Stopping lung damage before it turns deadly
Scientists discover new drug target for severe asthma, fibrosis

Date:
May 9, 2022
Source:
La Jolla Institute for Immunology
Summary:
New research shows that hypoxia can activate the same group of
immune cells that cause inflammation during asthma attacks.



FULL STORY ==========================================================================
If you've ever struggled to breathe, you've had a moment of hypoxia --
a lack of oxygen. Hypoxia can have long-term effects. In fact, doctors
describe hypoxia as an "initial insult."

========================================================================== Experiencing hypoxia is a known trigger for developing and worsening lung conditions such as severe asthma, chronic obstructive pulmonary disease
(COPD), and fibrosis. To treat and prevent these diseases, researchers
need to understand why a lack of oxygen would affect the immune system.

New research from scientists at La Jolla Institute for Immunology (LJI),
shows that hypoxia can activate the same group of immune cells that cause inflammation during asthma attacks. As a person with gasps for breath,
these cells flood the airways with molecules that damage the lungs.

"We show how lack of oxygen can be part of a feedback loop that can
contribute to even worse inflammation," says LJI Professor and Chief
Scientific Officer Mitchell Kronenberg, Ph.D., a member of the LJI Center
for Autoimmunity and Inflammation. "This work gives us insight into
the causes of fibrosis of the lung and severe asthma." Kronenberg and
his colleagues worked with a genetically altered mouse model to mimic
the signals of hypoxia in the airway's epithelial cells, which line the
paths to the lungs. They discovered that combining the hypoxia signals
with inflammatory signals stimulated the "innate," or rapidly responding immunity, and an immune cell type called an ILC2.

An ILC2's job is to make signaling molecules (called cytokines) that
quickly alert other immune cells to react to a pathogen. Unfortunately,
ILC2s sometimes over-react and respond to harmless environmental
allergens. In these cases, ILC2s churn out cytokines that drive mucus production and inflammation in the lungs. All this swelling and mucus
leads to hypoxia.



==========================================================================
As they report in Journal of Experimental Medicine, ILC2s respond to
hypoxia as well, adding to the lung damage already caused during an
asthma attack.

"That hypoxia may then contribute further to inflammation," says
Kronenberg.

The next step was to figure out exactly how epithelial cells activate
ILC2 during hypoxia. LJI Postdoctoral Fellow Jihye Han, Ph.D., led the
work to uncover an unexpected culprit: adrenomedullin (ADM). ADM is
known for its role in helping blood vessels dilate, but until now it
had no known role in immune function.

Kronenberg was surprised to see ADM involved -- but not shocked. "We're
finding that many molecules with no previously known role in the immune
system can also be important for immune function," says Kronenberg. "We
need to understand that more generally." The researchers showed that
human lung epithelial cells exposed to hypoxia also produced ADM. This
means ADM or its receptor could be targets for treating inflammatory
and allergic lung diseases.

The challenge is to find a balance between dampening the harmful immune response without leaving the body vulnerable to infections. Kronenberg
points out that the epithelial cell-ADM-ILC2 connection protected mice
from hookworm infections, which damage the lungs and gut.

"ADM is a new target for lung diseases and has been implicated in
bacterial pneumonia as well," says Kronenberg. "But blocking it would
have to be done carefully." Additional authors of the study, "Hypoxia 1 Induces Adrenomedullin from Lung Epithelia Stimulating ILC2 Inflammation
and Immunity," include first author Jihye Han, Qingqing Wan, Goo-Young
Seo, Kenneth Kim, Sarah el Baghdady, Jee H Lee, and Yun-Cai Liu.

This research was supported by the National Institutes of Health (grants R01AI123398 and U01 AI125955).


========================================================================== Story Source: Materials provided by
La_Jolla_Institute_for_Immunology. Original written by Madeline McCurry-Schmidt. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Jihye Han, Qingqing Wan, Goo-Young Seo, Kenneth Kim, Sarah el
Baghdady,
Jee H. Lee, Mitchell Kronenberg, Yun-Cai Liu. Hypoxia induces
adrenomedullin from lung epithelia, stimulating ILC2 inflammation
and immunity. Journal of Experimental Medicine, 2022; 219 (6) DOI:
10.1084/ jem.20211985 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/05/220509162810.htm

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