Salvianolactone acid A isolated from Salvia miltiorrhiza ameliorates lipopolysaccharide-induced acute lung injury in mice by regulating PPAR-γ

Background: Severe inflammation of the lungs results from acute lung injury (ALI), a common life-threatening lung disease with a high mortality rate. The ligand-activated transcription factor Peroxisome Proliferator-activated Receptor (PPAR) γ plays essential roles in diverse biological processes including inflammation, metabolism, development, and immune response. Salvianolactone acid A (SA) is a terpenoid derived from the herb Salvia miltiorrhiza. However, there is a scarcity of experimental evidence indicating whether the effect of SA on ALI occurs via PPAR-γ.

Methods: SA (20 or 40 mg/kg, i.g., 1 time/day) was administered to mice for 3 d, followed by the induction of ALI by intranasal lipopolysaccharide (LPS, 10 mg/kg). The lung function and levels of inflammation, Reactive Oxygen Species (ROS), immune cells, Apoptosis, and PPAR-γ were examined. The antagonistic activity of GW9662 (GW, 1 µM, specific PPAR-γ blocker) and PPAR-γ transfection silencing against SA (10 μM) in BEAS-2B cells induced by LPS (10 μg/ml, 24 h) was also investigated to assess whether the observed effects caused by SA were mediated by PPAR-γ.

Results: The results showed that lung histopathological injury, the B-line, the fluorescence intensity of live small animal, and the biomarkers in BALF or lung in the treatment of SA could regulate significantly. In addition, SA obviously decreased the levels of ROS and Apoptosis in the primary lung cells, and MDA, increased the levels of GSH-Px and SOD. SA reduced levels of macrophages and neutrophils. Furthermore, SA reduced the protein levels of Keap-1, Cleaved-caspase-3, Cleaved-caspase-9, p-p65/p65, NLRP3, IL-1β, and upregulated the levels of p-Nrf2/Nrf2, HO-1, Bcl-2/Bax, PPAR-γ, p-AMPK/AMPK in lung tissue. In addition, silencing and inhibition of PPAR-γ effectively decreased the protective effects of SA in BEAS-2B cells induced by LPS, which might indicate that the active molecules of SA regulate ALI via mediation by PPAR-γ, which exhibited that the effect of SA related to PPAR-γ.

Conclusions: The anti-ALI effects of SA were partially mediated through PPAR-γ signaling. These data provide the molecular justification for the usage of SA in treating ALI and can assist in increasing the comprehensive utilization rate of Salvia miltiorrhiza.

Acute lung injury; PPAR-γ; Salvianolactone acid A; Terpenoid.