Selective KIT-inhibition Supports Mast Cells as Key Drivers of Allergic Asthma Pathogenesis.

BACKGROUND

Asthma is a chronic respiratory disease characterized by airway inflammation, airway hyperresponsiveness (AHR) and airway remodeling. Mast cell numbers are increased in asthmatic airways and contribute to bronchoconstriction and inflammation; yet their role in asthma development remains elusive.

OBJECTIVE

To investigate mast cell contributions to allergic asthma by pharmacologically targeting KIT, a central regulator of mast cell survival and activation, using the selective inhibitor THB001.

METHODS

THB001 effects were assessed in human lung mast cells (HLMCs), isolated human bronchi, and guinea pig trachea. To probe mast cell contributions in vivo, guinea pigs were subjected to a house dust mite (HDM)-induced asthma model and treated with THB001. HDM-induced bronchoconstriction was recorded after each challenge. At the endpoint, airway responsiveness was evaluated, followed by bronchoalveolar lavage fluid and lung tissue collection for histological, biochemical and transcriptomic analyses.

RESULTS

THB001 suppressed KIT-dependent mast cell functions, inhibiting HLMCs degranulation and survival, and attenuating anti-IgE-induced bronchial contraction. In guinea pig tracheal segments, THB001 reduced HDM-induced responses, coinciding with a reduction in mast cells. In vivo, THB001 remodeled HDM-induced transcriptional signatures and lipid mediator release, prevented HDM-induced bronchoconstriction and AHR, and largely reversed HDM-induced increases in mast cells, inflammation, airway smooth muscle layer thickening and collagen deposition, with partial reduction of mucus-producing cells.

CONCLUSIONS

Mast cell-dependent signaling is a key driver of allergic asthma pathogenesis. Pharmacological inhibition of KIT effectively suppresses mast cell activity and prevents hallmark functional and structural features of asthma in a guinea pig model, supporting KIT inhibition as a potential therapeutic approach for allergic asthma.