Department of Respiratory and Critical Care Medicine, Chronic Airway Disease Laboratory, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong 510000, P.R. China.
Department of Respiratory and Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510630, P.R. China.
Mol Med Rep. 2020 Nov;22(5):3723-3734. doi: 10.3892/mmr.2020.11450. Epub 2020 Aug 21.
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.
MK2206 是一种 AKT 抑制剂，其通过何种细胞和分子机制来防止甲苯二异氰酸酯（TDI）诱导的哮喘中 AKT 的激活尚不清楚。因此，本研究旨在评估 MK2206 对 TDI 诱导的哮喘小鼠模型中气道 AKT 激活、炎症和重塑的潜在作用。共选择 24 只 BALB/c 小鼠，随机分为未处理组（AOO）、哮喘组（TDI）、MK2206 组（TDI+MK2206）和地塞米松组（TDI+DEX）。采用 Western blot 法检测磷酸化 AKT（p-AKT）、总 AKT、肺组织气道重塑指数、α-平滑肌肌动蛋白（α-SMA）和胶原 I 水平。采用 ELISA 法检测支气管肺泡灌洗液（BALF）中白细胞介素（IL）-4、-5、-6 和-13 及血清 IgE 等气道炎症因子。此外，还评估了各组的气道高反应性（AHR）和肺病理学变化。结果显示，与 AOO 组相比，哮喘组肺组织蛋白裂解物中 p-AKT 水平上调，肺组织中中性粒细胞、嗜酸性粒细胞和淋巴细胞计数增加。MK2206 和 DEX 治疗 TDI 诱导的小鼠，不仅能减轻 AKT 磷酸化，还能降低哮喘组小鼠肺组织中的中性粒细胞、嗜酸性粒细胞和淋巴细胞计数。同样，哮喘组 BALF 中分析的炎症细胞因子 IL-4、-5、-6 和-13 及血清 IgE 水平升高，在 TDI+MK2206 和 TDI+DEX 组中被证明有所减弱。此外，与 TDI 组相比，TDI+MK2206 组的 α-SMA 和 AHR 明显减弱。这些结果表明，MK2206 不仅抑制 AKT 激活，而且在化学诱导性哮喘中下调气道炎症和气道重塑中发挥作用。因此，本研究结果可能为进一步的联合治疗提供重要的见解。
