MOLECULAR CHARACTERISTICS AND CLINICAL ASPECTS OF ALPHA 1-ANTITRYPSIN DEFICIENCY

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Z AAT accumulates in the hepatocyte and is degraded prior to its release. Individuals with AAT deficiency have an increased risk of liver disease and emphysema. Many AAT-deficient individuals demonstrate an increased bronchodilator response (BDR). The presence of a BDR in AAT-deficient individuals is associated with an increased rate of decline in lung function as compared to individuals without a BDR. We examined 66 AAT deficient individuals for the prevalence of elevated IgE levels, asthma, and related allergic conditions. A history of allergies was significantly associated with asthma (p=0.004), elevated IgE levels (p=0.04), and higher PreFEV1 (p=0.02); however, asthma and elevated IgE were not associated with each other or with a higher PreFEV1. In this context, the BDR observed in AAT-deficient individuals may be mediated by processes other than those involving IgE. In studies investigating the mechanisms of AAT deficiency, we compared the intracellular (IC) fate of newly synthesized Z and M proteins in the presence of cyclohexamide (CHX) or after incubation at 41 degrees C. CHX prevents degradation of the Z protein and increases the amount of Z protein secreted by 4-6 fold. Incubation of cells at 41 degrees C slightly decreased IC degradation of Z AAT and increased secretion by 30% compared to cells incubated at 37 degrees C. This increase in secreted Z AAT may be the result of decrease IC protease activity and/or improved protein folding mediated by heatshock proteins. Together, these observations open the possibilities for new approaches to treatment of AAT deficiency.