Threshold of Biologic Response of the Small Airway Epithelium to Low Levels of Tobacco Smoke

Background: Healthy individuals exposed to low levels of cigarette smoke have a decrement in lung function and higher risk for lung disease compared to unexposed individuals. We hypothesized that healthy individuals exposed to low levels of tobacco smoke must have biologic changes in the small airway epithelium compared to healthy unexposed individuals. Methods: Small airway epithelium was obtained by bronchoscopy from 121 individuals; microarrays assessed genome wide gene expression, and urine nicotine and cotinine were used to categorized subjects as “nonsmokers,” “active smokers,” and “low exposure.” The gene expression data was used to determine the threshold and ID50 of urine nicotine and cotinine at which the small airway epithelium showed abnormal responses. Results: There was no threshold of urine nicotine without an abnormal small airway epithelial response, and only a slightly above detectable threshold abnormal response for cotinine. The nicotine ID50 for nicotine was 25 ng/ml and cotinine 104 ng/ml. Conclusions: The small airway epithelium detects and responds to low levels of tobacco smoke with transcriptome modifications. This provides biologic correlates of epidemiologic studies linking low level tobacco smoke exposure to lung health risk, health, identifies genes in the lung cells most sensitive to tobacco smoke and defines thresholds at the lung epithelium responds to inhaled tobacco smoke. Affymetrix arrays were used to assess the gene expression data of smoking-responsive genes in the in small airway epithelium obtained by fiberoptic bronchoscopy of 48 healthy non-smokers (non-smoker or Nsaets), 65 healthy smokers (smoker), 7 symptomatic smokers (SYMs) and a healthy occasional smoker (OcSs). YSB and LO contributed equally to the study.

背景：与未暴露人群相比，暴露于低浓度香烟烟雾的健康个体可出现肺功能下降，且肺部疾病患病风险更高。本研究提出假说：相较于未暴露的健康个体，暴露于低浓度烟草烟雾的健康个体的小气道上皮细胞必然存在生物学改变。
方法：本研究通过支气管镜检（bronchoscopy）采集了121名受试者的小气道上皮细胞；利用基因表达微阵列（microarrays）评估全基因组基因表达水平，并通过尿液尼古丁与可替宁水平将受试者划分为“非吸烟者”“主动吸烟者”与“低暴露组”。基于基因表达数据，确定使小气道上皮细胞出现异常响应的尿液尼古丁与可替宁阈值及半数响应浓度（ID50）。
结果：未发现可使小气道上皮细胞不出现异常响应的尿液尼古丁阈值，而可替宁仅存在略高于检测限的异常响应阈值。尼古丁的半数响应浓度为25 ng/ml，可替宁为104 ng/ml。
结论：小气道上皮细胞可感知并响应低浓度烟草烟雾，引发转录组（transcriptome）修饰。本研究结果为流行病学研究提供了生物学关联依据——后者将低浓度烟草烟雾暴露与肺部健康风险相关联；同时鉴定出肺部细胞中对烟草烟雾最为敏感的基因，并明确了肺部上皮细胞响应吸入性烟草烟雾的阈值。本研究采用Affymetrix芯片，通过纤维支气管镜检（fiberoptic bronchoscopy）采集了48名健康非吸烟者（非吸烟者或Nsaets）、65名健康吸烟者（smoker）、7名有症状吸烟者（SYMs）及1名健康偶发吸烟者（OcSs）的小气道上皮细胞，以此评估其中烟草响应基因的表达数据。
YSB与LO对本研究贡献均等。