Abstract Background In asthmatic patients, chronic inflammation further exacerbates disease severity and contributes resistance to conventional corticosteroid (CS) therapy. Cyclic-di- guanosine monophosphate (cyclic-di-GMP), a bacterial-derived pathogen-associated molecular pattern, triggers a robust interferon-mediated immune response in the lung that augments allergic airway inflammation. When combined with common allergens, c-di-GMP induces a shift in airway inflammation from Th2-high eosinophilic inflammation to a mixed Th2/Th17 inflammatory phenotype, thereby serving as an established in vivo mouse model of severe asthma. Our previous studies have demonstrated that Kp-10 (KISS1R agonist) attenuates airway remodeling both in in vitro and in vivo. Here, we hypothesize that activation of KISS1R by novel agonists will exert anti-inflammatory and anti-remodeling effects, ultimately reducing airway hyperresponsiveness (AHR) in severe asthmatic mice. Methods A severe asthmatic C57BL/6J mouse model was established by exposing mice to 0.5 µg Cyclic-di-GMP + mixed allergens contain equal amounts (10µg) of ovalbumin, and extracts from Alternaria Alternata, Aspergillus Fumigatus, Dermatophagoides Farinae (GMP/MA). Mice were intranasally administered with PBS, Kp-10 (1.17 mg/kg), and novel KISS1R agonists (KS1-3, 1.17 mg/kg) on alternate days during the 28 days of MA alone or GMP/MA exposure period. After 28 days, mice were anesthetized and subjected to FlexiVent for lung mechanics to determine elasticity (Ers), resistance (Rrs), and compliance (Crs). Bronchoalveolar lavage (BAL) and lung tissue were collected for differential leukocyte count and histopathology analysis (H&E, PAS and Masson’s Trichrome). Results FlexiVent analysis showed a significant increase of airway resistance (Rrs) and elastance (Ers) in GMP/MA exposed mice following methacholine (MCh) challenge compared to MA-alone or PBS group. Intranasal administration of KISS1R agonists significantly reduced the Rrs and Ers in GMP/MA mice, with the most pronounced effect observed in KS-3 treated mice. Differential leukocytes analysis revealed a significant reduction in eosinophils and neutrophils levels in mice treated with KISS1R agonists. Further, histology results confirm the protective role of KISS1R agonists displaying reduced immune cells infiltration and collagen deposition. Notably, KS-3 treatment showed more pronounced therapeutic effect among the other KISS1R agonists. Conclusion Overall, these findings enhance the therapeutic importance of Kp/KISS1R signaling in reducing AHR and remodeling in mixed Th2/Th17 inflammatory phenotype model of severe asthma. This abstract is funded by: NIH grant R01-HL146705 (Venkatachalem)
Ramakrishnan et al. (Fri,) studied this question.