bcl3基因可保护肺部免受损伤
文章来源:未知 文章作者:enread 发布时间:2011-02-09 01:35 字体: [ ]  进入论坛
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Lung injury is a common cause of death among patients with pneumonia1, sepsis(败血症) or trauma2 and in those who have had lung transplants. The damage often occurs suddenly and can cause life-threatening breathing problems and rapid lung failure. There are no effective treatments. Patients usually are put on ventilators(通风设备) to give their lungs a chance to heal, but there is little else doctors can do but wait and hope for the best.

Now, researchers at Washington University School of Medicine in St. Louis report they have identified a gene3 that limits damage to the lung during acute stress from illness, trauma or transplant. Defects in the bcl3 gene likely leave some patients more vulnerable to lung injury, they say.

The scientists also have demonstrated that this critical gene, which is active in bone marrow4 cells, can prevent lung injury in mice. The research is published in the Journal of Clinical Investigation5.

The new discovery lays the groundwork for developing therapies to reduce complications of pneumonia, trauma and lung transplants, which affect many thousands of people annually6 in the United States.

"Acute lung injury is a very serious problem," says senior author Andrew Gelman, PhD, assistant professor of surgery and of pathology(病理学) and immunology(免疫学) . "Patients' lungs fill with fluid, they can't breathe, and sadly there are no drugs available to reverse the condition."

The real culprits underlying7 acute lung injury are infection-fighting white blood cells called neutrophils(中性粒细胞) . When the body makes too many neutrophils, however, they begin to attack healthy tissue, causing even more damage and sometimes even death.

"In mice, we found that the bcl3 gene essentially8 controls how many neutrophils the body produces under acute stress in the lung," Gelman says.

The same gene exists in people. Mutations in bcl3 have long been associated with the development of leukemia(白血病) and lymphoma(淋巴瘤) . Only recently has it been found to play a role in inflammation.

The research team stumbled onto bcl3 as part of an effort to determine why a newly transplanted lung often becomes injured in the hours after surgery. The damage occurs as the blood begins to flow through the organ again and increases the risk of rejection9. In earlier studies, they had found that soon after a lung transplant, the new lung signals to the bone marrow to produce massive amounts of neutrophils.

"We wanted to understand how the lung is talking to the bone marrow and what is driving this extraordinary increase in neutrophils," Gelman says. "The lung tends to be unique in this manner; we don't see this with other organ transplants, such as the heart."

In a series of experiments in mice undergoing lung transplants, the researchers found that in response to acute stress in the lung, a cytokine called granulocyte colony stimulating10 factor (G-CSF) accumulates in the blood, which in turn stimulates12 the production of neutrophils in the bone marrow.

But there's a counterbalance(平衡力,自动抵消) built into the system. When G-CSF builds up in the blood, the bcl3 gene is activated13 in the bone marrow to begin shutting down neutrophil production.

When the scientists transplanted healthy mouse lungs into mice that lacked bcl3 in their bone marrow, things went haywire(发疯,限于混乱) . Without the gene, neutrophil production went unchecked, and the mice developed acute lung injury.

The investigators14 measured four times as many neutrophils in the blood of mice that lacked bcl3 compared with normal mice. The bcl3 gene, they showed, acts like a master switch to control the effects of G-CSF on neutrophil production.

While neutrophils are the key offenders15 of acute lung injury, completely blocking them from entering the lung is not a practical treatment.

"You need enough neutrophils in the lung to fight infection or repair lung damage but when there are too many, they cause irreversible injury," Gelman says. "It's a delicate balancing act."

Instead, the investigators showed they could prevent post-transplant lung injury by blocking G-CSF in mice that lacked blc3 in their bone marrow.

"This reduced the number of neutrophils that entered the lung," Gelman explains. "Other inflammatory cytokines, including GM-CSF and IL-3, still produced neutrophils but not enough to cause acute lung injury."

The researchers also showed they could prevent acute lung injury in a mouse model of sepsis by blocking G-CSF in mice that lacked bcl3.

Interestingly, G-CSF is routinely given to cancer patients undergoing chemotherapy to help them fight infections.

"There's been a lot of effort to stimulate11 neutrophil production in cancer patients because chemotherapy kills cancer cells and prevents the production of white blood cells, including neutrophils," Gelman says. "But what we're saying is that under acute stress to the lung, the effect of G-CSF on neutrophil production needs to be limited but certainly not eliminated."

In follow-up studies, Gelman and his colleagues want to get a better handle on how mutations in the bcl3 gene affect a person's susceptibility to acute lung injury from an infection or a transplant, he says.



点击收听单词发音收听单词发音  

1 pneumonia s2HzQ     
n.肺炎
参考例句:
  • Cage was struck with pneumonia in her youth.凯奇年轻时得过肺炎。
  • Pneumonia carried him off last week.肺炎上星期夺去了他的生命。
2 trauma TJIzJ     
n.外伤,精神创伤
参考例句:
  • Counselling is helping him work through this trauma.心理辅导正帮助他面对痛苦。
  • The phobia may have its root in a childhood trauma.恐惧症可能源于童年时期的创伤。
3 gene WgKxx     
n.遗传因子,基因
参考例句:
  • A single gene may have many effects.单一基因可能具有很多种效应。
  • The targeting of gene therapy has been paid close attention.其中基因治疗的靶向性是值得密切关注的问题之一。
4 marrow M2myE     
n.骨髓;精华;活力
参考例句:
  • It was so cold that he felt frozen to the marrow. 天气太冷了,他感到寒冷刺骨。
  • He was tired to the marrow of his bones.他真是累得筋疲力尽了。
5 investigation MRKzq     
n.调查,调查研究
参考例句:
  • In an investigation,a new fact became known, which told against him.在调查中新发现了一件对他不利的事实。
  • He drew the conclusion by building on his own investigation.他根据自己的调查研究作出结论。
6 annually VzYzNO     
adv.一年一次,每年
参考例句:
  • Many migratory birds visit this lake annually.许多候鸟每年到这个湖上作短期逗留。
  • They celebrate their wedding anniversary annually.他们每年庆祝一番结婚纪念日。
7 underlying 5fyz8c     
adj.在下面的,含蓄的,潜在的
参考例句:
  • The underlying theme of the novel is very serious.小说隐含的主题是十分严肃的。
  • This word has its underlying meaning.这个单词有它潜在的含义。
8 essentially nntxw     
adv.本质上,实质上,基本上
参考例句:
  • Really great men are essentially modest.真正的伟人大都很谦虚。
  • She is an essentially selfish person.她本质上是个自私自利的人。
9 rejection FVpxp     
n.拒绝,被拒,抛弃,被弃
参考例句:
  • He decided not to approach her for fear of rejection.他因怕遭拒绝决定不再去找她。
  • The rejection plunged her into the dark depths of despair.遭到拒绝使她陷入了绝望的深渊。
10 stimulating ShBz7A     
adj.有启发性的,能激发人思考的
参考例句:
  • shower gel containing plant extracts that have a stimulating effect on the skin 含有对皮肤有益的植物精华的沐浴凝胶
  • This is a drug for stimulating nerves. 这是一种兴奋剂。
11 stimulate wuSwL     
vt.刺激,使兴奋;激励,使…振奋
参考例句:
  • Your encouragement will stimulate me to further efforts.你的鼓励会激发我进一步努力。
  • Success will stimulate the people for fresh efforts.成功能鼓舞人们去作新的努力。
12 stimulates 7384b1562fa5973e17b0984305c09f3e     
v.刺激( stimulate的第三人称单数 );激励;使兴奋;起兴奋作用,起刺激作用,起促进作用
参考例句:
  • Exercise stimulates the body. 运动促进身体健康。 来自《简明英汉词典》
  • Alcohol stimulates the action of the heart. 酒刺激心脏的活动。 来自《现代英汉综合大词典》
13 activated c3905c37f4127686d512a7665206852e     
adj. 激活的 动词activate的过去式和过去分词
参考例句:
  • The canister is filled with activated charcoal.蒸气回收罐中充满了活性炭。
14 investigators e970f9140785518a87fc81641b7c89f7     
n.调查者,审查者( investigator的名词复数 )
参考例句:
  • This memo could be the smoking gun that investigators have been looking for. 这份备忘录可能是调查人员一直在寻找的证据。
  • The team consisted of six investigators and two secretaries. 这个团队由六个调查人员和两个秘书组成。 来自《简明英汉词典》
15 offenders dee5aee0bcfb96f370137cdbb4b5cc8d     
n.冒犯者( offender的名词复数 );犯规者;罪犯;妨害…的人(或事物)
参考例句:
  • Long prison sentences can be a very effective deterrent for offenders. 判处长期徒刑可对违法者起到强有力的威慑作用。
  • Purposeful work is an important part of the regime for young offenders. 使从事有意义的劳动是管理少年犯的重要方法。
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