{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T00:38:07Z","timestamp":1772930287937,"version":"3.50.1"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2000,4,1]],"date-time":"2000-04-01T00:00:00Z","timestamp":954547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2000,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Lung epithelium plays a significant role in modulating the inflammatory response to lung injury. Airway epithelial cells are targeted by hydrogen peroxide (H2O2) and oxygen radicals, which are agents commonly produced during inflammatory processes. The mechanisms and molecular sites affected by H2O2 are largely unknown but may involve the induction of sphingomyelin (SM) hydrolysis to generate ceramide, which serves as a second messenger in initiating an apoptotic response. Here we show that exposure of human airway epithelial (HAE) cells to 50 to 100 \u03bc M H2O2 induces within 5 to 10 min a greater than 2-fold activation of neutral sphingomyelinase activity with concomitant SM hydrolysis, ceramide generation, and apoptosis. On the other hand, activation of protein kinase C (PKC) by 12-O-tetradecanoylphorbol-13-acetate inhibits both H2O2-induced ceramide production and apoptosis. The apoptotic response could be restored by the addition of 25 \u03bc M cell-permeant C6-ceramide. These findings indicate that ceramide, the product of SM hydrolysis, plays an important role in H2O2-induced apoptosis in HAE cells, and that PKC counteracts ceramide-mediated apoptosis in these cells. We suggest that the mediation of epithelial cell apoptosis by ceramide and its inhibition by PKC constitute a central mechanism by which inflammatory processes are modulated in the epithelium of the lung.<\/jats:p>","DOI":"10.1165\/ajrcmb.22.4.3376","type":"journal-article","created":{"date-parts":[[2013,4,3]],"date-time":"2013-04-03T21:40:29Z","timestamp":1365025229000},"page":"460-468","source":"Crossref","is-referenced-by-count":51,"title":["Ceramide Path in Human Lung Cell Death"],"prefix":"10.1093","volume":"22","author":[{"given":"Chris","family":"Chan","sequence":"first","affiliation":[{"name":"Signal Transduction, Department of Medicine, University of California Davis School of Medicine, Davis, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tzipora","family":"Goldkorn","sequence":"additional","affiliation":[{"name":"Signal Transduction, Department of Medicine, University of California Davis School of Medicine, Davis, California"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2000,4,1]]},"reference":[{"key":"2026030700082029900_B1"},{"key":"2026030700082029900_B2","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1126\/science.7878464","article-title":"Apoptosis in the pathogenesis and treatment of disease.","volume":"267","author":"Thompson","year":"1995","journal-title":"Science"},{"key":"2026030700082029900_B3","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/376017a0","article-title":"The last cut is the deepest.","volume":"376","author":"Whyte","year":"1995","journal-title":"Nature"},{"key":"2026030700082029900_B4","doi-asserted-by":"crossref","first-page":"7162","DOI":"10.1073\/pnas.92.16.7162","article-title":"Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-d-asparate or nitric oxide\/superoxide in cortical cell cultures.","volume":"92","author":"Bonfoco","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026030700082029900_B5","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/B978-0-12-364932-4.50010-1","article-title":"Apoptosis: mechanisms and roles in pathology.","volume":"32","author":"Arends","year":"1991","journal-title":"Int. Rev. Exp. Pathol."},{"key":"2026030700082029900_B6","doi-asserted-by":"crossref","first-page":"3125","DOI":"10.1016\/S0021-9258(17)41834-5","article-title":"The sphingomyelin cycle and the second messenger function of ceramide.","volume":"269","author":"Hannun","year":"1994","journal-title":"J. Biol. Chem."},{"key":"2026030700082029900_B7","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1126\/science.8456305","article-title":"Programmed cell death induced by ceramide.","volume":"259","author":"Obeid","year":"1993","journal-title":"Science"},{"key":"2026030700082029900_B8","doi-asserted-by":"crossref","first-page":"2047","DOI":"10.1074\/jbc.270.5.2047","article-title":"Role of ceramide in cell cycle arrest.","volume":"270","author":"Jayadev","year":"1995","journal-title":"J. Biol. Chem."},{"key":"2026030700082029900_B9","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1073\/pnas.91.1.73","article-title":"Induction of apoptotic DNA damage and cell death by activation of the sphingomyelin pathway.","volume":"91","author":"Jarvis","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026030700082029900_B10","doi-asserted-by":"crossref","first-page":"15493","DOI":"10.1016\/S0021-9258(17)40706-X","article-title":"1-(-d-arabinofuranosylcytosine stimulates ceramide and diglyceride formation in HL-60 cells.","volume":"269","author":"Strum","year":"1994","journal-title":"J. Biol. Chem."},{"key":"2026030700082029900_B11","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1084\/jem.180.2.525","article-title":"Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis.","volume":"180","author":"Haimovitz-Friedman","year":"1994","journal-title":"J. Exp. Med."},{"key":"2026030700082029900_B12","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1084\/jem.180.4.1547","article-title":"Apoptotic signaling through CD95 (Fas\/Apo-1) activates an acidic sphingomyelinase.","volume":"180","author":"Cifone","year":"1994","journal-title":"J. Exp. 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Chem."},{"key":"2026030700082029900_B17","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/0092-8674(94)90275-5","article-title":"Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling.","volume":"78","author":"Wiegmann","year":"1994","journal-title":"Cell"},{"key":"2026030700082029900_B18","doi-asserted-by":"crossref","first-page":"4070","DOI":"10.1016\/S0021-9258(17)41744-3","article-title":"Characteristics and partial purification of a novel cytosolic, magnesium- independent, neutral sphingomyelinase activated in the early signal transduction of 1\u03b1,25-dihydroxivitamin D3-induced HL-60 cell differentiation.","volume":"269","author":"Okazaki","year":"1994","journal-title":"J. Biol. 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Physiol."},{"key":"2026030700082029900_B21","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1126\/science.274.5294.1855","article-title":"Functions of ceramide in coordinating cellular responses to stress.","volume":"274","author":"Hannun","year":"1996","journal-title":"Science"},{"key":"2026030700082029900_B22","first-page":"25","article-title":"Neutral sphingomyelinase.","volume":"26","author":"Chatterjee","year":"1993","journal-title":"Adv. Lipid Res."},{"key":"2026030700082029900_B23","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/BF01666138","article-title":"Culture of airway epithelial cells in serum-free medium.","volume":"13","author":"Robinson","year":"1991","journal-title":"J. Tiss. Cult. Meth."},{"key":"2026030700082029900_B24","first-page":"1945","article-title":"Detection of DNA strand breaks in individual apoptotic cells by the in situ terminal deoxynucleotidyl transferase and nick translation assays.","volume":"53","author":"Gorczyca","year":"1993","journal-title":"Cancer Res."},{"key":"2026030700082029900_B25","doi-asserted-by":"crossref","first-page":"5408","DOI":"10.1073\/pnas.89.12.5408","article-title":"Induction of apoptosis in cultured hepatocytes and in regressing liver by transforming growth factor \u03b21.","volume":"89","author":"Oberhammer","year":"1992","journal-title":"Proc. Natl. Acad. Sci. 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Chem."},{"key":"2026030700082029900_B28","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1126\/science.1313189","article-title":"TNF\u03b1 activates the sphingomyelin signal transduction pathway in a cell-free system.","volume":"255","author":"Dressler","year":"1992","journal-title":"Science"},{"key":"2026030700082029900_B29"},{"key":"2026030700082029900_B30","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S0167-4889(96)00068-7","article-title":"Effects of radiation on signal transduction: antibodies to EGF receptor sensitize A431 cells to radiation.","volume":"1314","author":"Balaban","year":"1996","journal-title":"Biochim. Biophys. 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Chem."},{"key":"2026030700082029900_B42","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1165\/ajrcmb.19.5.3249","article-title":"EGF receptor phosphorylation and signaling is targeted by H2O2 redox stress.","volume":"19","author":"Goldkorn","year":"1998","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2026030700082029900_B43","doi-asserted-by":"crossref","first-page":"31860","DOI":"10.1074\/jbc.273.48.31860","article-title":"Peroxynitrite induces covalent dimerization of EGF receptors: possible involvement of intermolecular dityrosine crosslinking.","volume":"273","author":"Van der Vliet","year":"1998","journal-title":"J. Biol. Chem."},{"key":"2026030700082029900_B44","first-page":"5114","article-title":"Glutathione regulation of ceramide path in lung epithelial cells.","volume":"27","author":"Lavrentiadou","year":"1999","journal-title":"Free Radic. Biol. 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Chem."},{"key":"2026030700082029900_B49","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/308693a0","article-title":"The role of protein kinase C in cell surface signal transduction and tumour promotion.","volume":"308","author":"Nishizuka","year":"1984","journal-title":"Nature"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/22\/4\/460\/67191409\/ajrcmb_22_4_460.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/22\/4\/460\/67191409\/ajrcmb_22_4_460.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T05:19:32Z","timestamp":1772860772000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/22\/4\/460\/8502791"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,4,1]]},"references-count":49,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2000,4,1]]},"published-print":{"date-parts":[[2000,4,1]]}},"URL":"https:\/\/doi.org\/10.1165\/ajrcmb.22.4.3376","relation":{},"ISSN":["1535-4989","1044-1549"],"issn-type":[{"value":"1535-4989","type":"electronic"},{"value":"1044-1549","type":"print"}],"subject":[],"published-other":{"date-parts":[[2000,4]]},"published":{"date-parts":[[2000,4,1]]}}}