Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California, USA.
Nat Med. 2011 Oct 16;17(11):1466-72. doi: 10.1038/nm.2450.
Although the lung is a defining feature of air-breathing animals, the pathway controlling the formation of type I pneumocytes, the cells that mediate gas exchange, is poorly understood. In contrast, the glucocorticoid receptor and its cognate ligand have long been known to promote type II pneumocyte maturation; prenatal administration of glucocorticoids is commonly used to attenuate the severity of infant respiratory distress syndrome (RDS). Here we show that knock-in mutations of the nuclear co-repressor SMRT (silencing mediator of retinoid and thyroid hormone receptors) in C57BL/6 mice (SMRTmRID) produces a previously unidentified respiratory distress syndrome caused by prematurity of the type I pneumocyte. Though unresponsive to glucocorticoids, treatment with anti-thyroid hormone drugs (propylthiouracil or methimazole) completely rescues SMRT-induced RDS, suggesting an unrecognized and essential role for the thyroid hormone receptor (TR) in lung development. We show that TR and SMRT control type I pneumocyte differentiation through Klf2, which, in turn, seems to directly activate the type I pneumocyte gene program. Conversely, mice without lung Klf2 lack mature type I pneumocytes and die shortly after birth, closely recapitulating the SMRTmRID phenotype. These results identify TR as a second nuclear receptor involved in lung development, specifically type I pneumocyte differentiation, and suggest a possible new type of therapeutic option in the treatment of RDS that is unresponsive to glucocorticoids.
尽管肺是空气呼吸动物的一个重要特征，但控制 I 型肺泡细胞形成的途径（即介导气体交换的细胞）仍未被很好地理解。相比之下，糖皮质激素受体及其同源配体长期以来被认为可以促进 II 型肺泡细胞的成熟；产前给予糖皮质激素常用于减轻婴儿呼吸窘迫综合征（RDS）的严重程度。在这里，我们展示了在 C57BL/6 小鼠中敲入核共抑制因子 SMRT（视黄酸和甲状腺激素受体沉默调节剂）的突变（SMRTmRID）会导致一种以前未被识别的呼吸窘迫综合征，这是由 I 型肺泡细胞的不成熟引起的。尽管对糖皮质激素无反应，但用抗甲状腺激素药物（丙硫氧嘧啶或甲巯咪唑）治疗可完全挽救 SMRT 引起的 RDS，这表明甲状腺激素受体（TR）在肺发育中具有未被认识到的重要作用。我们表明，TR 和 SMRT 通过 Klf2 控制 I 型肺泡细胞分化，而 Klf2 似乎又直接激活了 I 型肺泡细胞基因程序。相反，缺乏肺 Klf2 的小鼠缺乏成熟的 I 型肺泡细胞，并在出生后不久死亡，这与 SMRTmRID 表型非常相似。这些结果表明 TR 是参与肺发育的第二个核受体，特别是 I 型肺泡细胞分化，并提示在治疗对糖皮质激素无反应的 RDS 方面可能有新的治疗选择。
