Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt.
Department of Biochemistry, Faculty of Pharmacy, Minia University, El-minia, Egypt.
Life Sci. 2020 Aug 15;255:117743. doi: 10.1016/j.lfs.2020.117743. Epub 2020 May 1.
Radiation-induced lung injury (RILI) is a serious complication of radiation therapy. Development of an effective drug that selectively protects normal lung tissues and sensitizes tumor cells to radiotherapy is an unmet need. 2-Methoxyestradiol (2ME2) possesses polypharmacological properties, which qualifies it as an effective radioprotector. Our aim is to explore the potential protective effects of 2ME2 against early and late stages of RILI and the underlying mechanisms.
BALB/c mice were either treated with 2ME2 (50 mg/kg/day i.p., for 4 weeks); or received a single dose of 10 Gy ionizing radiation (IR) delivered to the lungs; or 10 Gy IR and 2ME2. Animal survival and pulmonary functions were evaluated. Immune-phenotyping of alveolar macrophages (AM) in the broncho-alveolar lavage fluids (BALF) was determined by flow cytometry. ELISA was used to evaluate the expression levels of TNF-α, TGF-β; and IL-10 in BALF. Lung tissues were used for histopathological examination or immunofluorescence staining for CD68 (pan-macrophage marker), Arginase-1 (Arg1, M2-specific marker), inducible nitric oxide synthase (iNOS, M1-specific marker) and HIF-1α. VEGF and γH2AX expression in lung tissues were detected by western blot.
The results demonstrated that 2ME2 improved the survival, lung functions and histopathological parameters of irradiated mice. Additionally, it attenuated the radiation-induced AM polarization and reduced the pneumonitis and fibrosis markers in lung tissues. Significant reduction of TNF-α and TGF-β with concomitant increase in IL-10 concentrations were observed. Moreover, the expression of HIF-1α, VEGF and γH2AX declined.
2ME2 is a promising radioprotectant with fewer anticipated side effects.
放射性肺损伤（RILI）是放射治疗的严重并发症。开发一种有效药物，选择性保护正常肺组织并使肿瘤细胞对放疗敏感，是一种未满足的需求。2-甲氧基雌二醇（2ME2）具有多药理学特性，使其成为一种有效的放射保护剂。我们的目的是探索 2ME2 对 RILI 早晚期的潜在保护作用及其潜在机制。
BALB/c 小鼠接受 2ME2（50mg/kg/天腹腔注射，持续 4 周）治疗；或单次给予肺部 10Gy 电离辐射（IR）；或 10GyIR 和 2ME2。评估动物存活率和肺功能。通过流式细胞术测定支气管肺泡灌洗液（BALF）中肺泡巨噬细胞（AM）的免疫表型。ELISA 用于评估 BALF 中 TNF-α、TGF-β和 IL-10 的表达水平。肺组织用于组织病理学检查或 CD68（泛巨噬细胞标志物）、精氨酸酶 1（Arg1，M2 特异性标志物）、诱导型一氧化氮合酶（iNOS，M1 特异性标志物）和 HIF-1α的免疫荧光染色。通过 Western blot 检测肺组织中 VEGF 和 γH2AX 的表达。
结果表明，2ME2 提高了照射小鼠的存活率、肺功能和组织病理学参数。此外，它减弱了辐射诱导的 AM 极化，并减少了肺组织中的肺炎和纤维化标志物。观察到 TNF-α和 TGF-β显著减少，同时 IL-10 浓度增加。此外，HIF-1α、VEGF 和 γH2AX 的表达下降。
2ME2 是一种有前途的放射保护剂，预计副作用较少。
