Defensins play a pivotal role in antimicrobial reactions, inflammatory responses, wound repair, and specific immunity. In inflammatory and infectious lung diseases, alpha-defensins are released from recruited neutrophils, and modulate a variety of lung cell functions. We found that human bronchial and alveolar epithelial cells treated with low and moderate concentrations (5 and 10 micro g/ml) of purified neutrophil-derived alpha-defensin-1 secreted more interleukin (IL)-8 and monocyte chemoattractant protein (MCP)-1 in a dose- and time-dependent manner. Under moderate and high concentrations (10 and 20 micro g/ml) of alpha-defensin-1, we observed typical apoptotic changes in the lung epithelial cells after stimulation for 24 h. Furthermore, alpha-defensin-1 triggered lung cell detachment in a time- and dose-dependent manner at moderate and high concentrations. Prior to the detachment, caspase-3 activity significantly increased. On confocal laser microscopy, rapid translocation of alpha-defensin-1 to the endoplasmic reticulum (ER) was noted. These findings suggest that neutrophil-derived alpha-defensin-1 has pro-inflammatory and apoptotic effects in human bronchial and alveolar epithelial cells, which are concentration-dependent and may be associated with ER activity.