Proteinase-antiproteinase imbalances are recognized in several diseases including the two most common lethal hereditary disorders of white populations, alpha(1)-antitrypsin (alpha(1)-AT) deficiency and
cystic fibrosis (CF). In alpha(1)-AT deficiency, the type Z variant of alpha(1)-AT forms
polymers in the endoplasmic reticulum of hepatocytes resulting in
liver disease in childhood. The block in alpha(1)-AT processing in hepatocytes significantly reduces levels of circulating alpha(1)-AT. This may lead in young adults to
panacinar emphysema due to insufficient protection of the lower respiratory tract from
neutrophil elastase, permitting progressive destruction of the alveoli. In CF, chronic bacterial lung
infections due to impaired mucociliary clearance lead to a vigorous influx of neutrophils in the airways. Released levels of neutrophil
serine proteinases, particularly
elastase, exceed the antiproteinase capacity of endogenous
serine proteinase inhibitors in the airways. Progressive proteolytic impairment of multiple defense pathways in addition to endobronchial obstruction and airway wall destruction are thought to be responsible for the reduced life expectancy in CF patients. Strategies to augment the antiproteinase defenses in the airways of patients with severe alpha(1)-AT deficiency or CF include the intravenous or
aerosol administration of
serine proteinase inhibitors. Studies in both patient groups using plasma-derived or transgenic alpha(1)-AT, recombinant
secretory leukoprotease inhibitor or synthetic
elastase inhibitors show promising results concerning
drug safety and efficacy.