CFTR Inhibition Provokes an Inflammatory Response Associated with an Imbalance of the Annexin A1 Pathway
CFTR Inhibition Provokes an Inflammatory Response Associated with an Imbalance of the Annexin A1 Pathway
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DOI：
10.2353/ajpath.2010.091149
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发表时间：
2010-07-01
影响因子：
6
通讯作者：
Perretti, Mauro
中科院分区：
文献类型：
--
作者：
Dalli, Jesmond;Rosignoli, Guglielmo;Perretti, Mauro
囊性纤维化（CF）是一种由CF跨膜传导调节因子（CFTR）基因突变引起的疾病，其特征在于肺部慢性细菌感染和炎症。先前已经表明CFTR的缺失与内源性抗炎蛋白膜联蛋白A1（AnxA 1）的较低表达相关，我们使用经验证的CFTR抑制剂进一步研究了这种可能的功能连接。用CFTR抑制剂-172（CFTR 172）治疗小鼠增强了酵母聚糖促进的急性腹膜炎，这一效应与腹膜细胞中较低的AnxA 1水平相关。用另一种化学上不同的CFTR抑制剂获得了类似的结果。CFTR 172的促炎作用在AnxAl（-/-）以及CFTR-/-小鼠中丧失。重要的是，对CFTR-/-动物或用CFTR 172处理的动物施用hrAnxA 1及其肽模拟物校正了在这些动物中观察到的过度的白细胞迁移。用人类多形核白细胞（PMN）进行的体外试验表明，CFTR 172通过促进微粒中蛋白质的释放来减少细胞相关的AnxA 1。我们认为，CF细胞中AnxA 1的反调节特性的影响减少有助于这种疾病的炎性表型特征。因此，这些发现为与CFTR抑制相关的炎性疾病的潜在机制提供了重要的见解，同时为控制CF的炎性表型提供了新的药理学靶点。(Am Pathol 2010，177：176-184 DOI：10.2353/ajpath.2010.091149）
Cystic fibrosis (CF), a disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, is characterized by chronic bacterial infections and inflammation in the lung. Having previously shown that deletion of CFTR is associated with lower expression of the endogenous anti-inflammatory protein Annexin A1 (AnxA1), we investigated further this possible functional connection using a validated CFTR inhibitor. Treatment of mice with the CFTR inhibitor-172 (CFTR172) augmented the acute peritonitis promoted by zymosan, an effect associated with lower AnxA1 levels in peritoneal cells. Similar results were obtained with another, chemically distinct, CFTR inhibitor. The pro-inflammatory effect of CFTR172 was lost in AnxAl(-/-), as well as CFTR-/- mice. Importantly, administration of hrAnxA1 and its peptido-mimetic to CFTR-/- animals or to animals treated with CFTR172 corrected the exaggerated leukocyte migration seen in these animals. In vitro assays with human Polymorphonuclear leukocyte (PMN) demonstrated that CFTR172 reduced cell-associated AnxA1 by promoting release of the protein in microparticles. We propose that the reduced impact of the counterregulatory properties of AnxA1 in CF cells contributes to the inflammatory phenotype characteristic of this disease. Thus, these findings provide an important insight into the mechanism underlying the inflammatory disease associated with CFTR inhibition while, at the same time, providing a novel pharmacological target for controlling the inflammatory phenotype of CF. (Am Pathol 2010, 177:176-184 DOI: 10.2353/ajpath.2010.091149)