BACKGROUND In cystic fibrosis (CF) airways excessive levels of serine trypsin-like proteases (TLPs) activate the epithelial sodium channel (ENaC) resulting in airways dehydration and promotion of mucus secretion. Despite this the relationship of TLP activity and clinical outcome has not been studied. METHODS We analysed supernatant (sol) prepared from CF sputum from adult CF patients in two study cohorts (29 and 33 samples, respectively). Protease activities were determined by measuring the hydrolysis of peptide-based substrates or by ELISA. Lung function was assessed by spirometry (FEV1). Mortality data was retrospectively obtained and time in months until death or transplantation used for subsequent survival analysis. RESULTS TLP activity inversely correlated with percent predicted FEV1 (r = -0.4, p = 0.03) and was greater in individuals who did not survive beyond 5-years from the time of sample collection. A Kaplan-Meier analysis demonstrated significantly reduced survival (p = 0.04) for individuals with high TLP activity [hazard ratio (HR) of 7.21 per log unit TLP activity (p = 0.03)]. In contrast, neutrophil elastase displayed no significant associations with lung function or patient survival. Similar findings were evident in the second study cohort. CONCLUSIONS Sputum TLP activity may represent a novel non-invasive biomarker and/or therapeutic target for CF lung disease.

中文翻译：

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痰胰蛋白酶样蛋白酶活性与囊性纤维化的临床结果有关

背景在囊性纤维化 (CF) 气道中，丝氨酸胰蛋白酶样蛋白酶 (TLP) 水平过高会激活上皮钠通道 (ENaC)，导致气道脱水并促进粘液分泌。尽管如此，尚未研究 TLP 活性与临床结果的关系。方法 我们分析了从两个研究组（分别为 29 和 33 个样本）中成年 CF 患者的 CF 痰液制备的上清液 (sol)。通过测量基于肽的底物的水解或通过 ELISA 来确定蛋白酶活性。通过肺活量测定法 (FEV1) 评估肺功能。死亡率数据是回顾性获得的，直到死亡或移植的时间（以月为单位）用于随后的生存分析。结果 TLP 活性与 FEV1 预测百分比呈负相关（r = -0.4，p = 0。03) 并且在从样本收集之日起未存活超过 5 年的个体中更大。Kaplan-Meier 分析表明，具有高 TLP 活性的个体生存率显着降低（p = 0.04）[风险比 (HR) 为 7.21/log 单位 TLP 活性 (p = 0.03)]。相比之下，中性粒细胞弹性蛋白酶与肺功能或患者存活率没有显着关联。类似的发现在第二个研究队列中也很明显。结论 痰 TLP 活性可能代表一种新的非侵入性生物标志物和/或 CF 肺病的治疗靶点。中性粒细胞弹性蛋白酶与肺功能或患者存活率没有显着关联。类似的发现在第二个研究队列中也很明显。结论 痰 TLP 活性可能代表一种新的非侵入性生物标志物和/或 CF 肺病的治疗靶点。中性粒细胞弹性蛋白酶与肺功能或患者存活率没有显着关联。类似的发现在第二个研究队列中也很明显。结论 痰 TLP 活性可能代表一种新的非侵入性生物标志物和/或 CF 肺病的治疗靶点。