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首页> 外文期刊>American Journal of Physiology >Progranulin is a substrate for neutrophil-elastase and proteinase-3 in the airway and its concentration correlates with mediators of airway inflammation in COPD
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Progranulin is a substrate for neutrophil-elastase and proteinase-3 in the airway and its concentration correlates with mediators of airway inflammation in COPD

机译：前颗粒蛋白是气道中嗜中性粒细胞弹性蛋白酶和蛋白酶3的底物，其浓度与COPD中气道炎症介质有关

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摘要

Progranulin (PGRN) is an anti-inflammatory protein, yet its digestion by neutrophil-derived proteinases generates products that can stimulate epithelial cell lines to secrete the neutrophil chemoattractant interleukin (IL)-8. Because dysregulated neutrophilic inflammation is implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD), the possible influence of PGRN and digestion products may be of relevance to understanding and treating inflammation in the disease. PGRN was measured in sputum sol-phase samples from patients with a clinical diagnosis of COPD and chronic sputum production in a clinically stable state; PGRN correlated negatively with bacterial load (colony-forming units/ml) (r = -0.446, P = 0.003, n = 43) and markers of neutrophilic inflammation, including neutrophil elastase (NE, nM) (r = -0.562, P = 0.008, n = 21) and proteinase-3 (PR3, nM) (r = -0.515, P = 0.017, n = 21). Products of PGRN digestion were detected in sputum sol phase, and PGRN conversion activity in sputum sol phase was inhibited with the serine proteinase inhibitor α1-antitrypsin. Digested PGRN at concentrations likely to be present in the airways did not stimulate IL-8 secretion from normal human bronchial epithelial (NHBE) cells. Infection of NHBE cells with live Haemophilus influenzae significantly increased PGRN secretion compared with untreated cells (P ≤ 0.001). The concentration of PGRN relates negatively to the amplified airway inflammation associated with bacterial colonization in clinically stable COPD. This relationship is driven by the proteolytic action of the neutrophil-derived proteinases NE and PR3; the products released by this action are unlikely to stimulate significant IL-8 secretion from epithelial cells in the airways.
机译：前颗粒蛋白（PGRN）是一种抗炎蛋白，但其被中性粒细胞蛋白酶消化后会产生可刺激上皮细胞系分泌中性粒细胞趋化性白介素（IL）-8的产物。由于中性粒细胞炎症失调与慢性阻塞性肺疾病（COPD）的病理生理有关，因此PGRN和消化产物的可能影响可能与了解和治疗该疾病的炎症有关。 PGRN是从临床诊断为COPD且临床上处于稳定状态的慢性痰产生的患者的痰液溶胶相样品中测得的; PGRN与细菌载量（菌落形成单位/ ml）（r = -0.446，P = 0.003，n = 43）和嗜中性炎症标志物，包括嗜中性白细胞弹性蛋白酶（NE，nM）呈负相关（r = -0.562，P = 0.008，n = 21）和蛋白酶3（PR3，nM）（r = -0.515，P = 0.017，n = 21）。在痰溶胶相中检测到PGRN消化产物，并且丝氨酸蛋白酶抑制剂α1-抗胰蛋白酶抑制了痰溶胶相中PGRN转化活性。可能存在于气道中的浓度的消化PGRN不会刺激正常人支气管上皮（NHBE）细胞分泌IL-8。与未经处理的细胞相比，用活的流感嗜血杆菌感染NHBE细胞会显着增加PGRN分泌（P≤0.001）。 PGRN的浓度与临床稳定的COPD中细菌定植相关的气道炎症反应呈负相关。这种关系是由中性粒细胞蛋白酶NE和PR3的蛋白水解作用驱动的。这种作用释放的产物不太可能刺激气道上皮细胞大量分泌IL-8。

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