PMID- 24816162 OWN - NLM STAT- MEDLINE DCOM- 20141128 LR - 20211021 IS - 1535-4989 (Electronic) IS - 1044-1549 (Print) IS - 1044-1549 (Linking) VI - 51 IP - 4 DP - 2014 Oct TI - Diacetyl induces amphiregulin shedding in pulmonary epithelial cells and in experimental bronchiolitis obliterans. PG - 568-74 LID - 10.1165/rcmb.2013-0339OC [doi] AB - Diacetyl (DA), a component of artificial butter flavoring, has been linked to the development of bronchiolitis obliterans (BO), a disease of airway epithelial injury and airway fibrosis. The epidermal growth factor receptor ligand, amphiregulin (AREG), has been implicated in other types of epithelial injury and lung fibrosis. We investigated the effects of DA directly on the pulmonary epithelium, and we hypothesized that DA exposure would result in epithelial cell shedding of AREG. Consistent with this hypothesis, we demonstrate that DA increases AREG by the pulmonary epithelial cell line NCI-H292 and by multiple independent primary human airway epithelial donors grown under physiologically relevant conditions at the air-liquid interface. Furthermore, we demonstrate that AREG shedding occurs through a TNF-alpha-converting enzyme (TACE)-dependent mechanism via inhibition of TACE activity in epithelial cells using the small molecule inhibitor, TNF-alpha protease inhibitor-1, as well as TACE-specific small inhibitor RNA. Finally, we demonstrate supportive in vivo results showing increased AREG transcript and protein levels in the lungs of rodents with DA-induced BO. In summary, our novel in vitro and in vivo observations suggest that further study of AREG is warranted in the pathogenesis of DA-induced BO. FAU - Kelly, Francine L AU - Kelly FL AD - Divisions of 1 Pulmonary, Allergy, and Critical Care Medicine, and. FAU - Sun, Jesse AU - Sun J FAU - Fischer, Bernard M AU - Fischer BM FAU - Voynow, Judith A AU - Voynow JA FAU - Kummarapurugu, Apparao B AU - Kummarapurugu AB FAU - Zhang, Helen L AU - Zhang HL FAU - Nugent, Julia L AU - Nugent JL FAU - Beasley, Robert F AU - Beasley RF FAU - Martinu, Tereza AU - Martinu T FAU - Gwinn, William M AU - Gwinn WM FAU - Morgan, Daniel L AU - Morgan DL FAU - Palmer, Scott M AU - Palmer SM LA - eng GR - R01 ES016836/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Am J Respir Cell Mol Biol JT - American journal of respiratory cell and molecular biology JID - 8917225 RN - 0 (AREG protein, human) RN - 0 (Amphiregulin) RN - 0 (Areg protein, rat) RN - 0 (EGF Family of Proteins) RN - 0 (Enzyme Inhibitors) RN - 0 (Flavoring Agents) RN - EC 3.4.24.- (ADAM Proteins) RN - EC 3.4.24.86 (ADAM17 Protein) RN - EC 3.4.24.86 (ADAM17 protein, human) RN - EC 3.4.24.86 (Adam17 protein, rat) RN - K324J5K4HM (Diacetyl) SB - IM MH - ADAM Proteins/antagonists & inhibitors/genetics/metabolism MH - ADAM17 Protein MH - Amphiregulin MH - Bronchiolitis Obliterans/*chemically induced/genetics/metabolism MH - Cell Line MH - Diacetyl/*toxicity MH - Dose-Response Relationship, Drug MH - EGF Family of Proteins/genetics/*metabolism MH - Enzyme Inhibitors/pharmacology MH - Epithelial Cells/*drug effects/metabolism/pathology MH - Flavoring Agents/*toxicity MH - Humans MH - Pulmonary Fibrosis/chemically induced/metabolism/pathology MH - RNA Interference MH - Respiratory Mucosa/*drug effects/metabolism/pathology MH - Time Factors MH - Transfection MH - Up-Regulation PMC - PMC4189481 OTO - NOTNLM OT - TNF-alpha-converting enzyme OT - amphiregulin OT - bronchiolitis obliterans OT - diacetyl OT - epidermal growth factor receptor EDAT- 2014/05/13 06:00 MHDA- 2014/12/15 06:00 PMCR- 2015/10/01 CRDT- 2014/05/13 06:00 PHST- 2014/05/13 06:00 [entrez] PHST- 2014/05/13 06:00 [pubmed] PHST- 2014/12/15 06:00 [medline] PHST- 2015/10/01 00:00 [pmc-release] AID - 10.1165/rcmb.2013-0339OC [doi] PST - ppublish SO - Am J Respir Cell Mol Biol. 2014 Oct;51(4):568-74. doi: 10.1165/rcmb.2013-0339OC.