Houttuynia Cordata Essential Oil Mitigates Airway Remodeling in Asthma by Rectifying IP3R‐mediated Ca 2+ Disruption

Asthma is a common chronic airway inflammatory disease that leads to airway narrowing during the attacks. Beta-adrenergic agonists provide temporary relaxation of airway during asthma attacks. While long-term usage of corticosteroids could improve asthma but it may bring adverse effects to the patients. Thus, an alternative or supplementary therapeutic approach is urgently needed. One potential therapeutic approach is targeting intracellular calcium (Ca2+) signaling in airway smooth muscle cells. It is reported that these intracellular calcium signals played an essential role in contractility regulations and airway remodeling. Meanwhile, Houttuynia Cordata (HC) is a frequently used traditional Chinese medicinal herb in asthma treatment due to its anti-allergic and anti-inflammatory properties. Thus, we hypothesized that HC may modulate intracellular Ca2+ signals and could be a promising candidate to relieve asthmatic airway remodeling. In this study, we investigated the role of intracellular Ca2+ channels in airway remodeling and elucidated the therapeutic mechanism of HC, particularly its effect on intracellular Ca2+ channels. We used interleukin 4 and 13 treated human bronchial smooth muscle cells (hBSMC), and house-dust mite sensitized BALB/C mice as an acute asthmatic cell and animal models. We found that the mRNA and protein levels of IP3R1, TPC2, and SERCA2A were elevated in asthmatic hBSMC, which are reconcilable to the observation in the asthmatic mouse model. Apart from enhanced Ca2+ channels expression, we found that the IP3-mediated calcium release in asthmatic hBSMC was also increased, suggesting IP3R plays an indispensable pathogenic role in asthma development. Intriguingly, pre-treatment of HC essential oil in cells candose-dependently reduced ATP-triggered Ca2+ release. To evaluate the in vivo effect of HC essential oil, we nebulized the HC essential oil to pre-treat the house-dust mite sensitized asthmatic mouse. Our result shows that HC essential oil pre-treatment significantly reduced neutrophil and eosinophil counts in bronchoalveolar lavage fluid. In addition, asthmatic airway remodeling indicators such as increased airway thickness, airway smooth muscle cells hyperplasia, hyperresponsiveness, and airway ring contractions were also mitigated by the HC pre-treatment. These results suggest HC essential oil can prevent airway remodeling and asthma development in asthmatic mouse model. Taken together, our current data suggested that HC essential oil mitigates asthma development by rectifying the disrupted Ca2+ signaling and prevents airway narrowing. HC may serve as a potential alternative treatment choice to prevent or treat asthma.