Introduction. Lipopolysaccharide (LPS) is thought to be one of the major inciters of the acute inflammatory response that can lead to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). While it is generally understood that alveolar epithelial cells are hyporesponsive to LPS stimulation, the reasons thereof are controversial. It has been shown that pathogenic challenge can render them responsive to LPS. Thus it is important to understand how the cells sense the presence of LPS and how they respond to LPS stimulation.Results. LPS stimulated small amounts of IL-8 release from A549 cells, which was increased in the presence of CD14. LPS stimulation also led to increased gene expression and actin depolymerization. Surprisingly, prolonged LPS stimulation at high concentrations induced cell death. This was not a caspase-mediated cell death; instead, cathepsin B may be the major player.Methods. Whole cells and lysates of an alveolar epithelial cell line (A549) were assayed using real-time PCR, Western blotting and flow cytometry for expression of LPS receptor complex molecules. IL-8 release, IL-8 promoter activist, and actin depolymerization were used as readouts for LPS stimulation. Cell viability was tested using the XTT assay.Conclusions. Contrary to many published reports, we showed that human alveolar epithelial cells can indeed respond to LPS stimulation. Although the mechanisms and players involved are not yet clear, the potential involvement of non-classical LPS receptors opens up opportunities for specific modulation of the epithelial response to LPS in the lung.