Z α1-antitrypsin polymerizes in the lung and acts as a neutrophil chemoattractant
Z α1-antitrypsin polymerizes in the lung and acts as a neutrophil chemoattractant
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DOI：
10.1378/chest.125.5.1952
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发表时间：
2004-05-01
期刊：
影响因子：
9.6
通讯作者：
McElvaney, NG
中科院分区：
文献类型：
--
作者：
Mulgrew, AT;Taggart, CC;McElvaney, NG
背景：α(1)-抗胰蛋白酶（A1AT）是一种在肝脏中合成并分泌到血浆中的丰富蛋白。从血浆中，MAT扩散到身体的各个部位，包括肺，在那里它提供了很多抗蛋白酶保护。目前对A1AT缺乏个体的肺气肿发病机制的理解主要集中在肝脏内突变蛋白的聚合，这导致循环A1AT缺乏和肺部蛋白酶-抗蛋白酶失衡。方法和结果：在这项研究中，我们评估了5名健康志愿者、5名ZA1AT缺乏症患者和1名接受肝移植的PiZZ表型患者的BAL液样本。我们发现肺本身就是A1AT的来源。此外，在肺中形成的Z蛋白聚合，这些聚合物可以通过酶联免疫吸附试验和Western blot分析在肺上皮衬里液中检测到。最后，我们发现聚合ZA1AT是一种有效的中性粒细胞化学引诱剂，类似于聚合MA1AT。结论：我们的研究结果表明，局部产生的ZA1AT聚合是A1AT缺乏患者肺部炎症的一个促成因素，标准的抗蛋白酶治疗可能无法解决这一问题。
Background: alpha(1)-antitrypsin (A1AT) is an abundant protein that is synthesized in the liver and is secreted into the plasma. From the plasma, MAT diffuses into various body compartments, including the lung where it provides much of the antiprotease protection. The current understanding of the pathogenesis of emphysema in A1AT-deficient individuals focuses on the polymerization of mutant protein within the liver, which results in a deficiency of circulating A1AT and a protease-antiprotease imbalance in the lungs.Methods and results: In this study, we evaluated BAL fluid samples from five healthy volunteers, five individuals with ZA1AT deficiency, and an individual with the PiZZ phenotype who had received a liver transplant. We show that the lung itself is a source of A1AT. In addition, the Z protein formed in the lung polymerizes, and these polymers are detectable in lung epithelial lining fluid by enzyme-linked immunosorbent assay and Western blot analysis. Finally, we show that polymeric ZA1AT is a potent neutrophil chemoattractant that is similar to polymerized MA1AT.Conclusions: Our findings suggest that the polymerization of locally produced ZA1AT is a contributory factor to the lung inflammation experienced by those with A1AT deficiency and that standard antiprotease therapies may not address this problem.