|Year of Publication
|Brekman A, Walters MS, Tilley AE, Crystal RG
|Am J Respir Cell Mol Biol
|Cell Differentiation, Cell Proliferation, Cells, Cultured, Cilia, Forkhead Transcription Factors, Gene Expression Regulation, Humans, Respiratory Mucosa, Smoking, Transcription, Genetic
Airway epithelium ciliated cells play a central role in clearing the lung of inhaled pathogens and xenobiotics, and cilia length and coordinated beating are important for airway clearance. Based on in vivo studies showing that the airway epithelium of healthy smokers has shorter cilia than that of healthy nonsmokers, we investigated the mechanisms involved in cigarette smoke-mediated inhibition of ciliogenesis by assessing normal human airway basal cell differentiation in air-liquid interface (ALI) cultures in the presence of nontoxic concentrations of cigarette smoke extract (CSE). Measurements of cilia length from Day 28 ALI cultures demonstrated that CSE exposure was associated with shorter cilia (P < 0.05), reproducing the effect of cigarette smoking on cilia length observed in vivo. This phenotype correlated with a broad CSE-mediated suppression of genes involved in cilia-related transcriptional regulation, intraflagellar transport, cilia motility, structural integrity, and basal body development but not of control genes or epithelial barrier integrity. The CSE-mediated inhibition of cilia growth could be prevented by lentivirus-mediated overexpression of FOXJ1, the major cilia-related transcription factor, which led to partial reversal of expression of cilia-related genes suppressed by CSE. Together, the data suggest that components of cigarette smoke are responsible for a broad suppression of genes involved in cilia growth, but, by stimulating ciliogenesis with the transcription factor FOXJ1, it may be possible to maintain close to normal cilia length despite the stress of cigarette smoking.
|Am. J. Respir. Cell Mol. Biol.
|PubMed Central ID
|P20 HL113443 / HL / NHLBI NIH HHS / United States
K23 HL103837 / HL / NHLBI NIH HHS / United States
P50 HL084936 / HL / NHLBI NIH HHS / United States
T32 HL094284 / HL / NHLBI NIH HHS / United States
UL1 RR024143 / RR / NCRR NIH HHS / United States
R01 HL107882 / HL / NHLBI NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States