GENERATION OF A TRANSGENIC MOUSE WITH LUNG-SPECIFIC OVEREXPRESSION OFTHE HUMAN INTERLEUKIN-1 RECEPTOR ANTAGONIST PROTEIN

The purpose of the studies described here was to test the hypothesis t hat overexpression of the human interleukin-1 receptor antagonist (IL- 1ra) in the distal airway epithelia of mice would result in ameliorati on of the inflammatory effects of IL-1 alpha. 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 b lot analysis of genomic DNA. RNA expression of the transgene was confi rmed by Northern blot analysis. Ln order to determine whether expressi on of the transgene conferred protection against inflammatory stimuli, control and transgenic mice were treated with IL-1 alpha by intratrac heal instillation. Six hours after treatment, bronchoalveolar lavage w as performed, which revealed a statistically significant decrease in t he degree of neutrophilia in the transgenic mice as compared with cont rol mice. Furthermore, there was a significant reduction in the whole- lung myeloperoxidase concentration. Reverse transcription-polymerase c hain reaction analysis of whole-lung RNA revealed a significant reduct ion in the messenger RNA/beta-actin ratio of macrophage inflammatory p rotein-1 alpha (MIP-1 alpha) and MIP-2 in the transgenic animals as co mpared with controls. The results of these studies indicate that dista l airway epithelial cell expression of human IL-1ra results in partial protection from IL-1 alpha-induced airway inflammation and injury.