A Small Molecule BH3-mimetic Suppresses Cigarette Smoke-Induced Mucous Expression in Airway Epithelial Cells

Sci Rep. 2018 Sep 14;8(1):13796. doi: 10.1038/s41598-018-32114-w.

Abstract

Cigarette smoke (CS) exposure is one of the primary risk factors associated with the chronic mucous hypersecretion (CMH). The antiapoptotic protein, Bcl-2 sustains hyperplastic mucous cells, and the airway epithelium of ex-smokers with CMH as well as mice exposed to chronic CS showed increased Bcl-2 expression. Therefore, we investigated whether Bcl-2 plays a role in CS-induced mucous expression. Primary airway epithelial cells (AECs) of murine and human origin were treated with CS extract (CSE), and there was a concentration- and time-dependent increase in secretory mucin (MUC5AC), mucous regulator (SPDEF) and Bcl-2 expression. Using differentiated human AECs cultured on air-liquid interface, EGFR and ERK1/2 pathways were interrogated. Bcl-2 activity was blocked using a small molecule BH3 mimetic ABT-263 that disrupts the Bcl-2 interaction with pro-apoptotic proteins. The ABT-263 treatment resulted in the downregulation of CSE-induced mucus expression and disrupted the EGFR-signaling while inducing the apoptosis and the pro-apoptotic protein, Bik expression. This strategy significantly suppressed the mainstream CS-induced mucous phenotype in a 3-D human airway epithelium model. Therefore, the present study suggests that CS induces Bcl-2 expression to help promote mucous cell survival; and small molecule BH3 mimetics targeting Bcl-2 could be useful in suppressing the CS-induced mucous response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins / metabolism
  • Cigarette Smoking / adverse effects*
  • Epithelial Cells / metabolism
  • Genes, erbB-1
  • Goblet Cells / metabolism
  • Humans
  • Hyperplasia / pathology
  • Lung / pathology
  • MAP Kinase Signaling System
  • Mice
  • Mucin 5AC / metabolism
  • Mucus / metabolism
  • Nicotiana / metabolism
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Proto-Oncogene Proteins c-ets / metabolism
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / metabolism*
  • Signal Transduction

Substances

  • Apoptosis Regulatory Proteins
  • Bax protein (53-86)
  • MUC5AC protein, human
  • Muc5ac protein, mouse
  • Mucin 5AC
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-ets
  • SPDEF protein, human
  • Spdef protein, mouse