alpha1-antitrypsin (alpha1AT) deficiency and cystic fibrosis (CF) are the two most common lethal hereditary disorders in the USA and Europe. The major clinical manifestations of both are in the lung. alpha1AT deficiency results from mutations in the alpha1AT gene (a 7 exon gene occupying 12 kb of chromosome 14) causing a systemic deficiency of alpha1AT, the major inhibitor of the destructive proteolytic enzyme, neutrophil elastase (NE). In the context of a deficiency of alpha1AT, NE released by neutrophils in the lung goes uninhibited, resulting in progressive destruction of the lung. CF results from mutations of the CF gene, a 27 exon gene occupying 250 kb of chromosome 7. All organs with exocrine glands are affected, but the major clinical manifestations are in the lung, with impacted mucus, chronic infection, inflammation, and airway and parenchymal lung derangements. Studies over the past year regarding alpha1AT deficiency have focused on continuing to identify new mutations in the alpha1AT gene, evaluating strategies for augmenting lung anti-NE defenses by aerosolization of proteins capable of inhibiting NE and gene therapy. Studies regarding CF have centered on understanding the expression of the CF gene, devising strategies for protecting the respiratory epithelium from the chronic neutrophil dominated inflammation that characterizes CF, and gene therapy.
