Immune Disease Institute, Boston, MA 02115, USA.
Eur Respir J. 2011 May;37(5):1083-90. doi: 10.1183/09031936.00073710. Epub 2010 Sep 3.
Neutrophil serine proteases (NSPs), especially elastase, are major agents of lung destruction in cystic fibrosis (CF) patients. This study investigated SerpinB1, a highly efficient inhibitor of NSPs, in CF lung disease. Bronchoalveolar lavage fluid (BALF) from 31 children with CF and 24 control children was examined for amount and molecular species of SerpinB1, and its mechanism of action was studied. CF BALF had more SerpinB1 than control BALF (geometric mean 3.9 (95% CI 2.60-5.62) versus 1.37 (1.20-1.55) μg·mL⁻¹; p<0.001). BALF levels of SerpinB1 were higher for infected versus uninfected CF subjects (5.5 versus 2.7 μg·mL⁻¹; p<0.04) and substantially higher for elastase-positive versus -negative CF subjects (8.41 versus 1.89 μg·mL⁻¹; p<0.001). Most SerpinB1 in CF BALF had been cleaved. Adding recombinant SerpinB1 to CF BALF stoichiometrically inhibited endogenous elastase, indicating that the inhibitor functions in the CF microenvironment. In vitro simulations comparing SerpinB1 and α₁-antitrypsin (SerpinA1) showed that both rapidly form irreversible inhibitory covalent complexes with elastase and that these differed in survival time. The SerpinB1-elastase complex survived only briefly due to fragmentation of bound elastase, releasing cleaved SerpinB1, the molecular form in CF BALF. The findings define an innate role for SerpinB1 in CF airways.
中性粒细胞丝氨酸蛋白酶（NSPs），特别是弹性蛋白酶，是囊性纤维化（CF）患者肺部破坏的主要因素。本研究调查了 SerpinB1，一种 NSPs 的高效抑制剂，在 CF 肺部疾病中的作用。检查了 31 名 CF 儿童和 24 名对照儿童的支气管肺泡灌洗液（BALF）中 SerpinB1 的含量和分子种类，并研究了其作用机制。CF BALF 中的 SerpinB1 多于对照 BALF（几何平均值 3.9（95%CI 2.60-5.62）与 1.37（1.20-1.55）μg·mL⁻¹；p<0.001）。与未感染的 CF 患者相比，感染的 CF 患者的 BALF 中 SerpinB1 水平更高（5.5 与 2.7 μg·mL⁻¹；p<0.04），与弹性酶阳性的 CF 患者相比，SerpinB1 水平更高（8.41 与 1.89 μg·mL⁻¹；p<0.001）。CF BALF 中的大多数 SerpinB1 已被切割。向 CF BALF 中添加重组 SerpinB1 可化学计量地抑制内源性弹性酶，表明抑制剂在 CF 微环境中起作用。体外模拟比较了 SerpinB1 和 α₁-抗胰蛋白酶（SerpinA1），结果表明两者都能迅速与弹性酶形成不可逆的抑制性共价复合物，并且这些复合物的存活时间不同。由于结合的弹性酶的片段化，SerpinB1-弹性酶复合物仅短暂存活，释放出切割的 SerpinB1，这是 CF BALF 中的分子形式。这些发现定义了 SerpinB1 在 CF 气道中的先天作用。
