Potential role of high-mobility group box 1 in cystic fibrosis airway disease
Potential role of high-mobility group box 1 in cystic fibrosis airway disease
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DOI：
10.1164/rccm.200712-1894oc
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发表时间：
2008-10-15
影响因子：
24.7
通讯作者：
Blalock, J. Edwin
中科院分区：
文献类型：
--
作者：
Rowe, Steven M.;Jackson, Patricia L.;Blalock, J. Edwin
理论基础高迁移率族蛋白1(HMGB1)是一种有效的炎症介质，在脓毒症和类风湿关节炎中升高，但其在囊性纤维化(CF)肺部疾病中的作用尚不清楚。目的：确定HMGB1是否参与囊性纤维化(CF)肺部炎症，包括中性粒细胞趋化和肺基质降解。方法：我们使用CF患者的痰和血清和Scnn 1b转基因(Scnn 1b-TG)小鼠模型，该模型在呼吸道过度表达PECH Na(+)通道，并模拟包括肺部炎症在内的CF表型。用Western印迹和ELISA法检测人分泌物和小鼠支气管肺泡灌洗液(BALF)中的HMGB1。体外测定中性粒细胞与人中性粒细胞孵育后的趋化能力。用串联质谱仪测定胶原片段中的脯氨酸-甘氨酸-脯氨酸(PGP)。测量和主要结果：在CF痰中检测到HMGB1的水平高于正常人分泌物。Western印迹和ELISA法显示SCNN1b-Tg小鼠HMGB1表达水平升高。我们证明了纯化的HMGB1刺激的人中性粒细胞的趋化作用部分依赖于CXC趋化因子受体，并且在Scnn1b-TG小鼠的CF痰和BALF中也可以复制这种情况。抗HMGB1抗体中和痰和BALF中的趋化性降低，这表明HMGB1参与了这些样本的趋化特性。气管内注射纯化的HMGB1可诱导中性粒细胞进入小鼠呼吸道，促进Pgp的释放。结论：HMGB1的表达与肺组织炎症和肺基质降解有关，作为一种生物标志物和潜在的治疗靶点值得进一步研究。
Rationale High-mobility group box 1 (HMGB1) is a potent inflammatory mediator elevated in sepsis and rheumatoid arthritis, although its role in cystic fibrosis (CF) lung disease is unknown.Objectives: To determine whether HMGB1 contributes to CF lung inflammation, including neutrophil chemotaxis and lung matrix degradation.Methods: We used sputum and serum from subjects with CF and a Scnn 1b-transgenic (Scnn 1b-Tg) mouse model that overexpresses Pepithelial Na(+) channel in airways and mimics the CF phenotype, including lung inflammation. Human secretions and murine bronchoalveolar lavage fluid (BALF) was assayed for HMGB1 by Western blot and ELISA. Neutrophil chemotaxis was measured in vitro after incubation with human neutrophils. The collagen fragment proline-glycine-proline (PGP) was measured by tandem mass spectroscopy.Measurements and Main Results: HMGB1 was detected in CF sputum at higher levels than secretions from normal individuals. Scnn 1b-Tg mice had elevated levels of HMGB1 by Western blot and ELISA. We demonstrated that dose-dependent chemotaxis of human neutrophils stimulated by purified HMGB1 was partially dependent on CXC chemokine receptors and that this could be duplicated in CF sputum and BALF from Scnn 1b-Tg mice. Neutralization by anti-HMGB1 antibody, in both the sputum and BALF-reduced chemotaxis, which suggested that HMGB1 contributed to the chemotactic properties of these samples. Intratracheal administration of purified HMGB1 induced neutrophil influx into the airways of mice and promoted the release of PGP. PGP was also elevated in Scnn 1b-Tg mice and CF serum.Conclusions: HMGB1 expression contributes to pulmonary inflammation and lung matrix degradation in CF airway disease and deserves further investigation as a biomarker and potential therapeutic target.