Triggering mechanisms of acute thunderstorm asthma: epithelial barrier disruption and immune dysregulation

Thunderstorm asthma (TA) refers to a phenomenon characterized by sudden onset, large-scale outbreaks, and potentially fatal acute exacerbations of asthma. Despite accumulating epidemiological evidence, its cellular and molecular mechanisms remain unclear. Recent studies have proposed a core framework involving "environmental triggers-epithelial barrier damage-immune dysregulation." During thunderstorms, high humidity and strong convection can cause pollen to hydrate and rupture into sub-pollen particles (SPPs) smaller than 2.5 μm, which may further combine with other pollutants such as particulate matter ≤ 2.5 μm(PM_2.5) and ozone (O₃) to form bioaerosols capable of penetrating small airways. These factors can lead to damage of the airway epithelial barrier, with sequential cellular and molecular pathophysiological changes including downregulation of various tight junction proteins in the epithelial barrier, imbalance of mucociliary clearance function, and upregulated secretion of epithelial alarmins such as interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP). This results in increased disease severity through activation of innate and adaptive immunity (e.g., type 2 innate lymphoid cells (ILC2)/T helper 2(Th2) axis activation leading to immunoglobulin E(IgE) upregulation, eosinophil activation, and mast cell degranulation; Th17-mediated neutrophilic inflammation; and toll-like receptor(TLR)-mediated innate immune processes and mucosal inflammation) and enhancement of intrinsic susceptibility factors (e.g., TLR gene polymorphisms and abnormal expression, DNA methylation and histone modifications, as well as microbiome-host interactions). According to research in meteorology, exposomics, and molecular immunology, we believe that airway epithelial barrier dysfunction and immune dysregulation play significant roles in TA. Future translational directions primarily involve establishing a population stratification and early warning system through combinations of meteorological factors with allergens/pollutants, thereby enhancing public protection and health management efforts to improve the early warning, prevention, and clinical management of TA.