The role of intracellular Ca²⁺ channels in airway remodeling of an asthmatic mouse model

Abstract

Asthma is a chronic respiratory inflammatory disease that has an increasing prevalence in the global population. In recent years, the idea of asthma phenotypes began to emerge, and this thesis focuses on the classic TH2 eosinophilic asthma. This type of asthma is centered around TH2-biased immune response, and it exhibits an array of airway remodeling events, such as white blood cell (eosinophils in particular) infiltration into airway, airway hyperresponsiveness and airway smooth muscle hyperplasia and hypertrophy.

As Ca2+ signaling plays a major role in modulating numerous intracellular events, especially in the contraction of airway smooth muscle, its alteration is likely a part of airway remodeling in asthma. In order to investigate the possible alteration, a house dust mite-based asthmatic mouse model and a simple interleukin-based human cell model were established, in which the mouse model was able to exhibit the mentioned airway remodeling events. In these models, the expression levels of multiple major intracellular Ca2+ channels in the airway smooth muscle cells were measured relative to the control group. It was found that IP3R, TPC and SERCA overexpressed, among which the IP3R overexpression gained the most focus, as it releases Ca2+ from the sarcoplasmic reticulum to the cytosol and starts the airway smooth muscle contraction mechanism.

Upon investigation of acetylcholine-induced Ca2+ release via IP3R in the human cell asthma model using fluorescent calcium imaging, it was found that the overexpression of IP3R leads to an enhanced Ca2+ release when activated. It was assumed that the enhanced Ca2+ release might result in hypersensitivity of airway smooth muscle, which was supported by the finding of enhanced acetylcholine-induced trachea contraction force of asthmatic mouse model, even when the muscle mass factor was removed. Therefore, IP3R overexpression plays a major role in the airway hyperresponsiveness of airway remodeling by causing hypersensitivity.

Using thapsigargin-induced Ca2+ store depletion, in which thapsigargin inhibited SERCA, thus allowing the sarcoplasmic reticulum Ca2+ to be depleted due to passive leak, it was found that the SERCA overexpression leads to enhanced Ca2+ store. The enhanced Ca2+ store might assist in the enhanced Ca2+ release. The role of TPC in airway smooth muscle is still unclear, therefore the effect of its overexpression remains unknown for now.

The traditional Chinese medicine Houttuynia cordata is suggested to have anti-inflammatory property which could be useful in asthma treatment. By having multiple inhalations of nebulized essential oil extracted from H. cordata during the establishing procedures of the asthmatic mouse model, the occurrence of the mentioned hallmark symptoms of asthma were able to be prevented. In addition, it was shown to have IP3R inhibiting property. Therefore, H. cordata is a possible candidate for asthma preventive and active treatment.