18β-Glycyrrhetinic acid monoglucuronide (GAMG) alleviates radiation-induced lung injury in mice by regulating macrophage polarization through the NF-κB signaling pathway

PURPOSE: Radiation-induced lung injury (RILI) is an unforeseeable outcome of radiotherapy, and there are yet no feasible alternatives to treatment. The objective of this study is to characterize the protection of RILI by 18β-Glycyrrhetinic acid monoglucuronide (GAMG, also referred to as glycyrrhetinic acid 3-O-mono-β-D-glucuronide)3-O-mono-β-D-glucuronide) and to explore the molecular mechanisms that may be implicated. METHODS: A murine model of radiation-induced lung injury (RILI) was established by administering a single 16 Gy dose of thoracic irradiation to the mice, followed by continuous intervention with GAMG. The investigation focused on assessing morphological and pathological alterations in lung tissue, quantifying inflammatory mediators, evaluating collagen deposition, and analyzing the expression of α-smooth muscle actin (α-SMA). Histopathological changes and collagen deposition were examined using Hematoxylin and Eosin (H&E) and Masson trichrome staining techniques. Cytokine concentrations in bronchoalveolar lavage fluid (BALF) were quantified via enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry (IHC) was utilized to assess markers indicative of M1-like macrophage polarization, specifically CD86 and inducible nitric oxide synthase (iNOS). Macrophage polarization status was further analyzed using flow cytometry. The activity of the NF-κB signaling pathway in lung tissue was investigated through Western blot analysis. RESULTS: The administration of GAMG effectively reduced symptoms of RILI and mitigated lung tissue damage in mice. Mechanistic studies revealed that GAMG inhibited radiation-induced activation of the NF-κB signaling pathway, while suppressing the differentiation of macrophages toward the pro-inflammatory M1-like phenotype in lung tissue. Further experiments showed that GAMG regulation of macrophage polarization may be achieved by inhibiting the NF-κB pathway. CONCLUSION: GAMG may decrease RILI via inhibiting NF-κB-induced inflammation and regulating macrophage polarization. This work aims to clarify the mechanism of action of GAMG, which could potentially serve as a therapeutic agent for preventing and treating lung damage caused by radiation.