Intraflagellar transport gene expression associated with short cilia in smoking and COPD.
Smoking and COPD are associated with decreased mucociliary clearance, and healthy smokers have shorter cilia in the large airway than nonsmokers. We hypothesized that changes in cilia length are consistent throughout the airway, and we further hypothesized that smokers with COPD have shorter cilia than healthy smokers. Because intraflagellar transport (IFT) is the process by which cilia of normal length are produced and maintained, and alterations in IFT lead to short cilia in model organisms, we also hypothesized that smoking induces changes in the expression of IFT-related genes in the airway epithelium of smokers and smokers with COPD. To assess these hypotheses, airway epithelium was obtained via bronchoscopic brushing. Cilia length was assessed by measuring 100 cilia (10 cilia on each of 10 cells) per subject and Affymetrix microarrays were used to evaluate IFT gene expression in nonsmokers and healthy smokers in 2 independent data sets from large and small airway as well as in COPD smokers in a data set from the small airway. In the large and small airway epithelium, cilia were significantly shorter in healthy smokers than nonsmokers, and significantly shorter in COPD smokers than in both healthy smokers and nonsmokers. The gene expression data confirmed that a set of 8 IFT genes were down-regulated in smokers in both data sets; however, no differences were seen in COPD smokers compared to healthy smokers. These results support the concept that loss of cilia length contributes to defective mucociliary clearance in COPD, and that smoking-induced changes in expression of IFT genes may be one mechanism of abnormally short cilia in smokers. Strategies to normalize cilia length may be an important avenue for novel COPD therapies.
Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Justina
J
Hessel
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Jonna
J
Heldrich
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Jennifer
J
Fuller
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Michelle R
MR
Staudt
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Sharon
S
Radisch
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Charleen
C
Hollmann
Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Ben-Gary
BG
Harvey
Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Robert J
RJ
Kaner
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Jacqueline
J
Salit
Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Jenny
J
Yee-Levin
Hoffmann-La Roche, Inc., Nutley, New Jersey, United States of America.
Sriram
S
Sridhar
Hoffmann-La Roche, Inc., Nutley, New Jersey, United States of America.
Sreekumar
S
Pillai
Hoffmann-La Roche, Inc., Nutley, New Jersey, United States of America.
Holly
H
Hilton
Hoffmann-La Roche, Inc., Nutley, New Jersey, United States of America.
Gerhard
G
Wolff
Hoffmann-La Roche, Inc., Nutley, New Jersey, United States of America.
Hans
H
Bitter
Hoffmann-La Roche, Inc., Nutley, New Jersey, United States of America.
Sudha
S
Visvanathan
Hoffmann-La Roche, Inc., Nutley, New Jersey, United States of America.
Jay
J
Fine
Hoffmann-La Roche, Inc., Nutley, New Jersey, United States of America.
Christopher S
CS
Stevenson
Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, United States of America ; Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Ronald G
RG
Crystal
Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, United States of America ; Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Ann E
AE
Tilley
D000328:Adult; D002923:Cilia / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D009079:Mucociliary Clearance; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology*; D012907:Smoking / Q000009:adverse effects*