Hansen G, Hoffjan S, Mosler K, Schuster A
Martin-Luther-University, Children's Hospital, 06120 Halle, Germany.
Lung. 2001;179(3):185-94. doi: 10.1007/s004080000060. Epub 2002 Feb 4.
Chronic inflammation in cystic fibrosis (CF) airways leads to high concentrations of deoxyribonucleic acid (DNA) and neutrophil elastase (NE). Both play a major role in CF lung pathophysiology and are aims of new therapeutic approaches: rhDNase degrades highly viscosic DNA and alpha1-proteinase inhibitor (alpha1-PI) inhibits NE activity and thereby pulmonary inflammation and hypersecretion. Given the reports on increased sputum NE concentrations upon rhDNase inhalation, there is a rationale for a combined rhDNase/alpha1-PI treatment. With the question of whether a combined therapy is feasible, we first investigated in vitro whether incubation of CF sputum with rhDNase changes proteolytic and secretagogue activity of sputum supernatants and its inhibition by alpha1-PI. Next, we studied whether incubation of alpha1-PI with rhDNase impairs the inhibitory effect of alpha1-PI on proteolytic activity of NE and the inhibitory effect of alpha1-PI on NE-induced secretion from a human mucoepidermoid cell line. Incubation of CF sputum with rhDNase led to a twofold increase in sputum NE activity. Correspondingly, the inhibitory effect of alpha1-PI on sputum NE activity and on secretion induced by these sputum samples was significantly reduced by rhDNase. Preincubation of alpha1-PI with rhDNase significantly reduced the inhibitory effect of alpha1-PI on purified NE activity and on NE-induced secretion. However, this effect was limited to alpha1-PI concentrations lower than those achievable after inhalation. Therefore, impairment of alpha1-PI function by rhDNase is not likely to be relevant in vivo, provided that a sufficient dosage of alpha1-PI is inhaled.
囊性纤维化（CF）气道中的慢性炎症会导致脱氧核糖核酸（DNA）和中性粒细胞弹性蛋白酶（NE）浓度升高。二者在CF肺部病理生理学中均起主要作用，也是新治疗方法的目标：重组人脱氧核糖核酸酶（rhDNase）可降解高粘性DNA，α1-蛋白酶抑制剂（α1-PI）可抑制NE活性，从而减轻肺部炎症和分泌过多。鉴于有报道称吸入rhDNase后痰液中NE浓度会升高，因此有理由采用rhDNase/α1-PI联合治疗。针对联合治疗是否可行的问题，我们首先在体外研究了用rhDNase孵育CF痰液是否会改变痰液上清液的蛋白水解和促分泌活性及其被α1-PI的抑制作用。接下来，我们研究了α1-PI与rhDNase一起孵育是否会削弱α1-PI对NE蛋白水解活性的抑制作用以及α1-PI对人黏液表皮样细胞系中NE诱导分泌的抑制作用。用rhDNase孵育CF痰液会使痰液NE活性增加两倍。相应地，rhDNase显著降低了α1-PI对痰液NE活性以及对这些痰液样本诱导的分泌的抑制作用。α1-PI与rhDNase预孵育显著降低了α1-PI对纯化NE活性以及对NE诱导分泌的抑制作用。然而，这种作用仅限于低于吸入后可达到浓度的α1-PI浓度。因此，只要吸入足够剂量的α1-PI，rhDNase对α1-PI功能的损害在体内不太可能具有相关性。
