为什么短期的肺部感染会导致肺部损伤？

资讯来源：Washington University in St. Louis

编辑翻译：奇奇

本文献于2021年8月24日发表在美国著名医学期刊《临床调查杂志》上。文中圣路易斯华盛顿大学医学院的研究人员发现了呼吸道感染后导致肺部损伤的线索，这为预防病毒感染引起的慢性肺部损伤提供了新的潜在治疗方法。

病毒性呼吸道疾病中最致命的时间有时实际上是在病毒从体内清除之后。在病毒被击败后的几周内，感染高峰期间出现的破坏性过程会导致器官损伤，从而导致慢性疾病甚至死亡。例如，在初次感染 COVID-19 后，有些人会持续咳嗽、呼吸困难和呼吸短促，这症状都是持续性肺部疾病的迹象。

圣路易斯华盛顿大学医学院的研究人员发现了呼吸道感染后肺部损伤如何发展的线索。在对小鼠的研究中，他们发现感染会触发一种名为IL-33的蛋白质的表达，这种蛋白质是肺部干细胞过度生长进入气室所必需的，并增加了肺部的粘液分泌和炎症。这项研究结果发表在8月24日的《临床研究杂志》(Journal of Clinical Investigation)上，揭示了预防病毒感染引起的慢性肺损伤的潜在干预点。

研究人员说：“疫苗、抗病毒药物、抗体疗法都是有帮助的，但它们对那些已经处于病情进展阶段的人来说并不是一个解决方案。我们已经在治疗因COVID-19引起的急性疾病方面做得更好，但最初损伤阶段之后发生的事情仍然是取得更好结果的主要障碍。在这一点上，我们还面临着数千万已经受到感染的人，其中很大一部分人患有长期疾病，特别是呼吸道症状的人。目前我们还没有一种治疗方法可以解决这个问题。”

人们早就认识到，急性呼吸道感染会导致慢性肺病。例如，因呼吸道合胞病毒住院的儿童患上哮喘的可能性是普通儿童的两到四倍，而且哮喘会持续很长一段时间，甚至可能持续终生。然而，急性呼吸道感染究竟是如何引发慢性疾病的，现在还尚不完全清楚，因此很难开发出预防或治疗它的疗法。

作为这项研究的一部分，Holtzman和他的同事，包括第一作者、医学讲师Kangyun Wu博士，研究了感染仙台病毒的小鼠。仙台病毒不会对人类造成严重疾病，但它会自然感染包括老鼠在内的其他动物，并导致呼吸道感染，而其发展与人类呼吸道感染非常相似。

研究人员检查了感染仙台病毒12天和21天的小鼠的肺组织，并将样本与未感染小鼠的肺组织进行了比较。他们发现，在未感染的小鼠体内，有两种干细胞有助于维持肺部与外界之间的屏障。然而，在感染仙台病毒后，这两个种群分别开始繁殖并扩散到肺部气室。基底细胞占据小气道和气囊，而AT2细胞仍局限于气囊。一些新的基底细胞成为产生粘液的细胞，而另一些则释放分子，引导免疫细胞到肺部。总的来说，这一过程导致肺部的气室减少，粘液增多，炎症持续存在，这些都会干扰呼吸。

进一步的实验表明，这一过程取决于蛋白质IL-33。在正常情况下，IL-33在肺干细胞核中增加，以应对压力或损伤，并帮助肺修复受损屏障。然而，在感染期间和感染后，IL-33可能扮演有害的角色。

为了评估IL-33在病毒后肺损伤中的作用，研究人员对小鼠进行基因改造，使其在肺干细胞的基础中缺乏IL-33。然后，科学家们用仙台病毒感染了这些小鼠，以及另一组未基因改造的小鼠。这两组小鼠在抵御最初的仙台病毒感染方面同样有效。但在感染三周后，缺乏IL-33的小鼠的肺部细胞过度生长、黏液和炎症更少，这表明它们肺部的有害变化的迹象较少。在感染7周后，基底细胞中没有IL-33的小鼠血液中的氧含量也更高，气道高反应性较低，这两种情况都是慢性肺病改善的迹象。

Holtzman教授说:“这些结果非常令人高兴，因为去除IL-33，失去基底干细胞，可能会使情况变得更糟。这些基因改造的小鼠可能已经死亡，因为它们不再能够对肺屏障的病毒损伤进行正常修复。但事实并非如此。缺乏这种基底细胞的小鼠反而有更好的结果。这就是我们很兴奋的地方。这些发现为我们找到纠正基底干细胞不良行为的疗法奠定了坚实的基础。”

Holtzman说，在 IL-33 和基底细胞活化之间的通路上靶向步骤可以形成广泛有效疗法的基础，以预防或治疗由各种病毒引起的肺部疾病，以及肺部和身体接触的其他部位的其他形式的损伤。

Holtzman说：“肺对损伤（包括病毒损伤）有一种相当固定的反应。病毒的特定类型、宿主的基因、最初疾病的严重程度——所有这些因素都会影响结果，但只是程度的问题。你仍然可以在不同的情况下看到相同的关键因素，这就是为什么我们相信可以有一个共同的治疗策略。我们有一个药物开发项目来寻找这样一种共同的策略，而这项研究正好符合这一点。”

英文原文

Why do Short-lived Lung Infections Lead to Long-lasting Lung Damage

The deadliest time in a viral respiratory illness sometimes is actually after the virus is cleared from the body. Destructive processes that are set in motion during an infection crest in the weeks after the virus is defeated, leading to organ damage that can cause chronic illness or even death. After an initial bout of COVID-19, for example, some people struggle with persistent cough, difficulty breathing and shortness of breath—signs of ongoing lung disease.

Researchers at Washington University Schoolof Medicine in St. Louis have found clues to just how lung damage develops in the aftermath of a respiratory infection. Studying mice, they found that infection triggers the expression of a protein called IL-33, which is needed for stem cells in the lung to overgrow into air spaces, and increases mucus production and inflammation in the lung. The findings, published Aug. 24 in the Journal of Clinical Investigation, reveal potential points of intervention to prevent chronic lung damage caused by viral infections.

“Vaccines, antivirals, antibody therapies are all helpful, but they are not a solution for people who are already on the road to progressive disease,” said researchers. “We've gotten better at taking care of the acute illness due to COVID-19, but what happens after that initial injury phase is still a major obstacle to a better outcome. At this point, we are also faced with tens of millions of people who already had infection, and a high percentage of them are having long-term disease, especially with respiratory symptoms. We don't have a treatment that can correct the problem.”

It's long been recognized that acute respiratory infections can lead to chronic lung disease. Children hospitalized with respiratory syncytial virus, for example, are two to four times more likely to develop asthma that persists for long periods, maybe even for a lifetime. How exactly an acute respiratory infection triggers chronic disease, however, is not fully understood, making it difficult to develop therapies to prevent ortreat it.

As part of this study, Holtzman and colleagues, including first author Kangyun Wu, Ph.D., an instructor in medicine, studied mice infected with Sendai virus. Sendai doesn't cause serious disease in people, but it naturally infects other animals including mice and causes respiratory infections that develop much like respiratory infections in people.

The researchers examined lung tissues from mice 12 and 21 days after infection with Sendai virus, and compared the samples to lung tissues of uninfected mice. They found that two populations of stem cells help maintain the barrier between the lung and the outside world in uninfected mice. After infection with Sendai virus, however, these two populations separately begin to multiply and spread into air spaces. Basal cells take over small airways and air sacs while AT2 cells remain confined to air sacs. Some of the new basal cells become mucus-producing cells while others release molecules that recruit immune cells to the lungs. Altogether, the process results in lungs with less air space, more mucus and ongoing inflammation that together interfere with breathing.

Further experiments showed that this process hinges on the protein IL-33. Under normal conditions, IL-33 increases in the nuclei of lung stem cells in response to stress or injury and helps the lung repair damaged barriers. During and after infection, though, IL-33 can take on a more detrimental role.

To assess the role of IL-33 in post-viral lung damage, the researchers genetically modified mice to lack IL-33 in the basal set of lung stem cells. The scientists then infected those mice—and a separate group of unmodified mice—with Sendai virus. The two groups of mice were equally effective at fighting off an initial Sendai virus infection. But three weeks after infection, the lungs of the mice that lacked IL-33 exhibited less cellular overgrowth, mucus and inflammation, indicating that they had fewer signs of harmful lung changes. At seven weeks after infection, the mice without IL-33 in basal cells also had higher oxygen levels in their blood and less airway hyperresponsiveness, both of which are signs of improvement in their chronic lung disease.

“These results were really nice to see because getting rid of IL-33 and in turn losing basal stem cells could have made things worse,” Holtzman said. “The engineered mice could have died because they were no longer able to perform the normal repair of the viral damage to the lung barrier. But that's not the case. The mice lacking this population of basal cells instead had much better outcomes. That's what we'reexcited about. These findings put us on firm ground to find therapies that correct the bad behavior of basal stem cells.”

Targeting steps on the pathway between IL-33 and basal cell activation could form the basis of broadly effective therapies to prevent or treat lung disease caused by a variety of viruses and perhaps other forms of injury in the lung and other sites where the body meets the outside world, Holtzman said.

“The lung has a pretty stereotyped response to injury, including viral injury,” Holtzman said. “The specific type of virus, the genetics of the host, the severity of the initial illness—all of these things influence the outcome, but they're just matters of degrees. You still see the same key elements across conditions, and that's why we believe that there can be a common strategy for treatment. We have a drug discovery program to find such a common strategy, and this study fits well with that.”

参考文献 

Kangyun Wu et al, Basal-epithelial stem cells cross an alarmin checkpoint for post-viral lung disease, Journal of Clinical Investigation(2021).

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