Eosinophil cationic protein alters pulmonary surfactant structure and function in asthma
Eosinophil cationic protein alters pulmonary surfactant structure and function in asthma
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DOI：
10.1016/j.jaci.2003.12.008
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发表时间：
2004-03-01
影响因子：
14.2
通讯作者：
Krug, N
中科院分区：
文献类型：
--
作者：
Hohlfeld, JM;Schmiedl, A;Krug, N
背景：哮喘患者的表面活性剂功能受损。源自血浆或炎症介质的抑制蛋白是导致这种功能障碍的良好候选者。嗜酸性粒细胞是哮喘中有效的效应细胞，激活后会释放炎症介质，尤其是反应性颗粒蛋白，如嗜酸性粒细胞阳离子蛋白 (ECP)。 目的：由于 ECP 在抑制表面活性剂功能中的潜在作用尚不清楚，我们测试了哮喘患者节段性过敏原激发后支气管肺泡灌洗液 (BALF) 中 ECP 水平是否与表面活性剂功能障碍相关的假设。此外，我们在体外测试了纯化的ECP对表面活性剂功能和结构的影响。方法：使用脉动气泡表面活性剂和毛细管表面活性剂评估从哮喘患者BALF中分离的表面活性剂的生物物理功能，并将其与ECP水平相关联。纯化的 ECP 和不同浓度的血浆蛋白与天然表面活性剂一起孵育。使用毛细管表面活性剂研究表面活性剂功能，并通过电子显微镜测定表面活性剂结构。结果：与基线相比，过敏原激发后哮喘患者的 BALF 中的 ECP 升高。过敏原激发后的 ECP 水平与表面活性剂功能障碍密切相关。在体外，ECP 会诱导表面活性剂功能的浓度依赖性抑制，这种抑制可被 ECP 抗体抑制。 ECP 比白蛋白或纤维蛋白原更有效。最后，ECP 会引起表面活性剂囊泡的严重超微结构变化，这种变化比纤维蛋白原或白蛋白引起的变化更为明显。结论：ECP 会导致哮喘中的表面活性剂功能障碍，进而导致气道阻塞。
Background: Impaired surfactant function has been demonstrated in patients with asthma. Inhibitory proteins originating from plasma or inflammatory mediators are good candidates to contribute to this dysfunction. Eosinophils are potent effector cells in asthma, which, on activation, release inflammatory mediators, especially reactive granula proteins such as eosinophil cationic protein (ECP).Objective: Because the potential role of ECP in the inhibition of surfactant function is not known, we tested the hypothesis of whether ECP levels in bronchoalveolar lavage fluid (BALF) of patients with asthma after segmental allergen provocation correlate to surfactant dysfunction. Furthermore, we tested the effect of purified ECP on surfactant function and structure in vitro.Methods: Surfactant isolated from BALF of asthmatic patients was assessed for biophysical function with the Pulsating Bubble Surfactometer and the Capillary Surfactometer and correlated to ECP levels. Purified ECP and plasma proteins at various concentrations were incubated with natural surfactant. Surfactant function was studied with the Capillary Surfactometer, and surfactant structure was determined by electron microscopy.Results: ECP is elevated in BALF from patients with asthma after allergen challenge compared with baseline. ECP levels after allergen challenge correlate well to surfactant dysfunction. In vitro, ECP induces a concentration-dependent inhibition of surfactant function that can be inhibited by antibodies against ECP. ECP is more potent compared with albumin or fibrinogen. Finally, ECP induces severe ultrastructural changes to surfactant vesicles that are more pronounced than changes induced by either fibrinogen or albumin.Conclusions: ECP contributes to surfactant dysfunction in asthma, which in turn could lead to airway obstruction.