Persson Caroline, Subramaniyam Devipriya, Stevens Tim, Janciauskiene Sabina
Department of Clinical Sciences, Wallenberg Laboratory, University Hospital Malmö, S-20502 Malmö, Sweden.
Chest. 2006 Jun;129(6):1683-92. doi: 10.1378/chest.129.6.1683.
alpha(1)-Antitrypsin (AAT)-Z deficiency is a risk factor for the development of COPD. Compared to wild-type M, AAT-Z has an increased tendency to polymerize, rendering it inactive as a serine proteinase inhibitor. It has been demonstrated that wild-type M- and Z-deficiency AAT polymers are chemotactic for human neutrophils. However, our own studies dispute a proinflammatory role for polymerized AAT-M and AAT-Z, suggesting rather that they are predominantly antiinflammatory, exhibiting inhibitory effects on lipopolysaccharide-stimulated human monocyte activation. The discrepancies between these observations prompted us to re-examine the effects of AAT.
The effects of native and polymerized AAT-M and AAT-Z with varying levels of endotoxin contamination (0.08 to 2.55 endotoxin units [EU]/mg protein) on human neutrophil chemotaxis and interleukin (IL)-8 release, in vitro, were evaluated. Neither native nor polymerized (M- or Z-deficient) AAT contaminated with low levels of endotoxin (</= 0.08 EU/mg protein) stimulated neutrophil chemotaxis, whereas N-formyl methionyl leucyl phenylalanine (fMLP), a positive control, increased chemotaxis fourfold. A small but nonsignificant increase in neutrophil chemotaxis, however, was observed with AAT preparations containing higher levels of endotoxin (>/= 0.88 EU/mg protein), and significant chemotaxis occurred when AAT was spiked with either endotoxin or zymosan. In support, native and polymeric AAT-M with low endotoxin contamination completely inhibited neutrophil IL-8 release triggered by the zymosan, while AATs with high endotoxin contamination strongly induced IL-8 release and did not inhibit zymosan-stimulated IL-8 release.
The proinflammatory effects of native and polymeric AAT may be critically dependent on the presence of other cell activators, bacterial or otherwise, while pure preparations of AAT appear to exert predominantly antiinflammatory activity.
α1-抗胰蛋白酶（AAT）-Z缺乏是慢性阻塞性肺疾病（COPD）发生的一个危险因素。与野生型M相比，AAT-Z聚合的倾向增加，使其作为丝氨酸蛋白酶抑制剂失去活性。已经证明野生型M和Z缺乏型AAT聚合物对人中性粒细胞具有趋化作用。然而，我们自己的研究对聚合的AAT-M和AAT-Z的促炎作用提出质疑，反而表明它们主要是抗炎的，对脂多糖刺激的人单核细胞活化具有抑制作用。这些观察结果之间的差异促使我们重新审视AAT的作用。
评估了具有不同内毒素污染水平（0.08至2.55内毒素单位[EU]/mg蛋白质）的天然和聚合的AAT-M和AAT-Z对人中性粒细胞趋化性和白细胞介素（IL）-8释放的体外影响。低水平内毒素（≤0.08 EU/mg蛋白质）污染的天然或聚合（M或Z缺乏型）AAT均未刺激中性粒细胞趋化性，而阳性对照N-甲酰甲硫氨酰亮氨酰苯丙氨酸（fMLP）使趋化性增加了四倍。然而，在含有较高水平内毒素（≥0.88 EU/mg蛋白质）的AAT制剂中观察到中性粒细胞趋化性有小幅但不显著的增加，当AAT加入内毒素或酵母聚糖时会出现显著的趋化性。作为支持，低内毒素污染的天然和聚合AAT-M完全抑制了酵母聚糖引发的中性粒细胞IL-8释放，而高内毒素污染的AAT强烈诱导IL-8释放且不抑制酵母聚糖刺激的IL-8释放。
天然和聚合AAT的促炎作用可能严重依赖于其他细胞激活剂（细菌或其他）的存在，而纯AAT制剂似乎主要发挥抗炎活性。
