Long-term impact of smoking on lung epithelial proliferation in current and former smokers

Background: Lung cancer risk remains elevated for many years after quitting smoking. To assess using proliferation indices in bronchial tissues as an intermediate endpoint biomarker in lung cancer chemoprevention trials, we d etermined the relationship between the extent, intensity, and cessation of tobacco smoking and proliferative changes in bronchial epithelial biopsy sp ecimens. Methods: Bronchial biopsy specimens were obtained from up to six epithelial sites in 120 current smokers (median pack-years, 42) and 207 former smoker s (median pack-years, 40; median quit-years, 8.1), Sections from the paraff in-embedded specimens were stained with hematoxylin-eosin to determine the metaplasia index and with an antibody to Ki-67 to determine the proliferati ve (labeling) index for the basal and parabasal (Ki-67 PLI) layers. All sta tistical tests were two-sided. Results: Biopsy sites with metaplasia had statistically significantly highe r Ki-67-labeling indices than those without metaplasia (P < .001) in both c urrent and former smokers. Increased proliferation was observed in multiple biopsy sites, with the average Ki-67 PLI of the subject strongly correlati ng with the metaplasia index (r =.72 for current smokers; P < .001), even i n sites without metaplasia (r =.23 for current smokers; P < .001), In curre nt smokers, the Ki-67 PLI was associated with the number of packs smoked/da y (P = .02) but not with smoking years or pack-years, In subjects who had q uit smoking, the Ki-67 PLI dropped statistically significantly within 1 yea r (P = .008) but remained detectable for more than 20 years, even in the ab sence of squamous metaplasia. Conclusion: Smoking appears to elicit a dose-related proliferative response in the bronchial epithelia of active smokers. Although the proliferative r esponse decreased gradually in former smokers, a subset of individuals had detectable proliferation for many years and may benefit from targeted chemo prevention, Bronchial epithelial proliferation, measured by Ki-67, may prov ide a useful biomarker in the assessment of lung cancer risk and in the res ponse to chemopreventive interventions.