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

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 increa...

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Autores principales:	Shah S. Hussain, Shebin George, Shashi Singh, Rahul Jayant, Chien-An Hu, Mohan Sopori, Hitendra S. Chand
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Airway Epithelial Cells (AECs) MUC1 Expression Epithelial Growth Factor Receptor (EGFR) Extracellular-signal Regulating Kinase 1/2 (ERK1/2) Human AECs Medicine R Science Q
Acceso en línea:	https://doaj.org/article/118db596e69245a78848a2480a554f26
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spelling	oai:doaj.org-article:118db596e69245a78848a2480a554f262021-12-02T15:09:07ZA Small Molecule BH3-mimetic Suppresses Cigarette Smoke-Induced Mucous Expression in Airway Epithelial Cells10.1038/s41598-018-32114-w2045-2322https://doaj.org/article/118db596e69245a78848a2480a554f262018-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-32114-whttps://doaj.org/toc/2045-2322Abstract 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.Shah S. HussainShebin GeorgeShashi SinghRahul JayantChien-An HuMohan SoporiHitendra S. ChandNature PortfolioarticleAirway Epithelial Cells (AECs)MUC1 ExpressionEpithelial Growth Factor Receptor (EGFR)Extracellular-signal Regulating Kinase 1/2 (ERK1/2)Human AECsMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-11 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Airway Epithelial Cells (AECs) MUC1 Expression Epithelial Growth Factor Receptor (EGFR) Extracellular-signal Regulating Kinase 1/2 (ERK1/2) Human AECs Medicine R Science Q
spellingShingle	Airway Epithelial Cells (AECs) MUC1 Expression Epithelial Growth Factor Receptor (EGFR) Extracellular-signal Regulating Kinase 1/2 (ERK1/2) Human AECs Medicine R Science Q Shah S. Hussain Shebin George Shashi Singh Rahul Jayant Chien-An Hu Mohan Sopori Hitendra S. Chand A Small Molecule BH3-mimetic Suppresses Cigarette Smoke-Induced Mucous Expression in Airway Epithelial Cells
description	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.
format	article
author	Shah S. Hussain Shebin George Shashi Singh Rahul Jayant Chien-An Hu Mohan Sopori Hitendra S. Chand
author_facet	Shah S. Hussain Shebin George Shashi Singh Rahul Jayant Chien-An Hu Mohan Sopori Hitendra S. Chand
author_sort	Shah S. Hussain
title	A Small Molecule BH3-mimetic Suppresses Cigarette Smoke-Induced Mucous Expression in Airway Epithelial Cells
title_short	A Small Molecule BH3-mimetic Suppresses Cigarette Smoke-Induced Mucous Expression in Airway Epithelial Cells
title_full	A Small Molecule BH3-mimetic Suppresses Cigarette Smoke-Induced Mucous Expression in Airway Epithelial Cells
title_fullStr	A Small Molecule BH3-mimetic Suppresses Cigarette Smoke-Induced Mucous Expression in Airway Epithelial Cells
title_full_unstemmed	A Small Molecule BH3-mimetic Suppresses Cigarette Smoke-Induced Mucous Expression in Airway Epithelial Cells
title_sort	small molecule bh3-mimetic suppresses cigarette smoke-induced mucous expression in airway epithelial cells
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/118db596e69245a78848a2480a554f26
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A Small Molecule BH3-mimetic Suppresses Cigarette Smoke-Induced Mucous Expression in Airway Epithelial Cells

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