{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T20:33:44Z","timestamp":1774125224886,"version":"3.50.1"},"reference-count":28,"publisher":"Proceedings of the National Academy of Sciences","issue":"3","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2005,1,18]]},"abstract":"<jats:p>\n            Mucus hypersecretion is a prominent manifestation in patients with chronic inflammatory airway diseases. MUC5AC mucin is a major component of airway mucus, and its expression is modulated by a TNF-\u03b1-converting enzyme (TACE)\u2013EGF receptor pathway that can be activated by reactive oxygen species (ROS). Dual oxidase 1 (Duox1), a homologue of glycoprotein p91\n            <jats:sup>phox<\/jats:sup>\n            , is expressed in airway epithelium and generates ROS. We hypothesize that Duox1 activates TACE, cleaving pro-TGF-\u03b1 into soluble TGF-\u03b1, resulting in mucin expression. To examine this hypothesis, we stimulated both normal human bronchial epithelial cells and NCI-H292 airway epithelial cells with phorbol 12-myristate 13-acetate and with human neutrophil elastase. These stimuli induced TACE activation, TGF-\u03b1 release, and mucin expression, effects that were inhibited by ROS scavengers, implicating ROS in TACE activation. Inhibition of epithelial NADPH oxidase or knockdown of Duox1 expression with small interfering RNA prevented ROS generation, TGF-\u03b1 release, and mucin expression by these stimuli, implicating Duox1 in TACE activation and mucin expression. Furthermore, the PKC\u03b4\/PKC\u03b8 inhibitor rottlerin prevented the effects induced by phorbol 12-myristate 13-acetate and human neutrophil elastase, suggesting that PKC\u03b4 and PKC\u03b8 are involved in Duox1 activation. From these results, we conclude that Duox1 plays a critical role in mucin expression by airway epithelial cells through PKC\u03b4\/PKC\u03b8-Duox1-ROS-TACE-pro-ligand-EGF receptor cascade.\n          <\/jats:p>","DOI":"10.1073\/pnas.0408932102","type":"journal-article","created":{"date-parts":[[2005,1,8]],"date-time":"2005-01-08T01:46:42Z","timestamp":1105148802000},"page":"767-772","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":213,"title":["Dual oxidase 1-dependent MUC5AC mucin expression in cultured human airway epithelial cells"],"prefix":"10.1073","volume":"102","author":[{"given":"Matt X. G.","family":"Shao","sequence":"first","affiliation":[{"name":"Cardiovascular Research Institute and Departments of Medicine and Physiology, University of California, San Francisco, CA 94143-0130"}]},{"given":"Jay A.","family":"Nadel","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute and Departments of Medicine and Physiology, University of California, San Francisco, CA 94143-0130"}]}],"member":"341","published-online":{"date-parts":[[2005,1,7]]},"reference":[{"key":"e_1_3_2_1_2","unstructured":"Nadel J. A. (2002) in Chronic Obstructive Lung Diseases eds. Voelkel N. F. & MacNee W. 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