Asthma shows marked sex differences, suggesting that estrogen-responsive pathways such as the G protein–coupled estrogen receptor 1 (Gper1) may differentially regulate airway hyperresponsiveness (AHR) and inflammation in males and females. This study tested whether loss of Gper1 alters allergen-induced airway dysfunction by directly comparing wild-type (WT) and Gper1 knockout (KO) mice following house dust mite (HDM) exposure. Male and female WT and KO mice (8–10 weeks; n=3–9/group) were intranasally exposed to 50 µL HDM or PBS for five weeks. Airway mechanics (respiratory system resistance Rrs, elastance Ers, Newtonian resistance Rn, tissue damping G, and tissue elastance H) were assessed via methacholine challenge using a flexiVent (Scireq), and peribronchial/perivascular inflammation and mucus-producing goblet cells were quantified from H Rrs increased from 2.198±0.199 to 6.430±3.185 cmH 2 O·s/mL (p< 0.05), Ers from 42.900±3.436 to 59.833±6.328 cmH 2 O·s/mL (p< 0.05), Rn from 1.117±0.033 to 1.641±0.102 cmH 2 O·s/mL (p< 0.05), G from 10.403±1.596 to 15.071±2.909 cmH 2 O·s/mL (p< 0.05), and H from 33.383±1.332 to 49.859±6.160 cmH 2 O·s/mL (p< 0.01). Compared to WT males, male Gper1 KO mice showed markedly greater AHR after HDM exposure, including higher Rrs (6.43±3.2 vs 3.49±0.7 cmH 2 O·s/mL; p=0.03), Ers (59.83±6.3 vs 57.64±8.07 cmH 2 O·s/mL; p=0.003), Rn (1.64±0.1 vs 1.28±0.1 cmH 2 O·s/mL; p=0.001), G (15.07±2.9 vs 11.06±2.7 cmH 2 O·s/mL; p=0.001), and H (49.86±6.1 vs 38.82±4.5 cmH 2 O·s/mL; p=0.002). In females, KO mice also exhibited increased AHR compared with PBS controls, with Rrs increasing from 1.23±0.2 to 2.79±0.8 cmH 2 O·s/mL, Ers from 31.43±1.9 to 47.00±6.7 cmH 2 O·s/mL, G from 6.16±0.5 to 8.63±0.8 cmH 2 O·s/mL, and H from 23.99±1.3 to 30.66±1.2 cmH 2 O·s/mL (all p< 0.05). However, when compared to WT females, Gper1 KO females showed less pronounced but significant responses to HDM, with some similar or slightly lower values (e.g., Ers= 47.00±6.7 vs WT 43.04±3.4 cmH 2 O·s/mL; p=0.01, G 8.63±0.8 vs 8.07±1.2 cmH 2 O·s/mL; p=0.03, H 30.66±1.2 vs 34.15±2.7 cmH 2 O·s/mL; p=0.006), demonstrating a potential interaction of genotype and sex. Histologically, HDM-treated male KO mice exhibited stronger inflammatory responses than WT males, with higher peribronchial cell counts (1.74×10 5 vs 1.38×10 5 cells/mm 2 ; p=0.001) but a non-significant reduction in perivascular infiltrates (0.90×10 5 vs 1.94×10 5 cells/mm 2 ). In contrast, female KO mice did not show worsened inflammation relative to WT females: KO females displayed peribronchial (1.53×10 5 vs WT 1.38×10 5 cells/mm 2 ) and perivascular (1.14×10 5 vs WT 1.25×10 5 cells/mm 2 ) counts that were equal or slightly lower (but not significant) than those of WT females. Goblet cell hyperplasia was elevated in KO males (6.5×10³ vs WT 4.7×10³ cells/mm 2 ; p=0.013), but KO females exhibited equal or fewer PAS + cells than their WT counterparts (6.4×10³ vs WT 8.57×10³ cells/mm 2 ). In conclusion, we found that Gper1 may be protective in males, where its loss enhances AHR, inflammation, and mucus metaplasia beyond WT responses. In females, loss of Gper1 does not worsen histological outcomes and may even improve them compared to males, suggesting that Gper1 does not play the same role in females as in males. These findings reveal a striking sex divergence in Gper1 function and highlight the necessity of sex-specific approaches in airway disease research. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
EKPRUKE et al. (Fri,) studied this question.