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Modeling the cellular and molecular mechanisms regulating ryegrass-induced asthma exacerbation

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posted on 2025-05-11, 19:59 authored by Panisara Meechan
Acute severe asthma exacerbations account for most the life-threatening events of this disorder and are the major healthcare cost related to disease burden. Thunderstorm asthma is an event that triggers a severe acute exacerbation of asthma and is mostly associated with exposure to allergens from Perennial ryegrass (Lolium perenne). The incidence of thunderstorm asthma is worldwide, and episodes are so rapid and severe. They have the potential to overwhelm the healthcare system. Current therapies (e.g., new type 2 biologics) for asthma indicates that individuals with different phenotypes may require specific treatments. The mainstay therapies (steroids and bronchodilators) and biological treatments for asthma may not always be effective in treating all exacerbations due to the type of trigger and subsequent nature of the exaggerated inflammatory response driving the exacerbation. In this study I have developed a mouse model of an acute ryegrass induced exacerbation of asthma to better understand the pathophysiological mechanisms underlying the thunderstorm asthma to evaluate current/potential novel therapies. We intraperitoneally sensitized and intranasally challenged the BALB/c mice with ryegrass, followed by an intratracheal provocation with ryegrass or PBS. The exacerbation model mimics clinical observations in thunderstorm patients in which only sensitized subjects are affected and the peak response occurs immediately after the allergen exposure. We showed that ryegrass exposure to the lower respiratory tract augmented the release of epithelial-derived IL-33, production of type 2 cytokines (IL-4, IL-5, and IL-13) and inflammatory cell infiltration characterized by pronounced eosinophilia, and induction of AHR and mucus hypersecretion. We observed both IL-13+ ILC2 and IL-13+ Th2, the key players in type 2 inflammation, in the exacerbation cellular infiltrates. ILC2 depletion using ICOS-T mice/diphtheria toxin and CD4+ T cells depletion using anti-CD4 antibody revealed that Th2 but not ILC2 were critical for type 2 inflammation and pathophysiological features of disease. Targeting the upstream (initiator) of the type 2 pathway by using anti-IL-33 monoclonal antibody (mAb) attenuated disease reducing AHR, numbers of BALF eosinophils/total inflammatory cells, gene expression of IL-33, IL-4, IL13, CCL24, CCL7, Arg1, IL-6, TNF-α, and the number of mucus-producing cells. Anti-IL-13 mAb also reduced AHR, BALF eosinophils/total inflammatory cells and mucus-producing cells. A steroid medication, dexamethasone (DEX) reduced AHR, numbers of BALF eosinophil and mucus-producing cells, however, type 2/inflammatory gene expression (e.g., IL-13 and IL-6) was not suppressed. We found that IL-13+ eosinophils numbers could be suppressed by DEX, by contrast IL-13+ Th2 levels might be partially responsive to DEX, while the levels of IL-13+ ILC2 were steroid-resistant. Vitamin D deficiency has been associated with asthma and the prevalence of vitamin D deficiency was observed during the thunderstorm asthma seasons. We fed mice a vitamin D deficient diet before the allergen treatment to investigate the link between vitamin D deficiency and rye-induced features of thunderstorm asthma. We found that vitamin D deficiency alone could induce type 2-skewed immune response. Moreover, vitamin D deficiency during ryegrass-induced asthma exacerbation accentuated IL-33-induced type 2 airway inflammation and pathophysiological features of disease.

History

Year awarded

2023.0

Thesis category

  • Doctoral Degree

Degree

Doctor of Philosophy (PhD)

Supervisors

Tay, Hock; Foster, Paul (University of Newcastle)

Language

  • en, English

College/Research Centre

College of Health, Medicine and Wellbeing

School

School of Biomedical Sciences and Pharmacy

Rights statement

Copyright 2022 Panisara Meechan

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