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美国学者发现一调节肺脏成熟的重要基因（SCIE
一下子从产道钻出，婴儿就必须要自己呼吸了。然而早在数周之前，一连串复杂的遗传信号就已经在为其吞第一口气做好了准备，使其发出清亮的第一声哭喊。现在，科学家们已经确认了启动整个相关细胞活动的“监工头”。
人类的胎儿在出生前的一个月就在为“外面的世界”做准备。准备工作的最后和最关键的步骤之一，就是胎肺开始制造表面活化蛋白，以降低肺内黏液层产生的表面张力，这对防止肺在充满空气时发生塌陷是非常必要的。最新的研究找到了一个叫做 Foxa2 的基因，就是它，启动了上述过程。
大约在十年之前，研究者们就怀疑可能是Foxa2 激活了表面活化基因，但是由于任何导致Foxa2 丧失功能的突变都会使动物在胚胎发育的早期就死亡，从而没有能在动物模型上试验成功。于是，俄亥俄洲辛辛那提儿童医疗中心的新生儿医师Jeffrey Whitsett 和他的同事们想到一个方法，在胎鼠的肺脏基本上完成发育但尚未完全成熟的时候，关闭小鼠Foxa2 基因的表达。这样的小鼠在出生后发生呼吸困难，并于12小时内死亡。尸体剖检发现小鼠肺未发育成熟，且缺乏表面活性物质。
他们这个团队接着检测了约22000个基因的表达，发现Foxa2 的表达可导致55个基因的表达或沉默，并在这个星期的Proceedings of the National Academy of Sciences（PNAS）上报道了他们的发现。这些表达的基因可产生降低表面张力的表面活性物质和脂肪酸，以及抗感染的复合物。“Foxa2 参与调节所有‘我就要出生了’的相关基因”，Whitsett 说。
“最终，这个发现会使早产儿的治疗更加有效，”三藩市加里佛尼亚大学的新生儿医师Samuel Hawgood 说。早产一个月以上的新生儿在出生以后如果没有给予足够的表面活化物质，他们就会在几小时内发生呼吸窘迫。如果Foxa2 在人类也起相同的效应，那么研究人员就可以知道是什么触发了开关，Hawgood 说：“那么，就有按照人们的意愿以药物途径激活它的可能。”Whitsett 同时也认为，这样的治疗对那些罹患肺部疾病，比如说肺炎的患者，也会很有帮助。
来源：
http://sciencenow.sciencemag.org/cgi/content/full/2004/929/4
原文：
The First Gasp
After popping through the birth canal and into the bright lights, babies must start breathing on their own. Before that first piercing scream, a complex genetic signaling has spent weeks getting ready for the first gulp of air. Now, scientists have finally identified the taskmaster that switches on the cellular players. Eventually, the results could help both premature babies and sick adults.
About a month before birth, the lungs of human babies prepare themselves for the outside world. In one of the final and most crucial steps of this preparation, the lungs begin making surfactant proteins that decrease the surface tension of the lungs' mucus lining, which is necessary to prevent the lungs from collapsing when filled with air. The new study finds that a gene called Foxa2 is the signal that sets this process in motion.
Researchers have suspected for about a decade that Foxa2 turns on surfactant genes, but they couldn't test this in animals because any mutations that knocked out Foxa2 killed the embryos too early in development. So neonatalogist Jeffrey Whitsett at Cincinnati Children's Hospital Medical Center, Ohio, and colleagues devised a way to turn the Foxa2 gene off in mouse lungs after the fetal mice had mostly developed but before their lungs fully matured. These newborn mice had trouble breathing after birth, and died within 12 hours. Autopsies revealed immature lungs and lack of surfactants.
The team then measured the expression of about 22,000 genes and found 55 genes that turned either on or off in Foxa2's presence, they report online this week in the Proceedings of the National Academy of Sciences. Turned on genes included those that produced the surfactants and fats that reduce surface tension, as well as infection fighting compounds. "Foxa2 turns out to regulate all the 'I'm going to be born' genes," says Whitsett.
"Ultimately, the finding could lead to more precise therapies for preterm babies," says neonatalogist Samuel Hawgood of the University of California, San Francisco. Babies born more than a month prematurely go into respiratory distress within a few hours after birth if they're not given artificial surfactants. If Fox2a has the same effect in humans and researchers can learn what flips the switch, Hawgood says, "then there may be possible pharmacological approaches to activating it at will." Such therapies could also help with diseases that affect the lungs, such as pneumonia, Whitsett adds.
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作者:admin@医学,生命科学 2010-12-23 17:11
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