Division of Pulmonary Sciences and Critical Care Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, 80045, USA.
Curr Mol Med. 2012 Aug;12(7):827-35. doi: 10.2174/156652412801318755.
α-1 anti-trypsin (AAT) is the most abundant circulating serine protease inhibitor (serpin) and an acute phase reactant. Systemic deficiency in AAT (AATD) due to genetic mutations can result in liver failure and chronic lung disease such as emphysema. Considered the prototypic serpin, the emphysema observed in patients with AATD, consisting of progressive destruction of the alveoli and small airway structures, formed the basis of the protease/anti-protease imbalance theory of chronic obstructive pulmonary disease (COPD). Over the past decade, however, investigations of AATD have described multiple functions of AAT beyond those generally attributed to its antiprotease activity. Evidence now suggests that AAT plays an important role in modulating immunity, inflammation, proteostasis, apoptosis, and possibly cellular senescence programs. When integrated in vivo, these processes contribute to the lung maintenance program which preserves the lung despite a constant bombardment by damage associated molecular patterns (DAMPs) and/or pathogenassociated molecular patterns (PAMPs) initiated by cigarette smoke, pollutants, or infections. In this review, we discuss the clinical aspects of AATD as they pertain to emphysema; including similarities and differences to cigarette smoke-induced emphysema. Examining the lung maintenance program, we next consider the multiple mechanisms of airspace destruction and explore the role AATD contributes. Finally, we consider the data regarding treatment of AATD, including AAT supplementation and its current limitations, and suggest further avenues of research informed by the multiple functions of AAT.
α-1 抗胰蛋白酶（AAT）是最丰富的循环丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂）和急性期反应物。由于基因突变导致的全身 AAT 缺乏症（AATD）可导致肝功能衰竭和慢性肺部疾病，如肺气肿。作为典型的丝氨酸蛋白酶抑制剂，AATD 患者观察到的肺气肿由肺泡和小气道结构的进行性破坏组成，这构成了慢性阻塞性肺疾病（COPD）蛋白酶/抗蛋白酶失衡理论的基础。然而，在过去的十年中，对 AATD 的研究描述了 AAT 的多种功能，这些功能超出了其抗蛋白酶活性通常归因的功能。现在有证据表明，AAT 在调节免疫、炎症、蛋白稳态、细胞凋亡和可能的细胞衰老程序方面发挥着重要作用。当这些过程在体内整合时，它们有助于肺部维持程序，尽管肺部不断受到与吸烟、污染物或感染有关的损伤相关分子模式（DAMPs）和/或病原体相关分子模式（PAMPs）的攻击，但仍能维持肺部。在这篇综述中，我们讨论了 AATD 的临床方面，这些方面与肺气肿有关；包括与吸烟引起的肺气肿的相似之处和不同之处。检查肺维持程序，我们接下来考虑气腔破坏的多种机制，并探讨 AATD 所起的作用。最后，我们考虑了关于 AATD 治疗的数据，包括 AAT 补充及其当前的局限性，并根据 AAT 的多种功能提出了进一步的研究途径。
