川芎嗪对内毒素诱导的急性肺损伤大鼠肺纤维化和炎症反应的调节作用

目的：探索川芎嗪对内毒素诱导的急性肺损伤大鼠肺纤维化和炎症反应的影响及其机制。方法：大鼠随机分为5组：对照组、LPS模型组、LPS+川芎嗪（50，100，200 mg·kg^-1）组。苏木素伊红（HE）染色观察肺组织病变。Masson染色分析肺纤维化。酶联免疫吸附实验（ELISA）检测白细胞介素（interleukin，IL）-6，IL-1β，肿瘤坏死因子（tTNF-α）和IL-18水平。蛋白印记检测α平滑肌肌动蛋白（α-SMA），转化生长因子β1（TGF-β1），Ⅰ型胶原蛋白（collagen type Ⅰ），Ⅲ型胶原蛋白（collagen type Ⅲ），PI3K，P-PI3K，AKT，P-AKT，mTOR和P-mTOR的蛋白水平。结果：LPS模型组大鼠肺组织湿/干重之比高于对照组（P<0.01）。与LPS模型组相比，LPS+川芎嗪（100，200 mg·kg^-1）组大鼠肺组织湿/干重之比降低（P<0.01）。川芎嗪处理可改善LPS模型组大鼠肺组织病变及纤维化。LPS模型组大鼠α-SMA，TGF-β1，collagen type Ⅰ和collagen type Ⅲ表达高于对照组（P<0.01）。与LPS模型组相比，LPS+川芎嗪（50，100，200 mg·kg^-1）组大鼠α-SMA、TGF-β1、collagen type Ⅰ和collagen type Ⅲ表达降低（P<0.01）。与对照组相比，LPS模型组大鼠IL-6、IL-1β、IL-18和TNF-α水平升高（P<0.01）。LPS+川芎嗪（50，100，200 mg·kg^-1）组大鼠IL-6、IL-1β、IL-18和TNF-α水平低于LPS模型组（P<0.01）。LPS模型组大鼠P-PI3K/PI3K，P-AKT/AKT和P-mTOR/mTOR比值高于对照组（P<0.01）。与LPS模型组相比，LPS+川芎嗪（50，100，200 mg·kg^-1）组大鼠P-PI3K/PI3K，P-AKT/AKT和P-mTOR/mTOR比值下降（P<0.01）。结论：川芎嗪可通过抑制PI3K/AKT/mTOR信号通路活化减轻内毒素诱导的急性肺损伤大鼠肺纤维化和炎症反应。

The effect of ligustrazine on pulmonary fibrosis and inflammatory response in acute lung injury rats induced by endotoxin

OBJECTIVE To explore the effect of ligustrazine on pulmonary fibrosis and inflammatory response in acute lung injury induced by endotoxin. METHODS Rats were randomly divided into five groups, including control group, LPS model group and LPS + ligustrazine (50, 100, 200 mg·kg^-1) groups. Pathological changes of lung tissues were observed by hematoxylin-eosin (HE) staining. Fibrosis of lung tissues was analyzed by Masson staining. The levels of interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF-α) and IL-18 were detected by enzyme-linked immunosorbent assay (ELISA). The protein levels of α-smooth muscle-actin (α-SMA), transforming growth factor-β1 (TGF-β1), collagen type Ⅰ, collagen type Ⅲ, PI3K, P-PI3K, AKT, P-AKT, mTOR and P-mTOR were measured by Western blot. RESULTS The rate of wet weight/dry weight (W/D) in LPS model group was higher than that of control group (P<0.01). Compared with LPS model group, the rates of W/D in LPS + ligustrazine (100, 200 mg·kg^-1) groups were decreased (P<0.01). The pathological changes and fibrosis of lung tissues were ameliorated by ligustrazine. The expressions of α-SMA, TGF-β1, collagen type Ⅰ and collagen type Ⅲ in LPS model group were higher than those of control group (P<0.01). Compared with LPS model group, the expressions of α-SMA, TGF-β1, collagen type Ⅰ and collagen type Ⅲ in LPS + ligustrazine (50, 100, 200 mg·kg^-1) groups were reduced (P<0.01). Compared with control group, the levels of IL-6, IL-1β, IL-18 and TNF-α in LPS model group were increased (P<0.01). The levels of IL-6, IL-1β, IL-18 and TNF-α in LPS + ligustrazine (50, 100, 200 mg·kg^-1) groups were lower than those in LPS model group (P<0.01). The rates of P-PI3K/PI3K, P-AKT/AKT and P-mTOR/mTOR in LPS model group were higher than those of control group (P<0.01). Compared with LPS model group, the rates of P-PI3K/PI3K, P-AKT/AKT and P-mTOR/mTOR in LPS + ligustrazine (50, 100, 200 mg·kg^-1) groups were decreased (P<0.01). CONCLUSION Ligustrazine alleviates the fibrosis and inflammatory response by inhibiting activation of PI3K/AKT/mTOR pathway in endotoxin-induced acute lung injury rats.