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.
Highlights
Secretory mucin that is primarily produced by mucous cells in the airway epithelium is MUC5AC, which is induced upon Cigarette smoke (CS) exposure and other airway injuries[8,23,24]
CS induces mucus production and mucous cell hyperplasia in airway epithelium[13,16,26,27], the molecular mechanisms involved in CS-induced mucous expression remain elusive
The Muc5ac mRNA levels were highest at 24 h post CS extract (CSE) treatment (Fig. 1D), and Spdef mRNA levels were increased within 3 h of CSE treatment (Fig. 1E)
Summary
Secretory mucin that is primarily produced by mucous cells in the airway epithelium is MUC5AC, which is induced upon CS exposure and other airway injuries[8,23,24]. In chronic airway diseases such as COPD and asthma, the debilitating mucus or phlegm production is highly associated with increased numbers of mucous cells with increased mucin synthesis and secretion[8] and this pathology is primarily driven by MUC5AC, as shown by a recent study[25]. In an animal model of chronic CS exposure, we had observed increased expression of Bcl-2 mRNA in mice exposed to CS for 16 weeks with 4-fold higher number of airway epithelial cells (AECs) showing Bcl-2 immunopositivity in CS-exposed mice compared to air-exposed controls[22]. We investigated the role of Bcl-2 in CS-induced mucous expression using cultured murine and human airway epithelial cells and tested whether targeting Bcl-2 using a small molecule BH3 mimetic compound, ABT-263, could help in modulating CS-induced mucous expression
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