Krotova Karina, Marek George W, Wang Rejean L, Aslanidi George, Hoffman Brad E, Khodayari Nazli, Rouhani Farshid N, Brantly Mark L
1 Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and.
2 Department of Pediatrics, University of Florida, Gainesville, Florida.
Am J Respir Cell Mol Biol. 2017 Aug;57(2):238-247. doi: 10.1165/rcmb.2016-0366OC.
Alpha-1 antitrypsin (AAT) deficiency-associated emphysema is largely attributed to insufficient inhibition of neutrophil elastase released from neutrophils. Correcting AAT levels using augmentation therapy only slows disease progression, and that suggests a more complex process of lung destruction. Because alveolar macrophages (Mɸ) express AAT, we propose that the expression and intracellular accumulation of mutated Z-AAT (the most common mutation) compromises Mɸ function and contributes to emphysema development. Extracellular matrix (ECM) degradation is a hallmark of emphysema pathology. In this study, Mɸ from individuals with Z-AAT (Z-Mɸ) have greater proteolytic activity on ECM than do normal Mɸ. This abnormal Z-Mɸ activity is not abrogated by supplementation with exogenous AAT and is likely the result of cellular dysfunction induced by intracellular accumulation of Z-AAT. Using pharmacologic inhibitors, we show that several classes of proteases are involved in matrix degradation by Z-Mɸ. Importantly, compared with normal Mɸ, the membrane-bound serine protease, matriptase, is present in Z-Mɸ at higher levels and contributes to their proteolytic activity on ECM. In addition, we identified matrix metalloproteinase (MMP)-14, a membrane-anchored metalloproteinase, as a novel substrate for matriptase, and showed that matriptase regulates the levels of MMP-14 on the cell surface. Thus, high levels of matriptase may contribute to increased ECM degradation by Z-Mɸ, both directly and through MMP-14 activation. In summary, the expression of Z-AAT in Mɸ confers increased proteolytic activity on ECM. This proteolytic activity is not rescued by exogenous AAT supplementation and could thus contribute to augmentation resistance in AAT deficiency-associated emphysema.
α-1抗胰蛋白酶（AAT）缺乏相关的肺气肿很大程度上归因于对中性粒细胞释放的中性粒细胞弹性蛋白酶抑制不足。使用增强疗法纠正AAT水平仅能减缓疾病进展，这表明肺破坏过程更为复杂。由于肺泡巨噬细胞（Mɸ）表达AAT，我们提出突变的Z-AAT（最常见的突变）的表达和细胞内积累会损害Mɸ功能，并导致肺气肿的发展。细胞外基质（ECM）降解是肺气肿病理学的一个标志。在本研究中，来自Z-AAT个体的Mɸ（Z-Mɸ）对ECM的蛋白水解活性比正常Mɸ更高。这种异常的Z-Mɸ活性不会因补充外源性AAT而消除，可能是Z-AAT细胞内积累诱导的细胞功能障碍的结果。使用药理抑制剂，我们表明几类蛋白酶参与了Z-Mɸ介导的基质降解。重要的是，与正常Mɸ相比，膜结合丝氨酸蛋白酶matriptase在Z-Mɸ中的水平更高，并有助于其对ECM的蛋白水解活性。此外，我们鉴定出基质金属蛋白酶（MMP）-14，一种膜锚定金属蛋白酶，是matriptase的新底物，并表明matriptase调节细胞表面MMP-14的水平。因此，高水平的matriptase可能直接或通过激活MMP-14导致Z-Mɸ对ECM的降解增加。总之，Z-AAT在Mɸ中的表达赋予了对ECM更高的蛋白水解活性。这种蛋白水解活性不会因补充外源性AAT而得到挽救，因此可能导致AAT缺乏相关肺气肿的增强治疗抵抗。
