Why do short-lived lung infections lead to long-lasting lung damage?
Study points to mechanism of post-viral lung damage; suggests targets of intervention

Date:
August 25, 2021
Source:
Washington University School of Medicine
Summary:
Researchers have found that two populations of stem cells in the
lung multiply during and after a viral respiratory infection,
sometimes triggering a detrimental remodeling process that can
cause persistent lung disease long after the virus has been cleared.



FULL STORY ==========================================================================
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 School of 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 theJournal 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 senior author Michael J. Holtzman, MD, the Selma and
Herman Seldin Professor of Medicine and a professor of cell biology & physiology. "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 or treat it.

As part of this study, Holtzman and colleagues, including first author
Kangyun Wu, PhD, 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're excited 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." ========================================================================== Story Source: Materials provided by
Washington_University_School_of_Medicine. Original written by Tamara
Bhandari. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Kangyun Wu, Kenji Kamimoto, Yong Zhang, Kuangying Yang, Shamus
P. Keeler,
Benjamin J. Gerovac, Eugene V. Agapov, Stephen P. Austin, Jennifer
Yantis, Kelly A. Gissy, Derek E. Byers, Jennifer Alexander-Brett,
Christy M. Hoffmann, Matthew Wallace, Michael E. Hughes, Erika
C. Crouch, Samantha A. Morris, Michael J. Holtzman. Basal-epithelial
stem cells cross an alarmin checkpoint for post-viral lung
disease. Journal of Clinical Investigation, 2021; DOI:
10.1172/JCI149336 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210825101434.htm

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