Acute Kisspeptin exposure reduces airway hyperresponsiveness in a mixed Th2/Th17 inflammatory phenotype mouse model of severe asthma

Rationale: Asthma is a chronic inflammatory disease of the airways that is characterized by airway hyperresponsiveness and remodeling. Multiple inflammatory endotypes have been described, each differing in the types of inflammatory mediators involved. The inflammatory markers associated with a given endotype can influence therapeutic responsiveness; notably, Th2/Th17 severe inflammation is often insensitive to several standard asthma treatments. Our group has previously identified Kisspeptin (Kp-10)/KISS1R signaling as having a protective role within the lung in the context of Th2 asthmatic inflammation. The effects of Kisspeptin within different asthmatic endotypes is currently unknown. Additionally, the acute effect of Kp-10 and its signaling on airway hyperresponsiveness is currently unknown. To properly model different asthmatic endotypes, a Mixed Allergen (MA) cocktail is used to induce a strong Th2 immune response. The addition of cyclic-di-GMP (GMP) to the MA cocktail (GMP/MA) reprograms the immune response to shift towards a mixed Th2/Th17 response, which resembles a severe asthma phenotype. Both of these allergen regiments are suitable to induce a strong asthmatic phenotype for the purpose of studying airway hyperresponsiveness. Objective: This study explores the acute effect of Kisspeptin during severe asthma. Methods: Wild-type C57BL/6J (Male and Female) mice were sensitized intranasally with vehicle PBS, MA, or GMP/MA. The MA cocktail was composed of equal amounts (10 µg each) of House Dust Mite Extract, A. fumigatus, A. alternata, and ovalbumin and GMP/MA was composed of 0.5 µg Cyclic-di-GMP + MA cocktail. Mice received intranasal dosing every other day for 28 days. Mice were administered with PBS or Kp-10 intranasally (1.17 mg/kg) prior to initiation of FlexiVent measurement of lung mechanics. Following this, lung tissue samples were processed for histology using Hematoxylin and Eosin and Sirius Red/Fast Green staining. Results: GMP/MA mice showed a significant increase in airway resistance and decrease in elastance compared to MA mice. MA and GMP/MA mice showed a significant increase in collagen deposition and immune cell infiltration, with GMP/MA showing a more pronounced increase as quantified by blind scoring of H however, these treatments did not affect airway elastance. Conclusions: This study highlights that Kisspeptin can be used as a rescue agent to improve airway function for both Th2-High and Th2/17 asthma. These results provide strong evidence for the clinical use of Kisspeptins within the management of asthma when traditional therapeutics fail. Acknowledgements: Supported by NIH grants R01-HL171245 (Venkatachalem and Britt), R01-HL146705 (Venkatachalem). 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.