Diacetyl induces amphiregulin shedding in pulmonary epithelial cells and in experimental bronchiolitis obliterans.

Journal Article (Journal Article)

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-α-converting enzyme (TACE)-dependent mechanism via inhibition of TACE activity in epithelial cells using the small molecule inhibitor, TNF-α 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.

Full Text

Duke Authors

Cited Authors

  • Kelly, FL; Sun, J; Fischer, BM; Voynow, JA; Kummarapurugu, AB; Zhang, HL; Nugent, JL; Beasley, RF; Martinu, T; Gwinn, WM; Morgan, DL; Palmer, SM

Published Date

  • October 2014

Published In

Volume / Issue

  • 51 / 4

Start / End Page

  • 568 - 574

PubMed ID

  • 24816162

Pubmed Central ID

  • PMC4189481

Electronic International Standard Serial Number (EISSN)

  • 1535-4989

Digital Object Identifier (DOI)

  • 10.1165/rcmb.2013-0339OC


  • eng

Conference Location

  • United States