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Protective effect of liriodendrin on IgG immune complex-induced acute lung injury via inhibiting SRC/STAT3/MAPK signaling pathway: a network pharmacology research

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Abstract

The primary objectives of this research were to investigate the protective effects of liriodendrin against IgG immune complex (IgG-IC)-induced acute lung injury (ALI) and to elucidate the underlying mechanisms. This study employed a mouse and cell model of IgG-IC-induced acute lung injury. Lung tissue was stained with hematoxylin–eosin to observe pathological alterations and arterial blood gas analysis was tested. Inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α), were measured using ELISA. The mRNA expression of inflammatory cytokines was assessed via RT-qPCR. Molecular docking and enrichment analysis were combined to identify the most potential signaling pathways modulated by liriodendrin, which were then verified using western blot analysis in IgG-IC-induced ALI models. We identified 253 shared targets between liriodendrin and IgG-IC-induced acute lung injury from the database. Through network pharmacology, enrichment analysis, and molecular docking, SRC was determined to be the most closely associated target of liriodendrin in IgG-IC-induced ALI. Pretreatment with liriodendrin notably reduced the increased cytokine secretion of IL-1β, IL-6, and TNF-α. Histopathological analysis of lung tissue demonstrated a protective effect of liriodendrin on IgG-IC-induced acute lung injury in mice. Arterial blood gas analysis showed liriodendrin ameliorated acidosis and hypoxemia efficiently. Further studies revealed that liriodendrin pretreatment substantially attenuated the elevated phosphorylation levels of SRC’s downstream components (JNK, P38, and STAT3), suggesting that liriodendrin may protect against IgG-IC-induced ALI via the SRC/STAT3/MAPK pathway. Our findings indicate that liriodendrin protects against IgG-IC-induced acute lung injury by inhibiting the SRC/STAT3/MAPK signaling pathway, suggesting that liriodendrin may serve as a potential treatment for acute lung injury caused by IgG-IC.

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Data availability

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Abbreviations

AKT1:

AKT serine/threonine kinase1

ALI:

Acute lung injury

ARDS:

acute respiratory distress syndrome

BALF:

Bronchoalveolar lavage fluid

C/EBP:

CCAAT/enhancer binding protein

EGFR:

epidermal growth factor receptor

ESR1:

estrogen receptor 1

ELISA:

enzyme-linked immunosorbent assay

GRB2:

growth factor receptor-bound protein2

GO:

Gene Ontology

HRAS:

HRas proto-oncogene, GTPase

HSP90AA1:

Heat shock protein 90 alpha family class a member1

IgG-IC:

IgG immune complex

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

KEGG:

Kyoto Encyclopedia of Genes and Genomes

MAPK1:

Mitogen-activated protein kinase1

MAPK14:

Mitogen-activated protein kinase14

NF-κB:

Nuclear factor kappa-B; PPI, protein–protein interaction

RHOA:

Ras homolog gene family, member A

SRC:

Proto-oncogene tyrosine-protein kinase, SRC

STAT3:

Signal transducer and activator of transcription3

TCM:

Traditional Chinese medicine

TNF-α:

Tumor necrosis factor-α

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Funding

This work was supported by the National Natural Science Foundation of China (No.81971858), the Inner Mongolia Natural Science Foundation (No.2022MS08029), the Tianjin Municipal Natural Science Foundation (No. 18JCQNJC13400; No. 19JCZDJC36200), and the science foundation of Tianjin Municipal Health Bureau (No. 2021044; No. 2021009) for their great supports in financing this research.

Author information

Authors and Affiliations

  1. Graduate School, Tianjin Medical University, Tianjin, China

    Sijia Zhang, Dongsheng Hu, Lingzhi Cui & Ximo Wang

  2. Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin Nankai Hospital, Tianjin, China

    Yuzhen Zhuo, Dihua Li, Lanqiu Zhang, Lei Yang & Ximo Wang

  3. Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine for Acute Abdominal Diseases, Tianjin University, Tianjin, China

    Ximo Wang

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  1. Sijia Zhang
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  4. Lingzhi Cui
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  5. Dihua Li
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Contributions

Sijia Zhang conducted the experiments, analyzed the experimental data, wrote the draft of the article, and prepared the graphs and tables; Dongsheng Hu prepared charts and wrote the draft of the paper; Yuzhen Zhuo, Lingzhi Cui, Dihua Li, and Lanqiu Zhang provided and analyzed the data. Lei Yang designed the experiments, revised the draft, and Ximo Wang conceived the final draft. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Lei Yang or Ximo Wang.

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Zhang, S., Hu, D., Zhuo, Y. et al. Protective effect of liriodendrin on IgG immune complex-induced acute lung injury via inhibiting SRC/STAT3/MAPK signaling pathway: a network pharmacology research. Naunyn-Schmiedeberg's Arch Pharmacol 396, 3269–3283 (2023). https://doi.org/10.1007/s00210-023-02534-1

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