Suzi Daotan Decoction alleviates asthmatic airway remodeling through the AMPK/SIRT1/PGC-1α signaling pathway and PI3K/AKT signaling pathway

Suzi Daotan Decoction (SZDTD), recorded in the "New Edition of the Sasang of Eastern Medicine", serves as a prominent formula for managing asthma in Shao-Yin individuals in Korean traditional medicine. This prescription demonstrates clinical efficacy in asthma treatment and is associated with anti-inflammatory and antioxidant properties. Nonetheless, the precise underlying mechanism remains incompletely understood. This study aims to elucidate the impact of SZDTD in ameliorating asthmatic airway remodeling and investigate whether its mechanism is related to the AMPK/SIRT1/PGC-1α and PI3K/AKT signaling pathways. Through network pharmacology analysis, the components and putative targets of SZDTD were investigated, along with the target genes associated with allergic asthma. Enrichment analysis identified the AMPK/SIRT1/PGC-1α and PI3K/AKT signaling pathways as relevant pathways. Subsequently, in an allergic asthma mouse model sensitized and challenged with ovalbumin (OVA), mice were orally administered a low dose of SZDTD, a high dose of SZDTD, or dexamethasone before the challenge. The control group received 0.9% NaCl only. The number of inflammatory cells was assessed using Diff-Quik staining. The levels of interleukin-4(IL-4), IL-5, IL-13 in broncho-alveolar lavage fluid (BALF), total immunoglobulin E(IgE), and OVA-specific IgE in serum were detected by Enzyme-linked immunosorbent assay. IL-4 and interferon γ (IFN-γ) in spleen and lymph were detected by flow cytometry. Histological staining was employed to observe lung tissue pathology. Protein levels were evaluated using Immunohistochemistry(IHC), Western blotting (WB), and immunofluorescence (IF). Furthermore, BEAS-2B human bronchial epithelial cells stimulated with LPS were treated with varying concentrations of SZDTD, and WB analysis was conducted to determine associated protein levels. SZDTD demonstrated a significant reduction in inflammatory cell infiltration, as well as decreased levels of IL-4, IL-5, and IL-13 in BALF, and total IgE and ovalbumin-specific IgE levels in serum. Flow cytometry analysis revealed that SZDTD treatment led to decreased levels of IFN-γ and IL-4 in the lymph nodes and spleen, with a more pronounced effect observed on IL-4 level. Moreover, results from MASSON staining indicated that SZDTD treatment markedly reduced the expression of α-SMA (α-smooth muscle actin) and mitigated collagen deposition symptoms. Furthermore, SZDTD stimulated the phosphorylation of Adenosine 5'-monophosphate-activated protein kinase (AMPK) and enhanced the expression of Silent information regulator 1 (SIRT1) and Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), while inhibiting the expression of P-PI3K, P-AKT. In vitro experiments showed that SZDTD promoted the phosphorylation of AMPK, increased the expression of SIRT1 and PGC-1α, and suppressed the expression of P-PI3K, P-AKT. SZDTD can alleviate airway remodeling in allergic asthma by a mechanism related to activation of AMPK/SIRT1/PGC-1α and inhibition of PI3K/AKT signaling pathways.