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Since inflammation modulates neuroplasticity, we studied the impact of inflammation caused by prolonged intermittent hypoxia on an important form of respiratory plasticity, acute intermittent hypoxia (three, 5 min hypoxic episodes, 5 min normoxic intervals) induced phrenic long-term facilitation (pLTF). Because chronic intermittent hypoxia elicits neuroinflammation and pLTF is undermined by lipopolysaccharide-induced systemic inflammation, we hypothesized that one night of intermittent hypoxia (IH-1) elicits spinal inflammation, thereby impairing pLTF by a p38 MAP kinase-dependent mechanism. pLTF and spinal inflammation were assessed in anesthetized rats pretreated with IH-1 (2 min hypoxia, 2 min normoxia; 8 h) or sham normoxia and allowed 16 h for recovery. IH-1 (1) transiently increased<jats:italic>IL-6<\/jats:italic>(1.5 \u00b1 0.2-fold;<jats:italic>p<\/jats:italic>= 0.02) and<jats:italic>inducible nitric oxide synthase<\/jats:italic>(<jats:italic>iNOS<\/jats:italic>) (2.4 \u00b1 0.4-fold;<jats:italic>p<\/jats:italic>= 0.01) mRNA in cervical spinal homogenates, (2) elicited a sustained increase in<jats:italic>IL-1<\/jats:italic>\u03b2 mRNA (2.4 \u00b1 0.2-fold;<jats:italic>p<\/jats:italic>&lt; 0.001) in isolated cervical spinal microglia, and (3) abolished pLTF (\u22121 \u00b1 5% vs 56 \u00b1 10% in controls;<jats:italic>p<\/jats:italic>&lt; 0.001). pLTF was restored after IH-1 by systemic NSAID administration (ketoprofen; 55 \u00b1 9%;<jats:italic>p<\/jats:italic>&lt; 0.001) or spinal p38 MAP kinase inhibition (58 \u00b1 2%;<jats:italic>p<\/jats:italic>&lt; 0.001). IH-1 increased phosphorylated (activated) p38 MAP kinase immunofluorescence in identified phrenic motoneurons and adjacent microglia. In conclusion, IH-1 elicits spinal inflammation and impairs pLTF by a spinal p38 MAP kinase-dependent mechanism. By targeting inflammation, we may develop strategies to manipulate respiratory motor plasticity for therapeutic advantage when the respiratory control system is compromised (e.g., sleep apnea, apnea of prematurity, spinal injury, or motor neuron disease).<\/jats:p>","DOI":"10.1523\/jneurosci.4539-14.2015","type":"journal-article","created":{"date-parts":[[2015,4,29]],"date-time":"2015-04-29T16:33:04Z","timestamp":1430325184000},"page":"6871-6880","source":"Crossref","is-referenced-by-count":69,"title":["Intermittent Hypoxia-Induced Spinal Inflammation Impairs Respiratory Motor Plasticity by a Spinal p38 MAP Kinase-Dependent Mechanism"],"prefix":"10.1523","volume":"35","author":[{"given":"Adrianne G.","family":"Huxtable","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie M.C.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0995-3644","authenticated-orcid":false,"given":"Timothy J.","family":"Peterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jyoti J.","family":"Watters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon S.","family":"Mitchell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2015,4,29]]},"reference":[{"key":"2023041304164780000_35.17.6871.1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00089.2014"},{"key":"2023041304164780000_35.17.6871.2","doi-asserted-by":"publisher","DOI":"10.1016\/0034-5687(96)00017-5"},{"key":"2023041304164780000_35.17.6871.3","doi-asserted-by":"crossref","first-page":"6239","DOI":"10.1523\/JNEUROSCI.22-14-06239.2002","article-title":"Phrenic long-term facilitation requires spinal serotonin receptor activation and protein synthesis","volume":"22","author":"Baker-Herman","year":"2002","journal-title":"J Neurosci"},{"key":"2023041304164780000_35.17.6871.4","doi-asserted-by":"publisher","DOI":"10.1038\/nn1166"},{"key":"2023041304164780000_35.17.6871.5","doi-asserted-by":"publisher","DOI":"10.1016\/S0034-5687(00)00131-6"},{"key":"2023041304164780000_35.17.6871.6","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.44.28766"},{"key":"2023041304164780000_35.17.6871.7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0030338"},{"key":"2023041304164780000_35.17.6871.8","doi-asserted-by":"publisher","DOI":"10.1002\/j.1552-4604.1998.tb04411.x"},{"key":"2023041304164780000_35.17.6871.9","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1520-636X(1996)8:2<163::AID-CHIR1>3.0.CO;2-K"},{"key":"2023041304164780000_35.17.6871.10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2006.00441.x"},{"key":"2023041304164780000_35.17.6871.11","doi-asserted-by":"crossref","first-page":"847","DOI":"10.2741\/3282","article-title":"Post-transcriptional gene regulation by MAP kinases via AU-rich elements","volume":"14","author":"Clark","year":"2009","journal-title":"Front Biosci"},{"key":"2023041304164780000_35.17.6871.12","doi-asserted-by":"publisher","DOI":"10.1038\/nature04223"},{"key":"2023041304164780000_35.17.6871.13","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-6-24"},{"key":"2023041304164780000_35.17.6871.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2005.11.066"},{"key":"2023041304164780000_35.17.6871.15","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3873-11.2012"},{"key":"2023041304164780000_35.17.6871.16","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00012.2013"},{"key":"2023041304164780000_35.17.6871.17","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0239-11.2011"},{"key":"2023041304164780000_35.17.6871.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2008.06.005"},{"key":"2023041304164780000_35.17.6871.19","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/S0090-9556(25)07014-X","article-title":"Stereoselective pharmacokinetics of ketoprofen in the rat. 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