Airway smooth muscle (ASM) is a key cell type in asthma, contributing to airway hyperreactivity (AHR) and remodeling (proliferation, fibrosis). Asthma is more prominent in women and multiple studies highlight a role for sex hormone effects on ASM. However, it is unclear whether sex hormones are protective or detrimental, given observations of enhanced inflammation vs. promotion of bronchodilation. These uncertainties led us to consider if mechanisms upstream or even independent of sex hormones play a role, or alternatively, if asthma involves loss of intrinsic protective mechanisms. Drawing upon data in CNS, particularly in puberty which associates with more asthma in women, and preliminary data, we propose that the gonadotrophin regulators kisspeptins (Kp) and their receptor (KISS1R) serve a normally protective, anti-remodeling role when locally expressed in airways. We further propose that inflammation/asthma and estrogens compromise Kp/KISS1R roles. There is currently no information on Kp/ KISS1R in airways and/or in asthma, but potential relevance lies in the fact that Kp signaling can regulate proliferation, migration and signaling elements also important for ASM remodeling and contractility. Preliminary studies show human ASM from females have less Kp and KISS1R compared to males, further reduced during asthma/inflammation. In addition, physiological levels of 17-?-estradiol (E2) reduce Kp in ASM. Functionally, Kp via KISS1R downregulates ASM proliferation and remodeling and reduces ASM [Ca2+]i. In a mixed allergen mouse model of asthma, Kp agonist (metastin) improved lung resistance and compliance. Our overall hypothesis is that ASM-derived Kp signaling has a protective role lost in inflammation and asthma, permitting AHR and remodeling. Our proposed studies will define the role of Kp and KISS1R in asthma via three Aims:
Aim 1 : Determine mechanisms by which inflammation and E2 regulate Kp/KISS1R in human ASM in the context of asthma.
Aim 2 : Determine mechanisms by which Kp/KISS1R signaling influences ASM structure and function in the context of asthma.
Aim 3 : In a mouse model of allergic asthma, determine role of Kp/KISS1R in AHR and remodeling. Using human ASM cells and tissues of male vs. female (asthmatics vs. non-asthmatics), Aim 1 explores the idea that asthma and inflammation or E2 decrease expression of Kp and KISS1R.
Aim 2 explores Kp/KISS1R-based signaling in human ASM proliferation, migration, ECM production, and autocrine role of ASM-derived Kp, further exploring interactions with inflammatory cytokines or E2. We will also explore if Kp/KISS1R is important for Ca2+/contractility.
Aim 3 applies a mixed allergen model of asthma to WT and KISS1R KO mice to study importance of Kp (metastin vs. KISS1R inhibitor). Ovariectomy (OVX) is used to distinguish E2 from Kp effects. Changes in airway contractility are assessed using FlexiVent and precision cut lung slices, and structural and molecular changes in ASM assessed by laser capture microdissection (LCM) and Clinical significance lies in understanding how Kp signaling influences airway immunofluorescence (IF). structure/function in the context of asthma, highlighting an entirely novel avenue to therapy.
The prevalence rate of asthma is higher in pre-pubescent and aging males, and in post-pubertal females, suggesting a role for female sex steroids such as estrogens in modulating this disease. However, studies suggest a possible role of other signaling mechanisms interplaying with estrogens. Kisspeptin is a crucial regulatory protein involved in female puberty as well as a modulator of sex steroids. In this context, we propose that a decrease in expression of kisspeptin and their function in asthmatics compared to non-asthmatics (specifically females) conveys a possible sex specific role of kisspeptin in asthma. Our studies use human airway smooth muscles from both male and female asthmatics vs. non-asthmatics, along with animal studies where we control estrogen levels. These studies will substantially enhance our understanding of how and why kisspeptin signaling influences the asthmatic airway. This is a necessary and clinically important step if we are to develop novel therapeutic strategies for asthma, possibly in a gender/sex specific fashion.
