MSGID: 1:317/3 6279ead6   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    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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