Salvianolic Acid A Protects against Lipopolysaccharide-Induced Acute Lung Injury by Inhibiting Neutrophil NETosis

Abstract

Salvianolic acid A (SAA) is one of bioactive polyphenol extracted from a Salvia miltiorrhiza (Danshen), which was widely used to treat cardiovascular disease in traditional Chinese medicine. SAA has been reported to be protective in cardiovascular disease and ischemia injury, with anti-inflammatory and antioxidative effect, but its role in acute lung injury (ALI) is still unknown. In this study, we sought to investigate the therapeutic effects of SAA in a murine model of lipopolysaccharide- (LPS-) induced ALI. The optimal dose of SAA was determined by comparing the attenuation of lung injury score after administration of SAA at three different doses (low, 5 mg/kg; medium, 10 mg/kg; and, high 15 mg/kg). Dexamethasone (DEX) was used as a positive control for SAA. Here, we showed that the therapeutic effect of SAA (10 mg/kg) against LPS-induced pathologic injury in the lungs was comparable to DEX. SAA and DEX attenuated the increased W/D ratio and the protein level, counts of total cells and neutrophils, and cytokine levels in the BALF of ALI mice similarly. The oxidative stress was also relieved by SAA and DEX according to the superoxide dismutase and malondialdehyde. NET level in the lungs was elevated in the injured lung while SAA and DEX reduced it significantly. LPS induced phosphorylation of Src, Raf, MEK, and ERK in the lungs, which was inhibited by SAA and DEX. NET level and phosphorylation level of Src/Raf/MEK/ERK pathway in the neutrophils from acute respiratory distress syndrome (ARDS) patients were also inhibited by SAA and DEX in vitro, but the YEEI peptide reversed the protective effect of SAA completely. The inhibition of NET release by SAA was also reversed by YEEI peptide in LPS-challenged neutrophils from healthy volunteers. Our data demonstrated that SAA ameliorated ALI via attenuating inflammation, oxidative stress, and neutrophil NETosis. The mechanism of such protective effect might involve the inhibition of Src activation.

Emerging Role of Neutrophil Extracellular Traps in Gastrointestinal Tumors: A Narrative Review

“…Salvia miltiorrhiza (Danshen) is a plant used medicinally for the treatment of cancer [92], and its root extract can prevent neutrophils from transferring to metastatic sites by inhibiting the activities of MPO and NADPH oxidase (NOX), thereby obstructing the formation of NETs [93]. This was also validated by the latest research that showed that one of the bioactive polyphenols extracted from Danshen called SAA, can attenuate oxidative stress, inflammation, and neutrophil NETosis to ameliorate acute lung injury [94]. Compared with traditional anticancer drugs, tumor nanotherapeutics have various unique advantages.…”

Research Progress on Regulation of Immune Response by Tanshinones and Salvianolic Acids of Danshen (Salvia miltiorrhiza Bunge)

“…It was confirmed that salvianolic acid B ( 19 ) could treat acute airway inflammation and oxidative stress by inhibiting TLR/TLR4/MyD88/NLRP3 pathways, significantly reducing the increase in the number and infiltration of neutrophils and macrophages in BALF induced by pm2.5, and decreasing the levels of SOD, IL-1β, and TNF-α [ 109 ]. Meanwhile, salvianolic acid A ( 17 ) inhibited neutrophil formation and reduced inflammation and oxidative stress, which ameliorated acute lung injury by inhibiting the scarecrow (Scr) pathway in vivo and in vitro [ 110 ].…”

Reactive Oxygen Species and Strategies for Antioxidant Intervention in Acute Respiratory Distress Syndrome

“…The ERK pathway regulates diverse cellular functions and is activated by various stimuli, such as growth hormones, oxidative stress, and inflammatory responses mediated by the phosphorylation of MAP/ERK Kinase (MEK) through MAPK kinase kinases (MAP3K) Raf [114]. Liu et al [115] revealed that LPS stimulation augmented oxidative stress, inflammation, and neutrophil NETosis through the phosphorylation of Raf, MEK, and ERK in a murine lung inflammation model and neutrophils from patients with ARDS. Similarly, the elevated phosphorylation of ERK and JNK mediated excessive ROS production in models of hyperoxia-induced in vitro and in vivo ARDS [26].…”