Adenoviral augmentation of elafin protects the lung against acute injury mediated by activated neutrophils and bacterial infection

During acute pulmonary infection, tissue injury may be secondary to the eff ects of bacterial products or to the effects of the host inflammatory respo nse. An attractive strategy for tissue protection. in this setting would co mbine antimicrobial activity with inhibition of human neutrophil elastase ( HNE), a key effector of neutrophil-mediated tissue injury. We postulated th at genetic augmentation of elafin (an endogenous inhibitor of HNE with intr insic antimicrobial activity) could protect the lung against acute inflamma tory injury without detriment to host defense. A replication-deficient aden ovirus encoding elafin cDNA significantly protected A549 cells against the injurious effects of both HNE and whole activated human neutrophils in vitr o. Intratracheal replication-deficient adenovirus encoding elafin cDNA sign ificantly protected murine lungs against injury mediated by Pseudomonas aer uginosa in vivo. Genetic augmentation of elafin therefore has the capacity to protect the lung against the injurious effects of both bacterial pathoge ns resistant to conventional antibiotics and activated neutrophils.