Study finds how persistent lung disease develops long after the virus has been cleared

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A new study has found why short-lived lung infections can cause long-lasting lung damage. The findings of the study were published within the 'Journal of Clinical Investigation'. The deadliest time during a viral respiratory disease sometimes is really after the virus is cleared from the body.

Destructive processes that are set in motion during an infection crest within the weeks after the virus is defeated, resulting in organ damage that will cause chronic illness or maybe death. After an initial bout of COVID-19, for instance,

some people struggle with a persistent cough, difficulty breathing, and shortness of breath -- signs of ongoing lung disease. Researchers at Washington University School of drugs in St. Louis have found clues to only how lung damage develops within the aftermath of a respiratory tract infection. Studying mice, they found that infection triggers the expression of a protein called IL-33, which is required for stem cells within the lung to overgrow into air spaces and increases mucus production and inflammation within the lung.

The findings revealed potential points of intervention to stop chronic lung damage caused by viral infections.

"Vaccines, antivirals, antibody therapies are all helpful, but they're not an answer for people that are already on the road to progressive disease," said senior author Michael J. Holtzman, MD, the Selma and Herman Seldin Professor of drugs and a professor of cell biology and physiology.

"We've gotten better at taking care of the acute illness thanks to COVID-19, but what happens then initial injury phase remains a serious obstacle to a far better outcome," continued Holtzman.

"At now, we also are faced with tens of many people that already had an infection, and a high percentage of them are having long-term disease, especially with respiratory symptoms. We do not have a treatment which will correct the matter," added Holtzman.

It's long been recognized that acute respiratory infections can cause chronic lung disease. Children hospitalized with the respiratory syncytial virus, for instance, are two to fourfold more likely to develop asthma that persists for long periods,

maybe even for a lifetime. How exactly an acute respiratory tract infection triggers the chronic disease, however, isn't fully understood, making it difficult to develop therapies to stop or treat it. As a part of this study, Holtzman and colleagues, including first author Kangyun Wu, Ph.D., a teacher in medicine, studied mice infected with the Sendai virus.

Sendai doesn't cause serious disease in people, but it naturally infects other animals including mice, and causes respiratory infections that develop very similar to respiratory infections in people.

The researchers examined lung tissues from mice 12 and 21 days after infection with the 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 therefore the outside world in uninfected mice. After infection with the 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. a number of the new basal cells become mucus-producing cells while others release molecules that recruit immune cells to the lungs.

Altogether, the method leads to 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 within the nuclei of lung stem cells in response to worry or injury and helps the lung repair damaged barriers.

During and after infection, though, IL-33 can combat 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 within the basal set of lung stem cells.

The scientists then infected those mice -- and a separate group of unmodified mice -- with the Sendai virus. The 2 groups of mice were equally effective at fighting off an initial Sendai viral 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 fewer airway hyperresponsiveness, both of which are signs of improvement in their chronic lung disease.

"These results were very nice to ascertain because getting obviate IL-33 and successively losing basal stem cells could have made things worse," said Holtzman.

"The engineered mice could have died because they were not ready to perform the traditional repair of the viral damage to the lung barrier. But that's not the case," explained Holtzman.

"The mice lacking this population of basal cells instead had far better outcomes. That is what we're excited about. These findings put us on firm ground to seek out therapies that correct the bad behavior of basal stem cells," added Holtzman. Targeting steps on the pathway between IL-33 and basal cell activation could form the idea of broadly effective therapies to stop or treat lung disease caused by a spread of viruses and maybe other sorts of injury within the lung and other sites where the body meets the surface world, Holtzman said.

"The lung features a pretty stereotyped response to injury, including viral injury," said Holtzman.

"The specific sort of virus, the genetics of the host, the severity of the initial illness -- all of those things influence the result, but they're just matters of degrees. You continue to see equivalent key elements across conditions, and that is why we believe that there is often a standard strategy for treatment," explained Holtzman.

"We have a drug discovery program to seek out such a standard strategy, and this study fits well thereupon," concluded Holtzman.

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