Biologic Phenotyping of the Human Small Airway Epithelial Response to Cigarette Smoking

The first changes associated with smoking are in the small airway epithelium (SAE). Given that smoking alters SAE gene expression, but only a fraction of smokers develop chronic obstructive pulmonary disease (COPD), we hypothesized that assessment of SAE genome-wide gene expression would permit biologic phenotyping of the smoking response, and that a subset of healthy smokers would have a COPD-like SAE transcriptome. SAE (10th-12th generation) was obtained via bronchoscopy of healthy nonsmokers, healthy smokers and COPD smokers and microarray analysis was used to identify differentially expressed genes. Individual responsiveness to smoking was quantified with an index representing the % of smoking-responsive genes abnormally expressed (ISAE), with healthy smokers grouped into high and low responders based on the proportion of smoking-responsive genes up- or down-regulated in each smoker. Smokers demonstrated significant variability in SAE transcriptome with ISAE ranging from 2.9 to 51.5%. While the SAE transcriptome of low responder healthy smokers differed from both high responders and smokers with COPD, the transcriptome of the high responder healthy smokers was indistinguishable from COPD smokers. The SAE transcriptome can be used to classify clinically healthy smokers into subgroups with lesser and greater responses to cigarette smoking, even though these subgroups are indistinguishable by clinical criteria. This identifies a group of smokers with a COPD-like SAE transcriptome.

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Tilley AE, O'Connor TP, Hackett NR, Strulovici-Barel Y, Salit J, Amoroso N, Zhou XK, Raman T, Omberg L, Clark A, Mezey J, Crystal RG