Tyner Jeffrey W, Kim Edy Y, Ide Kyotaro, Pelletier Mark R, Roswit William T, Morton Jeffrey D, Battaile John T, Patel Anand C, Patterson G Alexander, Castro Mario, Spoor Melanie S, You Yingjian, Brody Steven L, Holtzman Michael J
Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Clin Invest. 2006 Feb;116(2):309-21. doi: 10.1172/JCI25167.
Epithelial hyperplasia and metaplasia are common features of inflammatory and neoplastic disease, but the basis for the altered epithelial phenotype is often uncertain. Here we show that long-term ciliated cell hyperplasia coincides with mucous (goblet) cell metaplasia after respiratory viral clearance in mouse airways. This chronic switch in epithelial behavior exhibits genetic susceptibility and depends on persistent activation of EGFR signaling to PI3K that prevents apoptosis of ciliated cells and on IL-13 signaling that promotes transdifferentiation of ciliated to goblet cells. Thus, EGFR blockade (using an irreversible EGFR kinase inhibitor designated EKB-569) prevents virus-induced increases in ciliated and goblet cells whereas IL-13 blockade (using s-IL-13Ralpha2-Fc) exacerbates ciliated cell hyperplasia but still inhibits goblet cell metaplasia. The distinct effects of EGFR and IL-13 inhibitors after viral reprogramming suggest that these combined therapeutic strategies may also correct epithelial architecture in the setting of airway inflammatory disorders characterized by a similar pattern of chronic EGFR activation, IL-13 expression, and ciliated-to-goblet cell metaplasia.
上皮细胞增生和化生是炎症性疾病和肿瘤性疾病的常见特征,但上皮细胞表型改变的基础往往并不明确。在此,我们发现小鼠气道在呼吸道病毒清除后,长期的纤毛细胞增生与黏液(杯状)细胞化生同时出现。上皮细胞行为的这种慢性转变表现出遗传易感性,并且依赖于表皮生长因子受体(EGFR)信号向磷脂酰肌醇-3激酶(PI3K)的持续激活,该激活可防止纤毛细胞凋亡,还依赖于白细胞介素-13(IL-13)信号,该信号促进纤毛细胞向杯状细胞的转分化。因此,EGFR阻断(使用一种名为EKB-569的不可逆EGFR激酶抑制剂)可防止病毒诱导的纤毛细胞和杯状细胞增加,而IL-13阻断(使用s-IL-13Rα2-Fc)会加剧纤毛细胞增生,但仍可抑制杯状细胞化生。病毒重编程后EGFR和IL-13抑制剂的不同作用表明,这些联合治疗策略也可能纠正以慢性EGFR激活、IL-13表达以及纤毛细胞向杯状细胞化生的相似模式为特征的气道炎症性疾病中的上皮结构。