Research Suggests New Mechanism at Play in Some Severe Asthma Cases

A newly published study offers a better understanding of the mechanisms at play in a subset of patients with severe asthma. Scientists hope the new insights will help direct the development of more tailored approaches to asthma therapy.

For the study, a team of investigators from several US academic research hospitals set out to better understand the pathogenesis of severe asthma, which does not respond to treatment with corticosteroids and which affects about 10% of the 24 million Americans with asthma.

Some of those patients with severe asthma have substantial neutrophilia, and the investigators hypothesized that the presence of neutrophilia is indicative of mechanisms distinct from other types of inflammation.

To test their hypothesis, the team mimicked allergic lung inflammation by exposing a mouse model to house dust mites and endotoxin. When exposed to both the allergen and endotoxin, the mice showed an increase in lung neutrophils and neutrophil extracellular traps (NETs). NETs help defend a host by immobilizing invading microorganisms; however, they can also cause inflammation and injure organs. NETs are activated and released through NETosis. During vital NETosis, neutrophils eject their nuclear material to form NETs, then re-seal themselves, forming cytoplasts.

The animal model findings suggest NETosis and cytoplasts play an important role in sparking and amplifying the allergen-initiated neutrophilic immune responses in lung inflammation. To confirm the insights, the investigators analyzed fluid samples from the lungs of human patients with severe asthma. Indeed, a group of those patients also had high neutrophil counts as well as NETs and cytoplasts.

Lead author Bruce Levy, MD, chief of the division of pulmonary and critical care medicine at Brigham and Women’s Hospital, told MD Magazine^® that the findings suggest potential therapeutic pathways for investigators working on asthma.

“There are many reasons why patients can develop an increased neutrophil count,” he said. “If a patient has severe asthma with an increased lung neutrophil count, our findings have uncovered a new immunological mechanism for this type of inflammation that we hope will inform new (yet-to-be-developed) treatment.”

The findings are important because current clinical trials for new moderate and severe asthma therapies don’t distinguish between patients with high neutrophil counts.

Levy said these findings might also pave the way for existing therapies to be used to treat asthma.

“Anti-inflammatory therapies that target IL-17 are clinically approved for treatment of psoriasis,” he said. “While this therapy is not likely to work for all patients with severe asthma, the results in this study help identify a subset of patients that could benefit from anti-IL-17 Ab therapy.”

More broadly, Levy noted that although a number of asthma treatments are on the market, there is still considerable work to be done in order to better target and eventually cure the disease.

“We need new therapies that promote resolution of asthma,” he explained. “Currently, there are no curative therapies available. This is a goal for ongoing research on severe asthma.”

The study, “Neutrophil cytoplasts induce TH17 differentiation and skew inflammation toward neutrophilia in severe asthma,” was published online in Science Immunology.