Abstract
Rationale A recognized aspect of asthma is age and sex-related differences in epidemiology and clinical manifestation (boys>girls and women>men) suggesting a modulatory role of sex-steroids, particularly estrogen. However, the divergent role of estrogen in asthma pathophysiology suggests that upstream of estrogen might be crucial in asthma. Additionally, the central nervous system based studies have shown that kisspeptins (Kp) signaling is regulated by estrogen. Moreover, our recent studies have also shown that basal expression of Kp and its receptor (KISS1R) are reduced in human airway smooth muscle (ASM) cells in females as compared to males. Further, KISS1R-agonist, metastin (MTS) blunted PDGF-induced ASM cell proliferation. These shreds of evidence suggest that mechanisms upstream or independent of estrogen may be protective, but lost during the inflammatory conditions. In this study, we aimed to evaluate the effect of acute exposure of kisspeptins in regulating airway hyperresponsiveness (AHR) using a mixed allergen (MA)-induced mouse model of asthma. Methods WT C57BL/6J mice (males and females) were procured from Jackson Laboratory, USA and challenged intranasally with MA for 28 days according to NDSU IACUC approved protocol. The vehicle group received only PBS. On day 29, MTS (1.2mg/kg) was administered intranasally 10 min before the methacholine challenge. Mice were anesthetized and subjected to FlexiVent for lung mechanics to determine airway resistance (Rrs), elastance (Ers), compliance (Crs), Tissue damping (G) and elastance (H). Following this, bronchoalveolar lavage (BAL) and lung tissues were processed for differential leukocyte count (DLC) and histology (H&E and Masson's Trichome) respectively. Additionally, laser-capture microdissection (LCM) assisted qRT-PCR analysis in ASM cells was performed for genes relevant to airway remodeling. Results Interestingly, we observed thatunchallenged mice exposed to MTS alone showed decreased Rrs and improved Crs, albeit not significant compared to the vehicle group. MA-challenged mice showed a significant increase in Rrs, Ers, G, H and with reduced Crs compared to vehicle. Additionally, MA-challenged mice showed significant alterations in immune cell infiltration in the airways and remodeling changes, which were confirmed by DLC count and histology studies. MTS exposed mice showed significant improvement in MA-altered lung functions with decrease in Rrs, Ers, G, H and increased Crs compared to MA group. Conclusion Overall, our findings highlight the importance of acute kisspeptin signaling in ablating MA-induced airway inflammation and AHR. These findings suggest a novel and critical role for kisspeptin signaling in mitigating AHR, and serve as a potential therapeutic strategy to treat asthma.
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