Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase
Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase
复制标题
DOI：
10.1073/pnas.1309648110
复制
发表时间：
2013-09-10
影响因子：
11.1
通讯作者：
Janciauskiene, Sabina
中科院分区：
文献类型：
--
作者：
Jonigk, Danny;Al-Omari, Mariam;Janciauskiene, Sabina
α 1-α抗胰蛋白酶（AAT）强化疗法治疗AAT缺乏患者的进行性肺气肿的基本原理是基于抑制中性粒细胞弹性蛋白酶;然而，这种治疗的获益仍不清楚。在这里，我们表明，临床级AAT（弹性蛋白酶抑制活性）和重组形式的AAT（rAAT）没有抗弹性蛋白酶活性减少肺炎症反应的弹性蛋白酶缺陷小鼠的LPS。野生型和弹性蛋白酶缺陷小鼠无论是天然AAT或rAAT治疗表现出显着减少浸润中性粒细胞（23%和68%），灌洗液TNF-α水平（70%和80%），和中性粒细胞趋化因子KC（CXCL 1）（64%和90%），分别。在用AAT治疗的两种小鼠品系中，肺实质TNF-α、DNA损伤诱导转录物3和X-box结合蛋白-1 mRNA水平降低;与未治疗的患者相比，在用AAT治疗的AAT缺陷患者的肺中观察到这些基因以及IL-1 β基因表达的显著较低水平。在体外，来自WT和弹性蛋白酶缺陷小鼠中性粒细胞以及健康人中性粒细胞的LPS诱导的细胞因子被AAT或rAAT类似地减少;粘附于内皮细胞的人中性粒细胞被AAT或rAAT减少60-80%（P < 0.001）。在小鼠胰岛巨噬细胞中，AAT和rAAT均能显著降低LPS诱导的MHCII、Toll样受体2和Toll样受体4的表达（80%，P < 0.001）。一致地，在体内和体外，rAAT在比天然血浆衍生的AAT低40- 100倍的浓度下减少炎症反应。这些数据提供了AAT的抗炎和免疫调节特性可以独立于弹性蛋白酶抑制的证据。
The rationale of alpha 1-alpha ntitrypsin (AAT) augmentation therapy to treat progressive emphysema in AAT-deficient patients is based on inhibition of neutrophil elastase; however, the benefit of this treatment remains unclear. Here we show that clinical grade AAT (with elastase inhibitory activity) and a recombinant form of AAT (rAAT) without anti-elastase activity reduces lung inflammatory responses to LPS in elastase-deficient mice. WT and elastase-deficient mice treated with either native AAT or rAAT exhibited significant reductions in infiltrating neutrophils (23% and 68%), lavage fluid levels of TNF-alpha (70% and 80%), and the neutrophil chemokine KC (CXCL1) (64% and 90%), respectively. Lung parenchyma TNF-alpha, DNA damage-inducible transcript 3 and X-box binding protein-1 mRNA levels were reduced in both mouse strains treated with AAT; significantly lower levels of these genes, as well as IL-1 beta gene expression, were observed in lungs of AAT-deficient patients treated with AAT therapy compared with untreated patients. In vitro, LPS-induced cytokines from WT and elastase-deficient mouse neutrophils, as well as neutrophils of healthy humans, were similarly reduced by AAT or rAAT; human neutrophils adhering to endothelial cells were decreased by 60-80% (P < 0.001) with either AAT or rAAT. In mouse pancreatic islet macrophages, LPS-induced surface expression of MHC II, Toll-like receptor-2 and -4 were markedly lower (80%, P < 0.001) when exposed to either AAT or rAAT. Consistently, in vivo and in vitro, rAAT reduced inflammatory responses at concentrations 40- to 100-fold lower than native plasma-derived AAT. These data provide evidence that the anti-inflammatory and immunomodulatory properties of AAT can be independent of elastase inhibition.