Abstract
Airway remodeling and airway hyper-responsiveness are prominent features of asthma. Neurogenic inflammation participates in the development of asthma. Neurokinin substance P acts by binding to neurokinin-1 receptor (NK-1R). Airway smooth muscle cells (ASMC) are important effector cells in asthma. Increases in ASMC proliferation, migration, and cytoplasmic Ca2+ concentration are critical to airway remodeling and hyper-responsiveness. The effects of substance P on ASMC were investigated in Wistar rats challenged with a previously described asthmatic rat model. To exclude possible influences from other factors, the role of substance P was also investigated in primary cultured rat ASMC. Substance P and WIN62577-induced changes in cytoplasmic Ca2+ concentration were observed by fluorescence microscopy, and expression of Ca2+ homeostasis-regulating genes was assessed with real-time PCR. We found that cytoplasmic Ca2+ concentration increased in normal rat ASMC treated with substance P, but decreased in asthmatic rat ASMC treated with WIN62577, an antagonist of NK-1R. Real-time PCR analysis revealed increased Serca2 mRNA expression but decreased Ip3r mRNA expression after WIN62577 treatment in asthmatic rat ASMC. Flow cytometric analysis (FCM) revealed that most asthmatic rat ASMC stayed at G1 phase after combined treatment with WIN62577 and IL-13 in vitro. Transwell analysis suggested that ASMC migration was reduced after WIN62577 treatment. Therefore, we conclude that NK-1R is related to asthma mechanisms and a NK-1R antagonist downregulates calcium concentration in asthmatic ASMC by increasing Serca2 mRNA and decreasing Ip3r mRNA expression. The NK-1R antagonist WIN62577 inhibited ASMC IL-13-induced proliferation and ASMC migration in vitro and therefore may be a new therapeutic option in asthma.
Highlights
Asthma is a chronic inflammatory disease of the lower airways associated with various comorbidities and characterized by variable, often reversible, airway obstruction [1]
We found that cytoplasmic Ca2+ concentration increased in normal rat Airway smooth muscle cells (ASMC) treated with substance P, but decreased in asthmatic rat ASMC treated with WIN62577, an antagonist of NK-1R
Impaired replenishment of sarcoplasmic reticulum (SR) stores arising from reduced activity of the sarco/endoplasmic reticulum Ca2+ (SERCA) pump result in increased Ca2+ concentration, which can in turn impact a wide range of Ca2+-dependent smooth muscle functions [5]
Summary
Asthma is a chronic inflammatory disease of the lower airways associated with various comorbidities and characterized by variable, often reversible, airway obstruction [1]. ASMC proliferate and migrate, especially during airway remodeling [3]. The responsiveness of smooth muscle to diverse stimuli is controlled by changing the concentration of intracellar calium ion ([Ca2+]i). Impaired replenishment of SR stores arising from reduced activity of the sarco/endoplasmic reticulum Ca2+ (SERCA) pump result in increased Ca2+ concentration, which can in turn impact a wide range of Ca2+-dependent smooth muscle functions [5]. Abnormal Ca2+ handling by ASMC has been proposed previously to be an important determinant of the airway hyper-responsiveness that is characteristically present in asthma [6,7]. Drugs able to inhibit ASMC proliferation and migration or to decrease ASMC calcium concentration may be beneficial in alleviating airway hyper-responsiveness
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