A Small Molecule BH3-mimetic Suppresses Cigarette Smoke-Induced Mucous Expression in Airway Epithelial Cells.
Shah S HussainShebin GeorgeShashi SinghRahul Dev JayantChien-An HuMohan SoporiHitendra S ChandPublished in: Scientific reports (2018)
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.
Keyphrases
- poor prognosis
- small molecule
- endothelial cells
- high glucose
- diabetic rats
- signaling pathway
- small cell lung cancer
- cell death
- protein protein
- cell proliferation
- oxidative stress
- anti inflammatory
- cell cycle arrest
- high resolution
- mass spectrometry
- long non coding rna
- epidermal growth factor receptor
- type diabetes
- cancer therapy
- tyrosine kinase
- induced apoptosis
- endoplasmic reticulum stress
- adipose tissue
- drug delivery
- amino acid
- pluripotent stem cells
- combination therapy