Therapeutic effect of two strategies directed at disruption of pathogenic neutrophil extracellular vesicles in a murine emphysema model.
Therapeutic effect of two strategies directed at disruption of pathogenic neutrophil extracellular vesicles in a murine emphysema model.
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两种针对小鼠肺气肿模型中致病性中性粒细胞胞外囊泡破坏策略的治疗效果。
DOI：
10.1152/ajplung.00057.2023
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Russell,DerekW
中科院分区：
文献类型：
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作者：
Genschmer,KristopherR;Madison,Matthew;Viera,Liliana;Margaroli,Camilla;Gaggar,Amit;Blalock,JEdwin;Russell,DerekW
慢性阻塞性肺疾病（COPD）的特征是肺细胞外基质（ECM）重塑，导致阻塞。这部分是由来自活化的中性粒细胞（PMN）的细胞外囊泡（EV）驱动的，所述细胞外囊泡在其表面上表达中性粒细胞弹性蛋白酶（NE）的α-1抗胰蛋白酶（AAT）不敏感形式。预计这些EV通过Mac-1整联蛋白与胶原纤维结合，在此期间NE可以酶促降解胶原。硫酸鱼精蛋白（PS）是一种在人体中安全使用数十年的阳离子化合物，已在体外显示可将该NE从EV表面解离，使其对AAT敏感。此外，九肽抑制剂MP-9已被证明可防止EV与胶原蛋白的结合。我们试图测试PS、MP-9或两者的组合是否可以有效地预防动物COPD模型中NE+ EV驱动的ECM重塑。将EV与PBS、硫酸鱼精蛋白（25 μM）、MP-9（50 μM）或PS和MP-9的组合预孵育。将这些药物经气管内递送至麻醉的10至12周龄A/J雌性小鼠，持续7天。对一组小鼠实施安乐死，并将肺切片用于形态测定，另一组用于活体肺功能测试。通过PS或MP-9预处理，激活的中性粒细胞EV的肺泡破坏作用被废除。然而，在肺功能测试中，只有PS组（和PS/MP-9联合组）的肺功能恢复到接近对照水平。这些数据提供了一个洞察到有效使用PS在治疗环境EV衍生的肺泡damage.NEW &值得注意的硫酸鱼精蛋白促进中性粒细胞弹性蛋白酶（NE）从细胞外囊泡表面从激活的中性粒细胞的去除。这种“游离”NE不再受到其内源性抗蛋白酶α-1-抗胰蛋白酶抑制的保护。硫酸鱼精蛋白的这种功能突出了它作为COPD的潜在治疗策略，可以减轻疾病过程。
Chronic obstructive pulmonary disease (COPD) is characterized by lung extracellular matrix (ECM) remodeling that contributes to obstruction. This is driven, in part by extracellular vesicles (EVs) from activated neutrophils (PMNs), which express on their surface an α-1 antitrypsin (AAT) insensitive form of neutrophil elastase (NE). These EVs are predicted to bind to collagen fibers via Mac-1 integrins, during which time NE can enzymatically degrade the collagen. Protamine sulfate (PS), a cationic compound used safely for decades in humans, has been shown, in vitro, to dissociate this NE from the EV surface, rendering it AAT-sensitive. In addition, a nonapeptide inhibitor, MP-9, has been shown to prevent EV association with collagen. We sought to test whether PS, MP-9, or a combination of the two could effectively prevent NE+ EV-driven ECM remodeling in an animal COPD model. EVs were preincubated with PBS, protamine sulfate (25 μM), MP-9 (50 μM), or a combination of PS and MP-9. These were delivered intratracheally to anesthetized female 10- to 12-wk-old A/J mice for a 7-day time period. One group of mice was euthanized and lungs sectioned for morphometry, and the other group was used for live pulmonary function testing. The effect of alveolar destruction by activated neutrophil EVs was abrogated by pretreatment with PS or MP-9. However, in pulmonary function tests, only the PS groups (and combined PS/MP-9 groups) returned pulmonary function to near-control levels. These data presented here offer an insight into the effective use of PS in therapeutic setting for EV-derived alveolar damage.NEW & NOTEWORTHYProtamine sulfate facilitates the removal of neutrophil elastase (NE) from the surface of extracellular vesicles from activated neutrophils. This “free” NE is no longer protected from inhibition by its endogenous anti-protease, α-1-anti-trypsin. This function of protamine sulfate highlights it as a potential therapeutic strategy for COPD, which may attenuate the disease process.