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| Regulation of EI24 and Th1/Th2 Cell Ratio by Hesperidin in the Antagonism of Pulmonary Fibrosis and Its Potential Mechanisms |
| ZHANG Yan, MA Wen, YANG Hui, et al |
| The Affiliated Hospital of Guizhou Medical University, Guizhou Guiyang 550004, China |
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Abstract Objective: To observe the protective effects of hesperidin on bleomycin-induced pulmonary fibrosis in rats and explore its related mechanisms involving E2F-mediated transcription factor 2.4 (EI24) gene and Th1/Th2 balance.Methods: Sixty rats were randomly divided into six groups: sham operation group, model group, pirfenidone group (positive control, 0.12 g/kg pirfenidone), low-dose hesperidin group (12mg/kg), medium-dose hesperidin group (24mg/kg), and high-dose hesperidin group (36mg/kg), with 10 rats in each group. Pulmonary fibrosis was induced by tracheal injection of bleomycin. Lung function indicators, including forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and peak expiratory flow (PEF), were measured using a small animal ventilator. Histopathological evaluation was performed using hematoxylin-eosin and Masson staining. Enzyme-linked immunosorbent assay was used to detect the levels of cytokines in rat lung tissues in February 2023. Flow cytometry was employed to analyze the proportions of helper T cell (Th) subsets in rat lung tissues in February 2023. Protein immunoblotting was conducted to assess the expression of EI24 protein in lung tissues. Results: Compared to the model group, rats in the hesperidin treatment groups showed significantly increased FVC, FEV1, and PEF, and a notable decrease in the lung index (P<0.05). Hesperidin-treated rats exhibited reduced lung tissue damage, inflammation, fibrosis, and collagen deposition compared to the model group. Moreover, the levels of TGF-β1, Col I, HYP, IL-6, and TNF-α in lung tissues were significantly lower than those in the hesperidin treatment groups (P<0.05). Compared to the sham operation group, the model group showed significantly decreased expression of EI24 mRNA and protein; however, the medium-dose and high-dose hesperidin groups exhibited a significant increase in EI24 mRNA and protein expression compared to the model group (P<0.05). Additionally, the medium-dose and high-dose hesperidin groups showed a significant increase in the proportion of Th1 cell subsets and a decrease in Th2 cell subsets in lung tissues compared to the model group (P<0.05). Furthermore, the levels of IFN-γ were significantly elevated, while IL-13 and IL-4 levels were significantly decreased in lung tissues of the medium-dose and high-dose hesperidin groups compared to the model group (P<0.05). Conclusion: Hesperidin attenuates bleomycin-induced inflammatory cell infiltration, pro-inflammatory cytokine release, and excessive extracellular matrix deposition, thereby improving the process of pulmonary fibrosis in rats. The mechanism may involve the modulation of EI24 and Th1/Th2 immune cell balance.
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2024, Vol. 30 
