The purpose of the studies described here was to test the hypothesis that overexpression of the human interleukin-1 receptor antagonist (IL-1ra) in the distal airway epithelia of mice would result in amelioration of the inflammatory effects of IL-1alpha. The coding region of the human IL-1ra gene was placed under transcriptional control of the 5' flanking region of the human SP-C gene. Transgenic mice were generated by pronuclear injection of the transgene and identified by Southern blot analysis of genomic DNA. RNA expression of the transgene was confirmed by Northern blot analysis. In order to determine whether expression of the transgene conferred protection against inflammatory stimuli, control and transgenic mice were treated with IL-1alpha by intratracheal instillation. Six hours after treatment, bronchoalveolar lavage was performed, which revealed a statistically significant decrease in the degree of neutrophilia in the transgenic mice as compared with control mice. Furthermore, there was a significant reduction in the whole-lung myeloperoxidase concentration. Reverse transcription-polymerase chain reaction analysis of whole-lung RNA revealed a significant reduction in the messenger RNA/beta-actin ratio of macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-2 in the transgenic animals as compared with controls. The results of these studies indicate that distal airway epithelial cell expression of human IL-1ra results in partial protection from IL-1alpha-induced airway inflammation and injury.