Human neutrophil peptides and phagocytic deficiency in bronchiectatic lungs.
Human neutrophil peptides and phagocytic deficiency in bronchiectatic lungs.
复制标题
DOI：
10.1164/rccm.200808-1250oc
复制
发表时间：
2009-07
影响因子：
24.7
通讯作者：
Stefanos Voglis;K. Quinn;E. Tullis;Mingyao Liu;Melanie Henriques;C. Zubrinich;Ó. Peñuelas;Holman Chan;F. Silverman;V. Cherepanov;N. Orzech;A. Khine;A. Cantin;Arthur S Slutsky;G. Downey;Haibo Zhang
中科院分区：
文献类型：
--
作者：
Stefanos Voglis;K. Quinn;E. Tullis;Mingyao Liu;Melanie Henriques;C. Zubrinich;Ó. Peñuelas;Holman Chan;F. Silverman;V. Cherepanov;N. Orzech;A. Khine;A. Cantin;Arthur S Slutsky;G. Downey;Haibo Zhang
一个众所周知的临床悖论是，尽管多形核中性粒细胞（PMN）和高浓度人中性粒细胞肽（HNP）的存在丰富，但囊性纤维化（CF）患者的肺部持续存在严重的细菌感染，这两种物质都有望杀死细菌，但却未能做到这一点。其机制尚不清楚。本研究探讨了几种可能的机制来理解这一悖论。方法分别从有、无CF支气管扩张患者的痰液和血液中分离出中性粒细胞（PMN），进行吞噬实验。从CF患者中分离的HNP用于刺激健康PMN，然后进行吞噬试验。测量和主要结果从支气管扩张患者痰中分离的PMN显示与肺中高浓度HNP相关的吞噬功能缺陷。当健康的PMN与HNP一起孵育时，观察到吞噬能力降低与表面Fc γ RIII抑制、肌动蛋白丝重塑、细胞内Ca（2+）增强和脱粒有关。用胞内Ca（2+）阻断剂或α 1-蛋白酶抑制剂处理PMN以减弱HNP的活性，在很大程度上防止了HNP诱导的吞噬功能缺陷。与野生型小鼠相比，在Pallid小鼠（α 1蛋白酶抑制剂遗传缺陷）中腹膜内滴注HNP导致更大的PMN肺浸润和吞噬细胞缺陷。结论HNP或PMN单独具有抗菌作用，但由于相互作用而丧失抗菌作用。HNP的这些作用可能有助于解释炎症性肺病患者中观察到的临床矛盾，表明HNP是临床治疗的新靶点。
RATIONALE A well-known clinical paradox is that severe bacterial infections persist in the lungs of patients with cystic fibrosis (CF) despite the abundance of polymorphonuclear neutrophils (PMN) and the presence of a high concentration of human neutrophil peptides (HNP), both of which are expected to kill the bacteria but fail to do so. The mechanisms remain unknown. OBJECTIVES This study examined several possible mechanisms to understand this paradox. METHODS PMN were isolated from sputum and blood of subjects with and without CF or non-CF bronchiectasis for phagocytic assays. HNP isolated from patients with CF were used to stimulate healthy PMN followed by phagocytic tests. MEASUREMENTS AND MAIN RESULTS PMN isolated from the sputum of the bronchiectatic patients display defective phagocytosis that correlated with high concentrations of HNP in the lung. When healthy PMN were incubated with HNP, decreased phagocytic capacity was observed in association with depressed surface Fc gamma RIII, actin-filament remodeling, enhanced intracellular Ca(2+), and degranulation. Treatment of PMN with an intracellular Ca(2+) blocker or alpha1-proteinase inhibitor to attenuate the activity of HNP largely prevented the HNP-induced phagocytic deficiency. Intratracheal instillation of HNP in Pallid mice (genetically deficient in alpha1-proteinase inhibitor) resulted in a greater PMN lung infiltration and phagocytic deficiency compared with wild-type mice. CONCLUSIONS HNP or PMN alone exert antimicrobial ability, which was lost as a result of their interaction. These effects of HNP may help explain the clinical paradox seen in patients with inflammatory lung diseases, suggesting HNP as a novel target for clinical therapy.