["Phosphodiesterase 10A Is a Key Mediator of Lung Inflammation"],"prefix":"10.1093","volume":"206","author":[{"given":"Chia George","family":"Hsu","sequence":"first","affiliation":[{"name":"Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry , Rochester, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabeha","family":"Fazal","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry , Rochester, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5621-0512","authenticated-orcid":false,"given":"Arshad","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry , Rochester, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradford C","family":"Berk","sequence":"additional","affiliation":[{"name":"Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry , Rochester, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1397-6358","authenticated-orcid":false,"given":"Chen","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry , Rochester, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,6,15]]},"reference":[{"key":"2025030417503895300_r1","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1001\/jama.2016.0291","article-title":"Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries","volume":"315","author":"Bellani","year":"2016","journal-title":"JAMA"},{"key":"2025030417503895300_r2","doi-asserted-by":"crossref","first-page":"113","DOI":"10.4187\/respcare.04716","article-title":"Past and present ARDS mortality rates: a systematic review","volume":"62","author":"M\u00e1ca","year":"2017","journal-title":"Respir. 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