Abstract Rationale Asthma can be broadly classified into type 2 (T2)-high and T2-low subtypes. Despite therapeutic advances for T2-high asthma, effective options for T2-low disease remain limited. Irritant-induced asthma (IIA) is a representative T2-low phenotype characterized by neutrophilic inflammation and poor steroid responsiveness. Existing animal models, however, have practical limitations: chlorine gas models primarily capture short-lived, acute inflammation, whereas ozone models often require prolonged or repeated exposures to sustain disease features. To bridge this gap, we developed a simple, mid- to long-term, and reproducible mouse model using sodium hypochlorite (NaClO)—a controllable liquid irritant that is safer to handle than toxic gases. This approach better reflects real-world irritant exposures and enables the study of T2-low airway inflammation and therapeutic responses. Methods Male BALB/cJ mice received intratracheal NaClO to establish an acute IIA model. Airway hyperresponsiveness (AHR) was assessed using an invasive pulmonary function testing system. Bronchoalveolar lavage fluid (BALF) was analyzed for differential cell counts and cytokine levels. Lung histopathology evaluated epithelial injury and remodeling. Bulk RNA-seq was performed to profile time-dependent molecular pathways. Dexamethasone was administered intraperitoneally to assess steroid responsiveness. Results NaClO exposure elicited persistent AHR from the acute phase (24-72 h) to chronic phase (up to 4 weeks). BALF showed neutrophilic inflammation peaking at 72 h in the absence of eosinophilic infiltration. CXCL1 and IL-6 levels were significantly elevated in BALF. Histological analysis revealed epithelial injury at 24 h and goblet cell hyperplasia at 1 week, indicating epithelial damage and regeneration. RNA-seq analysis showed acute enrichment of inflammatory pathways followed by cell cycle/repair programs at later stages. Dexamethasone did not to ameliorate AHR, suggesting steroid resistance. Conclusions Intratracheal NaClO produces a practical, reproducible mouse model that captures key features of T2-low IIA—neutrophilic inflammation, steroid-insensitive AHR, and epithelial damage/regeneration. This model provides a translatable platform to dissect mechanisms and to prioritize candidate therapies for T2-low asthma, where clinical options remain limited. This abstract is funded by: JSPS KAKENHI
Nagai et al. (Fri,) studied this question.