The association between the anti-inflammatory protein CC10 and regression of bronchial dysplasia in individuals at high risk for lung cancer.

PR-07

Context: CC10 is a 10-kDa anti-inflammatory protein secreted by nonciliated Clara cells which are progenitor cells in the bronchiolar epithelium. It has been shown that CC10 levels in bronchoalveolar lavage fluid (BAL) and serum are significantly lower in current smokers compared with healthy non-smokers. Moreover, CC10 is infrequently expressed in non-small cell lung cancer (NSCLC) and overexpression of CC10 in NSCLC cell lines results in a less malignant phenotype. However, whether changes in CC10 expression are associated with regression of bronchial dysplasia is not known. Objective: We investigated whether higher BAL and plasma CC10 levels are associated with regression of bronchial dysplasia among smokers. Methods: We used specimens collected during a chemoprevention trial assessing the efficacy of budesonide vs. placebo to regress bronchial dysplasia in current (n=81) and former (n=22) smokers with bronchial dysplasia. Bronchoscopies and plasma collection were performed at baseline and after 6 months. Regression of lesions was defined as disappearance of dysplasia, while progression was defined as worsening by at least two histologic grades or development of new dysplastic lesions. Individuals were considered to have improvement if some or all lesions regressed completely and none progressed. BAL and plasma CC10 levels were measured at baseline and follow-up by a competitive ELISA. Results: The 6 month follow-up geometric mean BAL CC10 concentrations in subjects with improved bronchial lesions were approximately 62% higher than in those without improvement (arithmetic mean: 60.7 ± 58.4 ng/mg protein and 36.8 ± 37.6 ng/mg protein, respectively; geometric mean: 42.0 and 25.9 ng/mg protein, respectively; p = 0.007). The net change in the BAL CC10 levels was also significantly higher among those with improved lesions than those without (arithmetic mean: 17.9 ± 32.5 ng/mg and 1.5 ± 33.6 ng/mg protein, respectively, p=0.020). The odds ratio (OR) (95% confidence interval) of regression of lesions associated with one unit increase on the natural log-scale was 2.68 (1.36-5.28, p=0.005) for either the follow-up BAL or the change in BAL CC10 levels after adjustment for baseline CC10 levels. Further adjustment for age, sex, pack-years of smoking, smoking status, and treatment effect did not significantly alter the result [2.72 (1.31-5.64), p=0.007]. Plasma CC10 levels were not significantly associated with regression of bronchial dysplasia. Conclusions: These results show that BAL CC10 levels increase with regression of bronchial dysplasia in smokers with high lung cancer risk. Further investigations to explore the underlying mechanisms are warranted.