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EGFR-Dependent IL8 Production by Airway Epithelial Cells After Exposure to the Food Flavoring Chemical 2,3-Butanedione.

Publication ,  Journal Article
Kelly, FL; Weinberg, KE; Nagler, AE; Nixon, AB; Star, MD; Todd, JL; Brass, DM; Palmer, SM
Published in: Toxicol Sci
June 1, 2019

2,3-Butanedione (DA), a component of artificial butter flavoring, is associated with the development of occupational bronchiolitis obliterans (BO), a disease of progressive airway fibrosis resulting in lung function decline. Neutrophilic airway inflammation is a consistent feature of BO across a range of clinical contexts and may contribute to disease pathogenesis. Therefore, we sought to determine the importance of the neutrophil chemotactic cytokine interleukin-8 (IL-8) in DA-induced lung disease using in vivo and in vitro model systems. First, we demonstrated that levels of Cinc-1, the rat homolog of IL-8, are increased in the lung fluid and tissue compartment in a rat model of DA-induced BO. Next, we demonstrated that DA increased IL-8 production by the pulmonary epithelial cell line NCI-H292 and by primary human airway epithelial cells grown under physiologically relevant conditions at an air-liquid interface. We then tested the hypothesis that DA-induced epithelial IL-8 protein occurs in an epidermal growth factor receptor (EGFR)-dependent manner. In these in vitro experiments we demonstrated that epithelial IL-8 protein is blocked by the EGFR tyrosine kinase inhibitor AG1478 and by inhibition of tumor necrosis factor-alpha converting enzyme using the small molecule inhibitor, TAPI-1. Finally, we demonstrated that DA-induced IL-8 is dependent upon ERK1/2 and Mitogen activated protein kinase kinase activation downstream of EGFR signaling using the small molecule inhibitors AG1478 and PD98059. Together these novel in vivo and in vitro observations support that EGFR-dependent IL-8 production occurs in DA-induced BO. Further studies are warranted to determine the importance of IL-8 in BO pathogenesis.

Duke Scholars

Published In

Toxicol Sci

DOI

EISSN

1096-0929

Publication Date

June 1, 2019

Volume

169

Issue

2

Start / End Page

534 / 542

Location

United States

Related Subject Headings

  • Toxicology
  • Rats
  • Lung
  • Interleukin-8
  • Flavoring Agents
  • Extracellular Signal-Regulated MAP Kinases
  • ErbB Receptors
  • Epithelial Cells
  • Diacetyl
  • Bronchiolitis Obliterans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Kelly, F. L., Weinberg, K. E., Nagler, A. E., Nixon, A. B., Star, M. D., Todd, J. L., … Palmer, S. M. (2019). EGFR-Dependent IL8 Production by Airway Epithelial Cells After Exposure to the Food Flavoring Chemical 2,3-Butanedione. Toxicol Sci, 169(2), 534–542. https://doi.org/10.1093/toxsci/kfz066
Kelly, Francine L., Kaitlyn E. Weinberg, Andrew E. Nagler, Andrew B. Nixon, Mark D. Star, Jamie L. Todd, David M. Brass, and Scott M. Palmer. “EGFR-Dependent IL8 Production by Airway Epithelial Cells After Exposure to the Food Flavoring Chemical 2,3-Butanedione.Toxicol Sci 169, no. 2 (June 1, 2019): 534–42. https://doi.org/10.1093/toxsci/kfz066.
Kelly FL, Weinberg KE, Nagler AE, Nixon AB, Star MD, Todd JL, et al. EGFR-Dependent IL8 Production by Airway Epithelial Cells After Exposure to the Food Flavoring Chemical 2,3-Butanedione. Toxicol Sci. 2019 Jun 1;169(2):534–42.
Kelly, Francine L., et al. “EGFR-Dependent IL8 Production by Airway Epithelial Cells After Exposure to the Food Flavoring Chemical 2,3-Butanedione.Toxicol Sci, vol. 169, no. 2, June 2019, pp. 534–42. Pubmed, doi:10.1093/toxsci/kfz066.
Kelly FL, Weinberg KE, Nagler AE, Nixon AB, Star MD, Todd JL, Brass DM, Palmer SM. EGFR-Dependent IL8 Production by Airway Epithelial Cells After Exposure to the Food Flavoring Chemical 2,3-Butanedione. Toxicol Sci. 2019 Jun 1;169(2):534–542.
Journal cover image

Published In

Toxicol Sci

DOI

EISSN

1096-0929

Publication Date

June 1, 2019

Volume

169

Issue

2

Start / End Page

534 / 542

Location

United States

Related Subject Headings

  • Toxicology
  • Rats
  • Lung
  • Interleukin-8
  • Flavoring Agents
  • Extracellular Signal-Regulated MAP Kinases
  • ErbB Receptors
  • Epithelial Cells
  • Diacetyl
  • Bronchiolitis Obliterans