Tetramethylpyrazine Ameliorates Endotoxin-induced Acute Lung Injury by Relieving Golgi Stress via the Nrf2/HO-1 Signaling Pathway

Purpose: Endotoxin-induced acute lung injury (ALI) is a severe disease caused by an imbalanced host response to infection. It is necessary to explore novel mechanisms for the treatment of endotoxin-induced ALI. In endotoxin-induced ALI, tetramethylpyrazine (TMP) provides protection through anti-inflammatory, anti-apoptosis, and anti-pyroptosis effects. However, the mechanism of action of TMP in endotoxin-induced ALI remains unclear. Here, we aimed to determine whether TMP can protect the lungs by inhibiting Golgi stress via the Nrf2/HO-1 pathway. Methods and results Using lipopolysaccharide (LPS)-stimulated C57BL/6J mice and MLE12 alveolar epithelial cells, we observed that TMP pretreatment attenuated endotoxin-induced ALI. The LPS + TMP group showed lesser lung pathological damage and a lower rate of apoptotic lung cells than the LPS group. TMP pretreatment also decreased the levels of inflammatory factors and oxidative stress damage ( P  < 0.05). Additionally, TMP pretreatment reduced Golgi stress by increasing the Golgi matrix protein 130 (GM130), Golgi apparatus Ca 2+ /Mn 2+ ATPases (ATP2C1), and Golgin97 expression while decreasing the Golgi phosphoprotein 3 (GOLPH3) expression ( P  < 0.05). Furthermore, TMP pretreatment promoted Nrf2 and HO-1 expression ( P  < 0.05). Nrf2-knockout mice or Nrf2 siRNA-transfected MLE12 cells were pretreated with TMP to explore how the Nrf2/HO-1 pathway affected TMP-mediated Golgi stress in endotoxin-induced ALI models. We observed that Nrf2 gene silencing partially reversed the alleviating effect of Golgi stress and the pulmonary protective effect of TMP. Conclusion Our findings showed that TMP therapy reduces endotoxin-induced ALI by suppressing Golgi stress via the Nrf2/HO-1 signaling pathway in vivo and in vitro.