Tanshinone IIA alleviates blast-induced inflammation, oxidative stress and apoptosis in mice partly by inhibiting the PI3K/Akt/FoxO1 signaling pathway
Graphical abstract
Introduction
One out of 10 military casualties and 6–9 out of 10 civilian victims of terror incidents suffer lung blast injuries [1]. The lungs, gastrointestinal tract and brain are often vulnerable to blast injury, and lung blast injury is the most likely cause of severe casualties [2]. High-intensity detonation shock waves can destroy the alveolar septum, leading to severe pulmonary hemorrhaging, edema and inflammatory cell infiltration. Subsequently, these injuries may develop into acute respiratory distress syndrome, which seriously threatens the lives of patients and affects their quality of life [3]. Current treatment protocols for lung blasts mainly focus on supportive care, intensive therapy and mechanical ventilation, and no specific alternative therapy exists. Therefore, the lung blast injury mechanism must be studied to determined additional effective treatment methods.
To study the mechanism of lung blast injury, compressed-gas, combustion and small-explosion shock tubes have been used on rats and mice [4], large swine and dogs [[5], [6], [7]]. Many studies have found that the mechanism of lung blast injury is very complex, involving inflammation, oxidative stress, apoptosis and immune regulation [3,[8], [9], [10], [11]]. Inflammatory reactions play important roles in lung blast injuries. Leukocyte infiltration in the lung tissue and increased inflammatory cells, such as TNF-α, IL-1β and IL-6 severely aggravate lung tissue fibrosis and respiratory dysfunction. Tong et al. [12] showed that inflammation peaked 12–24 h after blast injury, then gradually decreased, while oxidative stress and apoptosis peaked 24–48 h after blast injury, with an obvious time delay. Similarly, oxidative stress markers were reported to increase 24 h after blast injury. Phosphatidylinositol-3-kinase (PI3K) is an intracellular phosphatidylinositol kinase, and Akt is the direct downstream effector of PI3K. The PI3K/Akt pathway is an important intracellular signaling pathway in regulating the cell cycle by transmitting various upstream signals. A previous study [13] showed that dexmedetomidine alleviated lipopolysaccharide-induced acute lung injury in rats, likely via the HMGB1-mediated PI3K/Akt signaling pathway. Moreover, hydrogen sulfide reduced PI3K/Akt-mediated formation of reactive oxygen species (ROS) in rats with ventilator-induced lung injury [14]. However, whether the PI3K/Akt signaling pathway is involved in LPS-induced acute lung injury remains unclear.
Tanshinone IIA (Tan IIA) is a Chinese herbal medicine with many active ingredients, widely distributed in China and Japan. Growing evidence suggests that Tan IIA has a wide range of anti-inflammatory [15], antioxidative [16,17], antiapoptotic [18] and antitumor activities [19]. Because of these active properties, Tan IIA is widely used to treat cardiovascular diseases [20,21], nervous system diseases [22], intestinal diseases [23,24], allergic diseases [25], diabetes [26] and various tumors, including gastric cancer [27], hepatocellular carcinoma [28] and colorectal cancer [29]. Sodium Tan IIA sulfonate has also been reported to alleviate MAPK/HIF-1α-mediated inflammation and oxidative stress in cigarette smoke-induced chronic obstructive pulmonary disease in mice [30]. However, whether Tan IIA can ameliorate inflammation, oxidative stress and apoptosis in lung blast-injury mice and whether the protective effect of Tan IIA is the correlated with PI3K/Akt/FoxO1 signaling pathway remain unclear.
In this study, we showed that Tan IIA alleviated blast-induced inflammation, oxidative stress and apoptosis in mice. We also demonstrated that the protective effects of Tan IIA were associated with inhibiting the PI3K/Akt/FoxO1 signaling pathway. Hence, our results indicate that Tan IIA may be a potential treatment for lung blast injury.
Section snippets
Animals and experimental groups
Fifty male C57BL/6 mice were provided by the Experimental Animal Department of the General Hospital of Northern Theater Command. All mice were housed one week before start of experiment under standard laboratory conditions at a stable temperature (20–24 °C) and humidity (55 + 5%) and a 12/12 h light/dark cycle with food and water ad libitum. Animals were maintained as per the guidelines for Care and Use of Laboratory Animals of the National Institutes of Health and Academy of General Hospital
Tan IIA attenuated blast-exposure-induced acute lung injury
Compared with the control group, the lung weight/body weight and W/D ratios were significantly increased in the blast group, whereas Tan IIA notably inhibited blast-induced ratio increases (Fig. 1A–B, p < 0.05). Compared with the control group, blast exposure significantly increased the Evans blue leakage, which was reduced by Tan IIA treatment (Fig. 1C–D, p < 0.05). Lung blast injury can significantly injure the lungs, which manifests as hemorrhaging, edema, alveolar septal rupture and obvious
Discussion
Accumulating evidence suggests that several pathological changes occur in the lungs after blast injury, including inflammation, oxidative stress, immune changes and apoptosis. In this study, the data showed that Tan IIA significantly inhibited blast-induced lung weight/body weight and W/D ratios, reversed Evans blue leakage and histopathological changes, and alleviated inflammatory cell infiltration, oxidative stress and tissue apoptosis. Additionally, Tan IIA significantly decreased p-PI3K and
Author contributions
Jing Li, Mingxiao Hou and Hongxu Jin designed experiments. Yunen Liu and Changci Tong wrote the manuscript. Yan Zhao revised and polished the manuscript. Ying Liu, Xiuyun Shi, Lin Shi and Peifang Cong completed animal experiment, pathological experiment, molecular biology experiment and protein experiment.
Declaration of competing interest
The authors declare that there are no conflicts of interest.
Acknowledgments
We thank Traci Raley, MS, ELS, from Liwen Bianji, Edanz Editing China, for editing a draft of this manuscript. We would like to acknowledge funding support by the grants of Liaoning Province Key Scientific and Technological Project (No. 201602774; No. 20170540947), and PLA fundation of China (No.BWS16J010; No. AWS14L008; No. CSY13J003).
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Contributed equally.