Cigarette smoke suppresses Bik to cause epithelial cell hyperplasia and mucous cell metaplasia.

Title Cigarette smoke suppresses Bik to cause epithelial cell hyperplasia and mucous cell metaplasia.
Publication Type Journal Article
Year of Publication 2011
Authors Mebratu YA, Schwalm K, Smith KR, Schuyler M, Tesfaigzi Y
Journal Am J Respir Crit Care Med
Volume 183
Issue 11
Pagination 1531-8
Date Published 06/2011
ISSN 1535-4970
Keywords Animals, Blotting, Western, Disease Models, Animal, Electrophoresis, Polyacrylamide Gel, Epithelial Cells, Female, Genes, bcl-2, Humans, Hyperplasia, Lung, Male, Metaplasia, Mice, Mice, Inbred C57BL, Middle Aged, Mucous Membrane, Mucus, Reverse Transcriptase Polymerase Chain Reaction, Smoking
Abstract

RATIONALE: Aberrant regulation of airway epithelial cell numbers in airways leads to increased mucous secretions in chronic lung diseases such as chronic bronchitis. Because the Bcl-2 family of proteins is crucial for airway epithelial homeostasis, identifying the players that reduce cigarette smoke (CS)-induced mucous cell metaplasia can help to develop effective therapies.

OBJECTIVES: To identify the Bcl-2 family of proteins that play a role in reducing CS-induced mucous cell metaplasia.

METHODS: We screened for dysregulated expression of the Bcl-2 family members.

MEASUREMENTS AND MAIN RESULTS: We identified Bik to be significantly reduced in bronchial brushings of patients with chronic epithelial cell hyperplasia compared with nondiseased control subjects. Reduced Bik but increased MUC5AC mRNA levels were also detected when normal human airway epithelial cells (HAECs) were exposed to CS or when autopsy tissues from former smokers with and without chronic bronchitis were compared. Similarly, exposure of C57Bl/6 mice to CS resulted in increased numbers of epithelial and mucous cells per millimeter of basal lamina, along with reduced Bik but increased Muc5ac expression, and this change was sustained even when mice were allowed to recover in filtered air for 8 weeks. Restoring Bik expression significantly suppressed CS-induced mucous cell metaplasia in differentiated primary HAEC cultures and in airways of mice in vivo. Bik blocked nuclear translocation of phospho-ERK1/2 to induce apoptosis of HAECs. The conserved Leu61 within Bik and ERK1/2 activation were essential to induce cell death in hyperplastic mucous cells.

CONCLUSIONS: These studies show that CS suppresses Bik expression to block airway epithelia cell death and thereby increases epithelial cell hyperplasia in chronic bronchitis.

DOI 10.1164/rccm.201011-1930OC
Alternate Journal Am. J. Respir. Crit. Care Med.
PubMed ID 21317312
PubMed Central ID PMC3137142
Grant List ES015482 / ES / NIEHS NIH HHS / United States
HL68111 / HL / NHLBI NIH HHS / United States