A deeper look at severe asthma yields NET results

Of the more than 24 million people in the U.S. who have asthma, 10 percent have severe asthma—a form of the disease that does not respond to treatment. The immunological mechanisms underlying severe asthma and asthmatic lung inflammation are not well understood. A new study by investigators from Brigham and Women’s Hospital published this week in Science Immunology models allergic lung inflammation and provides new insights into how asthma develops and progresses, with important implications for the most clinically advanced drugs designed to treat severe asthma.

To model allergic lung inflammation in a dirty indoor environment, the team exposed a mouse model to a common environmental indoor allergen—house dust mite—as well as to endotoxin, a toxin released by bacterial cells. Exposure to both stimuli triggered complex lung inflammation, including a phenomenon known as  NETosis.

In response to inflammatory triggers, white blood cells known as neutrophils form “neutrophil extracellular traps” (NETs). NETosis is the process by which NETs get activated and released. NETs can play a significant role in helping defend a host from invaders, but they can also cause organ injury and inflammation. Vital NETosis is a process in which neutrophils extrude their nuclear material, including DNA, to form NETs and then reseal their membranes to create cytoplasts—cells that lack a nucleus. Levy and colleagues found that in their model, NETosis and cytoplasts appeared to play a key role in triggering and amplifying an allergen-initiated neutrophilic immune response in .

In addition to studying animals, the team also examined samples of fluid from the lungs of human severe asthma patients,

Obstruction of the lumen of a bronchiole by mucoid exudate, goblet cell metaplasia, and epithelial basement membrane thickening in a person with asthma. Credit: Yale Rosen/Wikipedia/CC BY-SA 2.0

finding that a subset of patients had high neutrophil counts and detectable NETs and cytoplasts—important implications for how to design more precise clinical trials for severe asthma treatment.

Currently, clinical trials for new drugs to treat moderate and  do not stratify patients by neutrophil count or other important markers of . The team notes that markers of NETosis—including NETs and cytoplasts in sputum—may provide an opportunity to better tailor trials and treatments in subsets of asthma  for future clinical research.

 Explore further: A breath of fresh air for severe asthma research

More information: N. Krishnamoorthy el al., “Neutrophil cytoplasts induce Th17 differentiation and skew inflammation toward neutrophilia in severe asthma,” Science Immunology (2018). immunology.sciencemag.org/look … 6/sciimmunol.aao4747

By |2018-08-11T14:11:21+00:00August 11th, 2018|

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