Several biases may affect the results of our study. First, although we found that most of the cells undergoing apoptosis and proliferation are epithelial cells, we cannot exclude the possibility that endothelial cells, fibroblasts, and inflammatory cells also may undergo apoptosis and proliferation in the alveolar wall of patients with emphysema. Although in the present study, the TUNEL-positive cells were not positively stained for CD31, an endothelial cell marker, they could be stained for other antigens for endothelial cells. Second, asymptomatic smokers and nonsmokers had lung cancer, and the presence of lung cancer may have affected the apoptosis and proliferation of alveolar wall cells. To guard against this error, we cut lung tissue samples at least 5 cm away from the tumor. Third, lung volume reduction surgery is performed in patients with severe emphysema, and the surgeon selects the worst part of the lung. Thus, our finding of increased apoptosis and proliferation in emphysematous lungs may be different from the picture of the lungs of patients with mild emphysema. Fourth, TUNEL is not specific for apoptosis, and the results for the TUNEL may be influenced by necrosis. However, TUNEL is currently the most sensitive, reproducible, and prevalent method to detect apoptosis in tissues. Even if the results for TUNEL in our study included necrosis, our conclusion about an increased turnover of alveolar wall cells is still valid. Fifth, lung tissues obtained from asymptomatic smokers and nonsmokers also may have emphysema in some parts of the lungs. However, if this is the case, the difference in apoptosis and proliferation would be even greater between the patients with emphysema and the other groups of patients, thus confirming our finding of elevated levels of apoptosis and proliferation in patients with emphysema. Last, in our study, the patients with emphysema had a greater smoking history than the asymptomatic smokers, and this may have influenced the results in these two groups of patients. However, since the percentages of apoptotic cells and proliferating cells in the alveolar wall were similar between asymptomatic smokers and nonsmokers, a difference in smoking history per se cannot explain enhanced levels of apoptosis and proliferation in the patients with emphysema compared to the asymptomatic smokers.