Systems pharmacology reveals the mechanism of activity of Physalis alkekengi L. var. franchetii against lipopolysaccharide-induced acute lung injury.

Acute lung injury (ALI) is an important cause of mortality of patients with sepsis, shock, trauma, pneumonia, multiple transfusions and pancreatitis. Physalis alkekengi L. var. franchetii (Mast.) Makino (PAF) has been extensively used in Chinese folk medicine because of a good therapeutic effect in respiratory diseases. Here, an integrated approach combining network pharmacology, proton nuclear magnetic resonance-based metabolomics, histopathological analysis and biochemical assays was used to elucidate the mechanism of PAF against ALI induced by lipopolysaccharide (LPS) in a mouse model. We found that the compounds present in PAF interact with 32 targets to effectively improve the damage in the lung undergoing ALI. We predicted the putative signalling pathway involved by using the network pharmacology and then used the orthogonal signal correction partial least-squares discriminant analysis to analyse the disturbances in the serum metabolome in mouse. We also used ELISA, RT-qPCR, Western blotting, immunohistochemistry and TUNEL assay to confirm the potential signalling pathways involved. We found that PAF reduced the release of cytokines, such as TNF-α, and the accumulation of oxidation products; decreased the levels of NF-κB, p-p38, ERK, JNK, p53, caspase-3 and COX-2; and enhanced the translocation of Nrf2 from the cytoplasm to the nucleus. Collectively, PAF significantly reduced oxidative stress injury and inflammation, at the same time correcting the energy metabolism imbalance caused by ALI, increasing the amount of antioxidant-related metabolites and reducing the apoptosis of lung cells. These observations suggest that PAF may be an effective candidate preparation alleviating ALI.