Effect and mechanism of Xiao′er Zhixiao Pingchuan Granules in improving airway remodeling in asthmatic mice

To investigate the intervention effect of Xiao′er Zhixiao Pingchuan Granules (XEZXPCG) on ovalbumin (OVA)-induced airway remodeling in asthmatic mice and its potential mechanism by regulating macrophage migration inhibitory factor (MIF) and inhibiting the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway.

A total of 96 SPF-grade male BALB/c mice were randomly divided into blank, model, XEZXPCG low/medium/high-dose groups (2.05, 4.10, and 8.20 g/kg), adeno-associated virus (AAV) NC shRNA, AAV MIF shRNA (MIF gene silencing), and LY294002 (PI3K/Akt inhibitor, 1 mg/kg) groups (12 mice in each group). Asthma models were established through OVA sensitization and challenge. Airway resistance and the proportions of inflammatory cells (eosinophils and macrophages) in bronchoalveolar lavage fluid (BALF) were detected. Serum inflammatory factor (OVA-IgE, interleukin [IL]-1β, IL-6, tumor necrosis factor-alpha, and interferon-gamma) levels and BALF were quantified. Hematoxylin and eosin, Masson, and periodic acid-Schiff staining were used to evaluate airway wall thickness (Wat/Phm), smooth muscle area (Wam/Phm), collagen deposition, and goblet cell metaplasia. Western blotting, immunofluorescence, and real-time fluorescence-qPCR were used to detect MIF protein and mRNA expressions, as well as activation markers of the PI3K/Akt pathway and cell cycle-related proteins (including cyclin-dependant kinase 6[CDK6], Cyclin D1, Cyclin D3, and p21), in lung tissues.

Compared to the model group, a XEZXPCG medium or high-dose significantly reduced airway resistance (P < 0.05), improved the imbalance of eosinophil and macrophage proportions in BALF, and decreased inflammatory factor levels in serum and BALF (P < 0.05). XEZXPCG medium or high-dose alleviated airway epithelial damage, goblet cell hyperplasia, and collagen fiber deposition, and reduced the Wat/Phm and Wam/Phm (P < 0.05), with effects comparable to those of the AAV MIF shRNA and LY294002 groups. XEZXPCG medium and high-inhibited MIF protein/mRNA expression (P < 0.05), downregulated Akt phosphorylation (P < 0.05), upregulated p21 protein expression, and downregulated Cyclin D1, Cyclin D3, and CDK6 expressions (P < 0.05).

XEZXPCG alleviates airway inflammation and improves airway remodeling in OVA-induced asthmatic mice by inhibiting MIF expression, downregulating the PI3K/Akt signaling pathway, and regulating cell cycle progression. XEZXPCG enhances airway remodeling through MIF-mediated PI3K/Akt pathway regulation.