Role of mTOR in the development of asthma in mice with cigarette smoke-induced cellular senescence

Abstract

Abstract The role of cellular senescence in the development of asthma is not well known. We aimed to evaluate the susceptibility of mice with cellular senescence to asthma development and determine whether the mTOR pathway played an important role in this process. Cellular senescence was induced in mice by intranasal instillation of 2% cigarette smoke extract (CSE). Subsequently, a low dose (0.1 μg) of house dust mite (HDM) allergens, which causes no inflammation and airway hyperresponsiveness (AHR) in mice without cellular senescence, was administered intranasally. To evaluate the role of mTOR pathway in this model, rapamycin (TORC1 inhibitor) was injected intraperitoneally before CSE instillation. CSE significantly increased senescence-associated β-gal (SA-β-gal) activity in lung homogenate and S100A8/9+p-mTOR+ population in lung cells. Moreover, S100A8/9+ or HMGB1+ populations in airway epithelial cells with phospho-mTOR activity increased remarkably. Rapamycin attenuated all changes. Subsequent administration of low-dose HDM allergen induced murine asthma characterized by increased AHR, serum HDM-specific immunoglobulin E, and eosinophilic airway inflammation; these asthma characteristics disappeared after rapamycin injection. In vitro experiments showed significant activation of bone marrow-derived cells co-cultured with S100A9 or HMGB1 overexpressing MLE-12 cells treated with HDM allergen, compared to those treated with HDM allergen only. CSE increased the levels of senescence markers (S100A8/9 and HMGB1) in airway epithelial cells, making the mice susceptible to asthma development due to low-dose HDM allergens by activating dendritic cells. Since rapamycin significantly attenuated asthma characteristics, the mTOR pathway may be important in this murine model.