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[前沿] 过氧化氢有集结白血球功效

[前沿] 过氧化氢有集结白血球功效

前沿

原创与否 -
When you were a kid your mom poured it on your scraped finger to stave off infection. When you got older you might have even used it to bleach your hair. Now there's another possible function for this over-the-counter colorless liquid: your body might be using hydrogen peroxide as an envoy that marshals troops of healing cells to wounded tissue.

Using the zebrafish as an animal model, researchers in the lab of Harvard Medical School professor of systems biology Timothy Mitchison and Dana Farber Cancer Institute professor Thomas Look have discovered that when the tail fins of these creatures are injured, a burst of hydrogen peroxide is released from the wound and into the surrounding tissue. Teams of rescue-working white blood cells respond to this chemical herald, crawl to the site of damage, and get to work.

"We've known for quite some time that when the body is wounded, white blood cells show up, and it's really a spectacular piece of biology because these cells detect the wound at some distance," says Mitchison. "But we haven't known what they're responding to. We do know something about what summons white blood cells to areas that are chronically inflamed, but in the case of an isolated physical wound, we haven't really known what the signal is."

These findings are reported in the June 4 issue of the journal Nature.

Philipp Niethammer, a postdoc in Mitchison's lab, and Clemmens Grabber, a postdoc in Look's lab, initiated this research project with no interest in wound healing. Rather, they were studying a groups of molecules called reactive oxygen species, or ROS. These small oxygen-derived molecules, of which hydrogen peroxide is one, have the potential to be both helpful and hurtful. Niethammer and Grabber were simply curious to find ways to detect ROS molecules in an organism.

To do this, they took a gene engineered to change color in the presence of hydrogen peroxide and inserted it into zebrafish embryos. Once the embryos entered the larvae stage after a few days, this synthetic gene spread throughout the entire body, essentially "wiring" the fish so that any discreet location in which hydrogen peroxide appears would glow.

But how do you coax the fish to produce a reactive chemical like hydrogen peroxide in the first place?

Since white blood cells have long been known to produce hydrogen peroxide, one obvious way to initiate chemical production would be to inflict a small wound onto the fish, and then, using microscopy, observe patterns of this chemical as white blood cells gathered around the wound. But much to the researchers surprise, they found that hydrogen peroxide immediately appeared at the wound site, prior to the arrival of any white blood cell, and quickly disseminated into neighboring tissue.

They repeated the experiment, this time in zebrafish where they'd disabled a protein that was previously discovered to produce hydrogen peroxide in the human thyroid gland. Not only did hydrogen peroxide not appear at the wound site, but white blood cells failed to respond to the injury.

"This was our real eureka! moment," says Niethammer. "We weren't too surprised that we could block hydrogen peroxide production through this technique, but what we didn't expect at all was that white blood cells wouldn't respond. This proved that the white blood cells needed hydrogen peroxide to sense the wound, and move towards it."

Of course, zebrafish are not people, and while our genomes share many similarities with these tiny fish, it isn't yet clear that natural selection has conserved this process throughout the evolutionary family tree. Still, these findings offer something of a conceptual shift in how to view human conditions where hydrogen peroxide plays a role.

"When we look at how hydrogen peroxide works in people, this really starts getting intriguing," says Mitchison.

In the human body, hydrogen peroxide is produced primarily in three places: lung, gut, and thyroid gland. Because hydrogen peroxide, and the proteins responsible for producing other ROS molecules, are especially present in lung and gut, the researchers hypothesize that human diseases relevant to these findings would include any in the lung and gut that involve disproportionate levels of white blood cells, like asthma, chronic pulmonary obstruction, and some inflammatory gut diseases.

"Our lungs are supposed to be sterile; our guts are anything but," says Mitchison. "It's very logical that both those tissues produce hydrogen peroxide all the time. Perhaps in conditions like asthma, the lung epithelia is producing too much hydrogen peroxide because it's chronically irritated, which, if our findings translate to humans, would explain inappropriate levels of white blood cells. This is certainly a question worth pursuing."

Mitchison is currently laying the groundwork for investigating this hypothesis.

This research was funded by the National Institutes of Health.

http://www.scien5.com/?action-viewnews-itemid-419


当你是孩子的时候,妈妈把它倒在你擦伤的手指上来避免感染。当你老了,你可能用它来漂白头发。现在这种在商店就能买到的无色液体有了另一种可能的功能:你的身体可能使用过氧化氢来为受伤的组织召集大量的有愈合作用的细胞。
  利用斑马鱼作为动物模型,哈佛医学院的研究员生物系统学教授Timothy Mitchison和Dana Farber癌症研究所的Thomas Look教授发现,当这些生物的尾鳍受伤时,大量的过氧化氢被从伤口释放出来,进入了周围的组织。成队的起补救作用的白细胞对此做出反应,集结到受损部位发生作用。
  Mitchison说:"我们很久就已经知道当身体受伤后,白细胞就会出现,这是一种很特殊的生物学行为,因为这些细胞很远就能探测到伤口。但是我们不知道他们是根据什么做出反应的。我们知道一些事情关于什么把白细胞召集到慢性炎症部位,但是对于一个单独的机械伤害,我们还不知道这个信号是什么。"
  4月4 日的那期《自然》杂志报道了这些发现。
  Mitchison实验室的博士后Philipp Niethammer和Look实验室的博士后Clemmens Grabber发起了这项与伤口愈合无关的研究计划。他们而是研究了一群被称为氧活性粒子的分子,即ros。这些小的氧活性粒子,过氧化氢是其中的一个,同时有帮助和伤害的能力。Niethammer 和 Grabber 仅仅对寻找检测机体中的ros分子的方式感兴趣。
  为了实现这个目的,他们是使用了一种基因。这种基因被设计成遇到过氧化氢时会变色。他们把这种基因插入到斑马鱼的胚胎里。数天后当胚胎发育成幼鱼后,这种人工合成的基因会扩散到整个鱼体。鱼就像被完整的布上了线,很小的过氧化氢出现的地方颜色就会出现。
  但是首先你如何让鱼产生一种类似过氧化氢的活性化学物质呢?
  既然很久之前就知道白细胞产生过氧化氢,一种显而易见的产生化学物质的方式就是给鱼一些小伤口,然后,利用显微镜,观察当白细胞聚集到伤口时这种物质的表现。但是让研究者惊讶的是,他们发现在受伤的地方过氧化氢立刻表现了出来,这要比白细胞的到来要早,然后过氧化氢就弥散到周围组织中。
  他们报道了这个实验,在这次的斑马鱼中,他们让一种先前被发现在人类甲状腺肿产生过氧化氢的蛋白质失去功能。不仅过氧化氢没有出现在受伤的部位,而且白细胞也没有能够对伤害产生反应。
  Niethammer说:“这是我们真正的瞬间发现。我们对于通过这种方式能阻断过氧化氢不是很惊奇,但是我们完全没有料到白细胞也不再反应。这证明白细胞需要过氧化氢来辨别伤口和移向伤口。
  当然,斑马鱼不是人,尽管人类的基因组与这种小鱼的基因组有很多相似之处,然而自然选择是否通过进化保留了这个过程仍然不清楚。对于如何看待过氧化氢在人体中的角色,这些发现仍然提供了概念上的转变。
  Mitchison说“当我们看待过氧化氢在人体中的作用时,这确实是令人感兴趣的。”
  在人体中,过氧化氢主要在三个地方产生:肺,肠和甲状腺。因为过氧化氢和能产生其他ros分子的蛋白质,在肺和肠道中较多,研究者猜测那些在肺和肠道中的疾病与这些发现相关,这些疾病包括白细胞水平异常的疾病,像哮喘,慢性阻塞性肺病和一些肠道炎性疾病。
  Mitchison目前为探究这个假说做基础工作。
  这项研究由国家卫生研究院资助。


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