Diacetyl Induces Amphiregulin Shedding in Pulmonary Epithelial Cells and in Experimental Bronchiolitis Obliterans.

Diacetyl Induces Amphiregulin Shedding in Pulmonary Epithelial Cells and in Experimental Bronchiolitis Obliterans. Am J Respir Cell Mol Biol. 2014 May 9; 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 Abstract 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 (EGFR) 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 (ALI). Furthermore, we demonstrate that AREG shedding occurs through a tumor necrosis factor-alpha converting enzyme (TACE)-dependent mechanism via inhibition of TACE activity in epithelial cells using the small molecule inhibitor, TAPI-1, as well as TACE specific siRNA. Finally, we demonstrate supportive in vivo results showing increase AREG transcript and protein levels in the lungs of rodents...
Source: Am J Respir Cell Mol... - Category: Respiratory Medicine Authors: Tags: Am J Respir Cell Mol Biol Source Type: research