Well-Known and Less Well-Known Functions of Alpha-1 Antitrypsin Its Role in Chronic Obstructive Pulmonary Disease and Other Disease Developments
Well-Known and Less Well-Known Functions of Alpha-1 Antitrypsin Its Role in Chronic Obstructive Pulmonary Disease and Other Disease Developments
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DOI：
10.1513/annalsats.201507-468kv
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发表时间：
2016-08-01
影响因子：
8.3
通讯作者：
Welte, Tobias
中科院分区：
文献类型：
--
作者：
Janciauskiene, Sabina;Welte, Tobias
Alpha-1 抗胰蛋白酶 (A1AT) 是一种急性期蛋白，最出名的是丝氨酸蛋白酶（特别是中性粒细胞弹性蛋白酶、蛋白酶 3 和组织蛋白酶 G）的抑制剂。遗传性 A1AT 缺陷与肺气肿之间联系的发现催生了蛋白酶-抗蛋白酶失衡的概念，以解释慢性阻塞性肺疾病的致病机制 肺部疾病，以及同时开发血浆纯化的人 A1AT 增强疗法。这种蛋白酶-抗蛋白酶失衡的概念很难得到证明，因为没有单一机制可以解释慢性阻塞性肺病的复杂病理学。新的研究已经开始将 A1AT 描述为一种抗炎和免疫调节蛋白，与其抗蛋白酶活性无关。我们最近发现 A1AT 与游离脂肪酸结合，正是这种形式的 A1AT 诱导血管生成素样蛋白 4 的表达和释放，血管生成素样蛋白 4 是一种与血脂异常和炎症相关的蛋白。后一项发现进一步强化了这样的观点：将 A1AT 疗法描述为抗丝氨酸蛋白酶可能过于简单化。初步研究结果表明，A1AT 可用于治疗与遗传性 A1ATD 不一定相关的疾病，并表明需要对 A1AT 蛋白的浓度、结构和功能之间的关系进行更详细的研究。
Alpha-1 antitrypsin (A1AT) is an acute-phase protein, and is best known as an inhibitor of the serine proteases, specifically, neutrophil elastase, proteinase 3, and cathepsin G. The discovery of the connection between inherited A1AT deficiency and emphysema resulted in the concept of a proteinase-antiproteinase imbalance to explain the pathogenic mechanisms of chronic obstructive pulmonary disease, as well as the concomitant development of augmentation therapy with plasma-purified human A1AT. This proteinase-antiproteinase imbalance concept has been difficult to prove, as no single mechanism can account for the complex pathology of chronic obstructive pulmonary disease. New studies have begun to characterize A1AT as an antiinflammatory and an immunoregulatory protein, independent of its antiprotease activity. We recently found that A1AT binds to free fatty acids, and it is this form of A1AT that induces the expression and release of angiopoietin-like protein 4, a protein associated with dyslipidemia and inflammation. This latter finding further strengthens the idea that describing A1AT therapy as antiserine protease is perhaps an oversimplification. The preliminary findings suggest that A1AT could be used for the management of diseases not necessarily related to inherited A1ATD, and points toward a need for more detailed investigations into the relationships between the concentration, structure, and function of A1AT protein.