The Role of Neutrophils in Alpha-1 Antitrypsin Deficiency
The Role of Neutrophils in Alpha-1 Antitrypsin Deficiency
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DOI：
10.1513/annalsats.201509-634kv
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发表时间：
2016-08-01
影响因子：
8.3
通讯作者：
McElvaney, Noel G.
中科院分区：
文献类型：
--
作者：
McCarthy, Cormac;Reeves, Emer P.;McElvaney, Noel G.
α-1抗胰蛋白酶缺乏症（AATD）的特征是循环α-1抗胰蛋白酶水平低，肺气肿、肝病和脂膜炎的风险增加。AATD中α-1抗胰蛋白酶水平的降低使肺易受主要来自嗜中性粒细胞衍生的蛋白酶（主要是中性粒细胞弹性蛋白酶）的无对抗的蛋白水解活性的影响。这会导致肺气肿。肝病的发病机制还不太清楚，但可能是由于肝脏中的“功能获得”炎症过程，由异常折叠的α-1抗胰蛋白酶的细胞内滞留引起。与AATD相关的脂膜炎最可能是由于皮肤中的蛋白水解活性不受抑制。尽管AATD传统上被认为是由肺中蛋白酶-抗蛋白酶失衡引起的病症，但越来越多的人认识到AATD是一种炎性疾病，无论是在肺中还是在与该病症相关的肺外表现中。这种炎症主要是中性粒细胞驱动的，有几种α-1抗胰蛋白酶相关机制参与增强这种嗜中性粒细胞反应。AAT强化治疗AATD的基本原理通常是基于恢复肺中的抗蛋白酶平衡，但其有益作用也可能全身发挥，进一步揭示了AATD相关疾病的发病机制，并表明α-1抗胰蛋白酶在其他炎症性疾病中的潜在用途。
Alpha-1 antitrypsin deficiency (AATD) is characterized by low levels of circulating alpha-1 antitrypsin and an increased risk for emphysema, liver disease, and panniculitis. The reduced levels of alpha-1 antitrypsin in AATD predispose the lung to unopposed proteolytic activity, predominantly from neutrophil-derived proteases, chiefly neutrophil elastase. This leads to emphysema. The mechanisms subtending the liver disease are less well understood, but are probably due to a "gain-of function" inflammatory process in the liver, stoked by intracellular retention of aberrantly folded alpha-1 antitrypsin. The panniculitis associated with AATD is most likely due to unopposed proteolytic activity in the skin. Although AATD has been traditionally viewed as a condition arising from a protease-antiprotease imbalance in the lung, it is increasingly recognized that AATD is an inflammatory disorder, both in the lung and in the extrapulmonary manifestations associated with the condition. This inflammation is predominantly neutrophil driven, and there are several alpha-1 antitrypsin-related mechanisms involved in potentiating this neutrophilic response. The rationale for AAT augmentation therapy in AATD is classically based on restoring the antiprotease balance in the lung, but its beneficial effects may also be exerted systemically, further exposing the pathogenesis of AATD-related disease and indicating a potential usage for alpha-1 antitrypsin in other inflammatory conditions.