Park Sung-Woo, Verhaeghe Catherine, Nguyenvu Louis T, Barbeau Rebecca, Eisley Christopher J, Nakagami Yasuhiro, Huang Xiaozhu, Woodruff Prescott G, Fahy John V, Erle David J
Lung Biology Center, University of California San Francisco, San Francisco, California 94143, USA.
Am J Respir Crit Care Med. 2009 Oct 1;180(7):603-10. doi: 10.1164/rccm.200811-1768OC. Epub 2009 Jul 23.
Increased production of mucus is a prominent feature of asthma. IL-13-driven mucous cell metaplasia is associated with decreased expression of the transcription factor FOXA2 and increased expression of the related transcription factor FOXA3 in animal and cell culture models.
Establish how changes in FOXA2 and FOXA3 expression contribute to mucous metaplasia and determine whether FOXA2 and FOXA3 expression is altered in asthma.
Mice expressing a Foxa2 transgene in airway epithelial cells and mice deficient in Foxa3 were analyzed after allergen sensitization and challenge. Expression of FOXA2, FOXA3, MUC5AC, and the highly IL-13-inducible gene CLCA1 was analyzed in airway biopsies from subjects with asthma and control subjects.
Expression of a Foxa2 transgene reduced allergen-induced mucous metaplasia by 45% compared with control transgenic mice (P < 0.05) whereas inactivation of Foxa3 had no detectable effects on mucous metaplasia. Expression of FOXA2 was reduced in subjects with asthma and was negatively correlated with MUC5AC and CLCA1 levels in subjects with asthma. In contrast, FOXA3 expression was not significantly correlated with MUC5AC and was positively correlated with CLCA1.
Increasing Foxa2 expression reduced mucous metaplasia in an allergic mouse model. Subjects with asthma had decreased FOXA2 expression, suggesting that therapeutic approaches that increase FOXA2 expression or function could be beneficial for reducing mucus production in asthma. Unlike FOXA2, FOXA3 did not regulate mucous metaplasia.
黏液分泌增加是哮喘的一个显著特征。在动物和细胞培养模型中，白细胞介素-13驱动的黏液细胞化生与转录因子FOXA2表达降低及相关转录因子FOXA3表达增加有关。
确定FOXA2和FOXA3表达的变化如何导致黏液化生，并确定哮喘患者中FOXA2和FOXA3表达是否改变。
对在气道上皮细胞中表达Foxa2转基因的小鼠和缺乏Foxa3的小鼠进行变应原致敏和激发后分析。对哮喘患者和对照受试者的气道活检组织中FOXA2、FOXA3、MUC5AC和白细胞介素-13高度诱导基因CLCA1的表达进行分析。
与对照转基因小鼠相比，Foxa2转基因的表达使变应原诱导的黏液化生减少了45%（P<0.05），而Foxa3的失活对黏液化生没有可检测到的影响。哮喘患者中FOXA2的表达降低，且与哮喘患者中MUC5AC和CLCA1水平呈负相关。相比之下，FOXA3的表达与MUC5AC无显著相关性，与CLCA1呈正相关。
在过敏性小鼠模型中增加Foxa2表达可减少黏液化生。哮喘患者FOXA2表达降低，提示增加FOXA2表达或功能的治疗方法可能有助于减少哮喘中的黏液分泌。与FOXA2不同，FOXA3不调节黏液化生。
