Xiebai San alleviates acute lung injury by inhibiting the phosphorylation of the ERK/Stat3 pathway and regulating multiple metabolisms

Abstract

Background: Acute lung injury (ALI) often leads to serious respiratory diseases with high incidence rates and mortality. For centuries, Xiebai San (XBS) has been a classical traditional Chinese medicine (TCM) about respiratory illness such as pneumonia in children. However, the related mechanism of XBS against ALI remains indistinct.

Purpose: To reveal specific targets of XBS in lipopolysaccharide (LPS)-induced ALI mice using integrated pharmacology.

Study design: The integrated method was to expound mechanism and targets of XBS inhibited ALI.

Methods: The primary components in XBS were identified by ultra high performance liquid chromatography-quadrupole time of flight-mass spectrometry (UHPLC-QTOF-MS). The potential drug targets were established using network pharmacology. The anti-ALI effect of XBS was evaluated in mice. Additionally, therapeutic targets were screened by integrating metabolome and transcriptome and verified in lung tissue.

Results: In total, 163 chemical components were identified in XBS, and a network of "3 drugs-18 components-86 targets" for XBS against ALI was constructed. In ALI mice, XBS alleviated lung inflammation by decreasing permeation and expression of neutrophils, tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in bronchoalveolar lavage fluid (BALF), serum, and lung tissue. Next, the transcriptome of lung tissue was analyzed and enriched, indicating the importance of mitogen-activated protein kinase (MAPK), Janus kinase-signal transducer and activator of transcription (JAK-STAT), and others, which was consistent with network pharmacology prediction. Also, western blotting and immunohistochemistry results showed that XBS was against ALI mainly by inhibiting extracellular signal regulated kinase (ERK) and signal transducer and activator of transcription 3 (Stat3) phosphorylation. In addition, the metabolome of lung tissue revealed that XBS mainly regulated pathways involved in arachidonic acid, glycerophospholipid, and tryptophan metabolisms. The expression levels of leukotriene, phosphatidylcholine, kynurenine, and others were also verified.

Conclusion: XBS alleviated inflammation of ALI by inhibiting the phosphorylation of the ERK/Stat3 pathway and regulating arachidonic acid, glycerophospholipid, and tryptophan metabolisms. This study will guide clinical precision medicine and promote modernization of XBS.

Keywords: Acute lung injury; Metabolome; Network pharmacology; Transcriptome; Xiebai San.