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JCI:发现控制肺部粘液产生的基因开关

来源:生命经纬 2009-09-19 11:51

辛辛那提儿童医院医学中心Jeffrey Whitsett等人发现了能引起肺部产生过量粘液的主要基因开关。这项发现或许不仅能影响普通感冒的治疗方法,还能减轻慢性肺病——囊性纤维化病(cystic fibrosis,CF)患者的痛苦。

这项发现发表在9月14日Journal of Clinical Investigation杂志上。这项研究对机体内细胞如何产生慢性肺部感染和过量粘液产生的机制提供的全新的认识。

课题组发现SPDEF可作为主导基因调节一系列包括控制粘液产生的下游基因。在其他器官系统中(如消化系统)SPDEF是控制粘液产生的活性因子。但在健康人的肺部,该基因是沉默的,因此健康肺部不会产生大量的粘液。

研究人员利用卵清蛋白(ovalbumin)引发小鼠肺部产生过敏反应和炎症,发现小鼠肺部组织中SPDEF的表达显著升高,并且在小鼠的肺部产生过量的粘液。当关闭小鼠SPDEF基因后,发现炎症和过量粘液产生的情况不再出现。这表明SPDEF可以作为一种潜在的治疗和诊断靶标。

在出现呼吸系统炎症和粘液过量分泌的小鼠中,研究人员发现SPDEF关闭的某些基因,有助于保护肺部组织不受感染和损伤。反之,SPDEF激活的基因如FOXA3, AGR2和mucins能够诱发炎症和过量粘液。(生物谷Bioon.com)

生物谷推荐原始出处:

J. Clin. Invest. doi:10.1172/JCI39731.

SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production

Gang Chen1, Thomas R. Korfhagen1, Yan Xu1, Joseph Kitzmiller1, Susan E. Wert1, Yutaka Maeda1, Alexander Gregorieff2, Hans Clevers2 and Jeffrey A. Whitsett1

1The Perinatal Institute, Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati School of Medicine, Cincinnati, Ohio, USA.
2Netherlands Institute of Developmental Biology, Utrecht, The Netherlands.

Various acute and chronic inflammatory stimuli increase the number and activity of pulmonary mucus-producing goblet cells, and goblet cell hyperplasia and excess mucus production are central to the pathogenesis of chronic pulmonary diseases. However, little is known about the transcriptional programs that regulate goblet cell differentiation. Here, we show that SAM-pointed domain–containing Ets-like factor (SPDEF) controls a transcriptional program critical for pulmonary goblet cell differentiation in mice. Initial cell-lineage–tracing analysis identified nonciliated secretory epithelial cells, known as Clara cells, as the progenitors of goblet cells induced by pulmonary allergen exposure in vivo. Furthermore, in vivo expression of SPDEF in Clara cells caused rapid and reversible goblet cell differentiation in the absence of cell proliferation. This was associated with enhanced expression of genes regulating goblet cell differentiation and protein glycosylation, including forkhead box A3 (Foxa3), anterior gradient 2 (Agr2), and glucosaminyl (N-acetyl) transferase 3, mucin type (Gcnt3). Consistent with these findings, levels of SPDEF and FOXA3 were increased in mouse goblet cells after sensitization with pulmonary allergen, and the proteins were colocalized in goblet cells lining the airways of patients with chronic lung diseases. Deletion of the mouse Spdef gene resulted in the absence of goblet cells in tracheal/laryngeal submucosal glands and in the conducting airway epithelium after pulmonary allergen exposure in vivo. These data show that SPDEF plays a critical role in regulating a transcriptional network mediating the goblet cell differentiation and mucus hyperproduction associated with chronic pulmonary disorders.

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