| Han Xiaodan,Yuan Tong,Song Di,Zhang Junling,Shi Yonggang.FOXO4-DRI, a synthetic peptide targeting FOXO4, reverses radiation-induced lung fibrosis[J].Chinese Journal of Radiological Medicine and Protection,2023,43(9):669-675 |
| FOXO4-DRI, a synthetic peptide targeting FOXO4, reverses radiation-induced lung fibrosis |
| Received:April 19, 2023 |
| DOI：10.3760/cma.j.cn112271-20230419-00126 |
| KeyWords:Radiation-induced pulmonary fibrosis FOXO4-DRI Cell senescence Oxidative stress |
| FundProject:国家自然科学基金（81903254） |
| Author Name | Affiliation | E-mail | | Han Xiaodan | Department of Radiation Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China | hanxiaodan1202@163.com | | Yuan Tong | Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin 300192, China | | | Song Di | Zhengzhou University, Zhengzhou 450001, China | | | Zhang Junling | Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin 300192, China | | | Shi Yonggang | Department of Radiation Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China | |
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| Abstract:: |
| Objective To evaluate whether FOXO4-DRI could reverse radiation-induced pulmonary fibrosis (RIPF) and to explore the underlying mechanism.Methods C57BL/6 mice were randomly divided into 4 groups:control, FOXO4-DRI, radiation, and radiation+FOXO4-DRI. Mice in radiation or radiation+FOXO4-DRI groups received 17 Gy X-ray radiation on the right side of the whole chest. Mice in FOXO4-DRI and radiation+FOXO4-DRI groups were injected with FOXO4-DRI intraperitoneally at 16 and 20 weeks after irradiation, respectively. The right lungs were collected at 24 weeks after irradiation and subjected to HE staining and Masson trichrome staining to observe the morphological changes and collagen deposition. Immunohistochemistry was used to evaluate the expressions of col1α1 and α-SMA in lung tissues. β-gal staining was used to observe senescent cells. The level of reactive oxygen species in lung tissue was detected. The expressions of P21, P16Ink4a and senescence-associated secretory phenotype (SASP) mRNA were detected by qRT-PCR, and the expression of related proteins were assessed by Western blot.Results FOXO4-DRI reduced collagen deposition (t=6.18, P<0.05), down-regulated the expression of col1α1 and α-SMA (t=4.69, 3.20, P<0.05), and reduced the number of β-gal positive cells (t=6.09, P<0.05) in the lung tissue of RIPF mice. FOXO4-DRI also down-regulated the gene and protein expressions of P21 and P16Ink4a (t=5.31, 3.32 and 4.77, 3.37, P<0.05) and inhibited the expressions of SASP genes IL-1α, IL-1β, TNF-α and MMP2 (t=4.36, 4.84, 4.47, 3.82, P<0.05), reduced reactive oxygen species (t=2.84, P<0.05), and promoted the activation of p-AKT and p-PI3K proteins (t=-7.13,-12.61, P< 0.05) in the lung tissue of RIPF mice.Conclusions FOXO4-DRI reverses RIPF by activating the PI3K/AKT signaling pathway, reducing oxidative stress and inhibiting cellular senescence. |
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