Jr., Cardiovascular Research Center, Massachusetts General Hospital - East, 149 13 St., Charlestown, MA 02129.
Am J Physiol Lung Cell Mol Physiol. 2013 Oct 15;305(8):L569-81. doi: 10.1152/ajplung.00401.2012. Epub 2013 Aug 9.
Nitric oxide (NO) regulates lung development through incompletely understood mechanisms. NO controls pulmonary vascular smooth muscle cell (SMC) differentiation largely through stimulating soluble guanylate cyclase (sGC) to produce cGMP and increase cGMP-mediated signaling. To examine the role of sGC in regulating pulmonary development, we tested whether decreased sGC activity reduces alveolarization in the normal and injured newborn lung. For these studies, mouse pups with gene-targeted sGC-α1 subunit truncation were used because we determined that they have decreased pulmonary sGC enzyme activity. sGC-α1 knockout (KO) mouse pups were observed to have decreased numbers of small airway structures and lung volume compared with wild-type (WT) mice although lung septation and body weights were not different. However, following mild lung injury caused by breathing 70% O2, the sGC-α1 KO mouse pups had pronounced inhibition of alveolarization, as evidenced by an increase in airway mean linear intercept, reduction in terminal airway units, and decrease in lung septation and alveolar openings, as well as reduced somatic growth. Because cGMP regulates SMC phenotype, we also tested whether decreased sGC activity reduces lung myofibroblast differentiation. Cellular markers revealed that vascular SMC differentiation decreased, whereas myofibroblast activation increased in the hyperoxic sGC-α1 KO pup lung. These results indicate that lung development, particularly during hyperoxic injury, is impaired in mouse pups with diminished sGC activity. These studies support the investigation of sGC-targeting agents as therapies directed at improving development in the newborn lung exposed to injury.
一氧化氮（NO）通过尚未完全阐明的机制调节肺发育。NO 通过刺激可溶性鸟苷酸环化酶（sGC）产生 cGMP 并增加 cGMP 介导的信号转导，来控制肺血管平滑肌细胞（SMC）分化。为了研究 sGC 在调节肺发育中的作用，我们检测了 sGC 活性降低是否会减少正常和受伤新生肺的肺泡化。为此，我们使用了基因靶向 sGC-α1 亚单位截断的小鼠幼仔，因为我们确定它们的肺 sGC 酶活性降低。与野生型（WT）小鼠相比，sGC-α1 敲除（KO）小鼠幼仔的小气道结构数量和肺容量减少，尽管肺分隔和体重没有差异。然而，在经历 70%O2 呼吸引起的轻度肺损伤后，sGC-α1 KO 小鼠幼仔的肺泡化明显受到抑制，这表现在气道平均线性截距增加、终末气道单位减少以及肺分隔和肺泡开口减少，同时躯体生长也受到抑制。由于 cGMP 调节 SMC 表型，我们还检测了 sGC 活性降低是否会减少肺肌成纤维细胞分化。细胞标志物显示，在高氧 sGC-α1 KO 幼鼠肺中，血管 SMC 分化减少，而肌成纤维细胞激活增加。这些结果表明，在 sGC 活性降低的小鼠幼仔中，肺发育，特别是在高氧损伤期间，受损。这些研究支持针对 sGC 靶向药物的研究，作为针对暴露于损伤的新生肺发育的治疗方法。
