We report here a direct stepwise dissection of the inflammatory response in an animal lacking CFTR, providing a more comprehensive delineation of the cellular basis linking CFTR deficiency with inflammatory pathogenesis of the CF airways, and consequently insights for development of specific therapies aimed at restoring innate immune potential of CF patients and thus identify novel treatment approaches to alleviate neutrophil inflammation-driven tissue damage, with improvement in both quality of life and life expectancy. Here, CFTR is linked to cystic fibrosis.