MOLECULAR CHARACTERISTICS AND CLINICAL ASPECTS OF ALPHA 1-ANTITRYPSIN DEFICIENCY

Z-AAT在肝细胞内蓄积，在释放前被降解。 AAT缺乏的个体患肝病的风险增加 还有肺气肿。许多AAT缺乏的个体表现出增加的 支气管扩张反应(BDR)。AAT缺陷患者中BDR的存在 个体与肺衰退率的增加有关 与没有BDR的个人相比，它的功能更好。我们检查了66个AAT 缺乏免疫球蛋白E水平升高、哮喘、 以及相关的过敏性疾病。有过敏史的人 与哮喘有关(p=0.004)，IgE水平升高(p=0.04)，以及 PreFEV1升高(p=0.02)；然而，哮喘和IgE升高没有 相互关联或与更高的PreFEV1相关联。在这方面， 在AAT缺陷个体中观察到的BDR可能是由过程调节的 除了涉及IgE的那些。 在研究AAT缺乏机制的研究中，我们比较了 新合成的Z和M蛋白在细胞内(IC)的去向 环己胺(CHX)的存在或在41℃孵育后 防止Z蛋白的降解，增加Z蛋白的含量 蛋白质分泌倍数为4-6倍。细胞在41℃下的孵育 ZAAT的IC降解率略有下降，分泌量增加30% 与37摄氏度孵育的细胞相比，这种分泌物的增加 Z-AAT可能是IC蛋白酶活性降低和/或改善的结果 热休克蛋白介导的蛋白质折叠。加在一起，这些 观察结果开启了新的治疗方法的可能性 AAT缺乏症。

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.