The AKT inhibitor MK2206 suppresses airway inflammation and the pro‑remodeling pathway in a TDI‑induced asthma mouse model.

Abstract

The cellular and molecular mechanisms via which MK2206, an AKT inhibitor, prevents the activation of AKT in toluene diisocyanate (TDI)-induced asthma remain unclear. Thus, the present study aimed to evaluate the potential effects of MK2206 on airway AKT activation, inflammation and remodeling in a TDI-induced mouse model of asthma. A total of 24 BALB/c mice were selected and randomly divided into untreated (AOO), asthma (TDI), MK2206 (TDI + MK2206), and dexamethasone (TDI + DEX) groups. Phosphorylated AKT (p-AKT), total AKT, airway remodeling indices, α-smooth muscle actin (α-SMA) and collagen I levels in pulmonary tissue were measured using western blotting. Airway inflammation factors, including interleukin (IL)-4, −5, −6, and −13 in bronchoalveolar lavage fluid (BALF) and IgE in serum, were determined using ELISA. Additionally, the airway hyperresponsiveness (AHR) and pulmonary pathology of all groups were evaluated. The results of the present study demonstrated that p-AKT levels in lung protein lysate were upregulated, and neutrophil, eosinophil and lymphocyte counts were increased in the lungs obtained from the asthma group compared with the AOO group. Both MK2206 and DEX treatment in TDI-induced mice resulted not only in the attenuation of AKT phosphorylation, but also reductions in neutrophil, eosinophil and lymphocyte counts in the lungs of mice in the asthma group. Consistently, increases in the levels of the inflammatory cytokines IL-4, −5, −6 and −13 analyzed in BALF, and serum IgE in the TDI group were demonstrated to be attenuated in the TDI + MK2206 and TDI + DEX groups. Furthermore, α-SMA and AHR were significantly attenuated in the TDI + MK2206 group compared with the TDI group. These results revealed that MK2206 not only inhibited AKT activation, but also served a role in downregulating airway inflammation and airway remodeling in chemical-induced asthma. Therefore, the findings of the present study may provide important insight into further combination therapy.