Parmar Jasvir S, Mahadeva Ravi, Reed Benjamin J, Farahi Neda, Cadwallader Karen A, Keogan Mary T, Bilton Diana, Chilvers Edwin R, Lomas David A
Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, United Kingdom.
Am J Respir Cell Mol Biol. 2002 Jun;26(6):723-30. doi: 10.1165/ajrcmb.26.6.4739.
Plasma deficiency of alpha(1)-antitrypsin is most commonly due to the Z mutation ((342)Glu--> Lys) and is associated with early-onset panlobular emphysema. The lung disease in these patients is attributed to the relative deficiency of circulating alpha(1)-antitrypsin resulting in uncontrolled neutrophil-derived proteolytic activity. We have previously demonstrated that the local deficiency of Z alpha(1)-antitrypsin is exacerbated by the formation of polymers within the lung and now show that this polymerization not only inactivates alpha(1)-antitrypsin but also converts the molecule to a chemoattractant for human neutrophils. The chemotactic action of polymeric alpha(1)-antitrypsin was substantially greater than that seen with other conformers, was of similar magnitude to C5a, and was apparent over a range of physiologically relevant concentrations (EC(50) 0.0045 +/- 0.002 mg/ml). The biologic activity of polymeric alpha(1)-antitrypsin was confirmed by the demonstration that polymers, but not native alpha(1)-antitrypsin, induced neutrophil shape change and stimulated myeloperoxidase release and neutrophil adhesion. Polymeric alpha(1)-antitrypsin had no effect on basal or N-formyl-Met-Leu-Phe- stimulated superoxide anion release or constitutive apoptosis. The chemotactic properties of polymeric alpha(1)-antitrypsin may provide an explanation for the excessive neutrophils found in the lungs of Z alpha(1)-antitrypsin homozygotes and suggests a new paradigm for the pathogenesis of emphysema in these patients.
α1-抗胰蛋白酶的血浆缺乏最常见于Z突变（（342）Glu→Lys），并与早发性全小叶型肺气肿相关。这些患者的肺部疾病归因于循环中α1-抗胰蛋白酶的相对缺乏，导致中性粒细胞衍生的蛋白水解活性不受控制。我们之前已经证明，肺内聚合物的形成会加剧Zα1-抗胰蛋白酶的局部缺乏，现在表明这种聚合不仅会使α1-抗胰蛋白酶失活，还会将该分子转化为人类中性粒细胞的趋化剂。聚合α1-抗胰蛋白酶的趋化作用明显大于其他构象异构体，与C5a的趋化作用强度相似，并且在一系列生理相关浓度范围内（EC50 0.0045±0.002 mg/ml）都很明显。通过证明聚合物而非天然α1-抗胰蛋白酶可诱导中性粒细胞形态改变、刺激髓过氧化物酶释放和中性粒细胞黏附，证实了聚合α1-抗胰蛋白酶的生物活性。聚合α1-抗胰蛋白酶对基础或N-甲酰甲硫氨酸-亮氨酸-苯丙氨酸刺激的超氧阴离子释放或组成性凋亡没有影响。聚合α1-抗胰蛋白酶的趋化特性可能为Zα1-抗胰蛋白酶纯合子肺部发现的过多中性粒细胞提供解释，并为这些患者肺气肿的发病机制提出新的范例。
