Kisspeptin regulates airway hyperresponsiveness and remodeling in a mouse model of asthma

Abstract

Asthma is a multifactorial disease of origin characterized by airway hyperresponsiveness (AHR) and airway remodeling. Several pieces of evidence from other pathologies suggest that Kisspeptins (Kp) regulate cell proliferation, migration, and invasion, mechanisms that are highly relevant to asthma. Our recent in vitro studies show Kp‐10 (active peptide of Kp), via its receptor, KISS1R, inhibits human airway smooth muscle cell proliferation. Here, we hypothesize a crucial role for Kp‐10 in regulating AHR and airway remodeling in vivo. Utilizing C57BL/6J mice, we assessed the effect of chronic intranasal Kp‐10 exposure on mixed allergen (MA)‐induced mouse model of asthma. MA‐challenged mice showed significant deterioration of lung function compared to those exposed to vehicle (DPBS); Kp‐10 treatment significantly improved the MA‐altered lung functions. Mice treated with Kp‐10 alone did not show any notable changes in lung functions. MA‐exposed mice showed a significant reduction in KISS1R expression as compared to vehicle alone. MA‐challenged mice showed significant alterations in immune cell infiltration in the airways and remodeling changes. Proinflammatory cytokines were significantly increased upon MA exposure, an effect abrogated by Kp‐10 treatment. Furthermore, biochemical and histological studies showed Kp‐10 exposure significantly reduced MA‐induced smooth muscle mass and soluble collagen in the lung. Overall, our findings highlight the effect of chronic Kp‐10 exposure in regulating MA‐induced AHR and remodeling. © 2023 The Pathological Society of Great Britain and Ireland.

Airway-associated adipose tissue accumulation is increased in a kisspeptin receptor knockout mouse model

“…We demonstrate that Kiss1 and Kiss1r genes are expressed within homogenised lung tissue from mice, consistent with findings on mouse ASM isolated after laser capture microdissection [ 19 ]. Expression of Kiss1 was similar across genotypes and Kiss1r was only expressed in WT and Het mice, validating the use of the Kiss1r KO mouse model.…”

“…Expression of Kiss1r is reduced in ASM from asthmatic subjects compared with non-asthmatic subjects, and in cell culture Kiss1r antagonism increases ASM proliferation [ 7 ]. In an allergic mouse model, intranasal instillation of Kiss1 reduced ASM thickness [ 19 ]. The interrelationship between Kiss1 / Kiss1r signalling, airway-associated adipose tissue accumulation and ASM remodelling is an area of research that should receive greater focus in the future.…”