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In some tissues, Akt phosphorylates and activates endothelial nitric oxide synthase (eNOS) to produce nitric oxide (NO) that has anti-inflammatory effects. NO production has antibacterial and antiviral effects in the airway, and increasing NO may be a useful anti-pathogen strategy. Akt also stimulates the nuclear factor erythroid 2\u2013related factor 2 (Nrf-2) transcription factor, which transcribes antioxidant genes. Therefore, we hypothesized that activation of the Akt\/eNOS pathway, which also activates Nrf-2, may have protective effects in human airway cells against injury.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>To directly test the effects of Akt signaling in the airway, we treated A549 and 16HBE cells as well as primary bronchial, nasal, and type II alveolar epithelial cells with small molecule Akt activator SC79. We examined the effects of SC79 on eNOS activation, NO production, Nrf-2 target levels, and interleukin-8 (IL-8) transcription during exposure to TNF-\u03b1 or <jats:italic>Pseudomonas<\/jats:italic> flagellin (TLR5 agonist). Additionally, air\u2013liquid interface bronchial cultures were treated with cadmium, an oxidative stressor that causes airway barrier breakdown.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>SC79 induced a\u2009~\u2009twofold induction of p-eNOS and Nrf-2 protein levels blocked by PI3K inhibitor LY294002. Live cell imaging revealed SC79 increased acute NO production. Quantitative RT-PCR showed a\u2009~\u2009twofold increase in Nrf-2 target gene transcription. TNF-\u03b1 or flagellin-induced IL-8 levels were also significantly reduced with SC79 treatment. Moreover, the transepithelial electrical resistance decrease observed with cadmium was ameliorated by SC79, likely by an acute increase in tight junction protein ZO-1 levels.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Together, the data presented here demonstrate SC79 activation of Akt induces potentially anti-pathogenic NO production, antioxidant gene transcription, reduces IL-8 transcription, and may protect against oxidative barrier dysfunction in a wide range of airway epithelial cells.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12931-021-01865-y","type":"journal-article","created":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T21:20:34Z","timestamp":1634678434000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Small-molecule Akt-activation in airway cells induces NO production and reduces IL-8 transcription through Nrf-2"],"prefix":"10.1186","volume":"22","author":[{"given":"Indiwari","family":"Gopallawa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li Eon","family":"Kuek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nithin D.","family":"Adappa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James N.","family":"Palmer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5826-6686","authenticated-orcid":false,"given":"Robert J.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,10,19]]},"reference":[{"issue":"1","key":"1865_CR1","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1183\/09031936.06.00053805","volume":"28","author":"I Rahman","year":"2006","unstructured":"Rahman I, Adcock IM. 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