Abstract
Purpose
Radiation-induced pulmonary fibrosis (RIPF) is a major side effect after radiotherapy for thoracic malignancies. However, rare anti-RIPF therapeutics show definitive effects for treating this disease. Ubiquitin-specific peptidase 11 (USP11) has been reported to promote transforming growth factor β (TGFβ) signaling which plays an essential role underlying RIPF. Herein, we explored the role of USP11 on RIPF.
Materials and methods
In the present study, USP11-knockout (Usp11-/-) mice were used to explore the effects of USP11 on RIPF. The lung tissue was obtained after receiving 30 Gy X-ray irradiation. The expression of USP11, TGF-β1, and a-SMA was determined by immunohistochemical and Western Blot, respectively. γ-H2AX foci and TUNEL positive cells were detected by fluorescent technique to assess DNA damage and apoptosis. High-throughput proteomic analysis was applied to further explore the related mechanisms. The transwell co-culture method was used to investigate bystander effects in HELF cells induced by irradiated HMEC-1 cells in vitro.
Results
Here we found that radiation activated USP11 in vivo and in vitro. Our results showed that USP11 deficiency effectively decreased serum TGF-β1 level, suppressed α-SMA expression, and mitigated pulmonary fibrosis. In addition, fewer γ-H2AX foci and decreased apoptotic cells were identified after irradiation in the primary cells isolated from the lungs of Usp11-/- mice. High-throughput proteomics analysis results showed that 22-upregulated and 158-downregulated proteins were identified in the lung tissues of Usp11-/- mice after irradiation. Furthermore, gene set enrichment analysis (GSEA) revealed that USP11 deficiency affects the tight junction signaling pathway.
Conclusions
We verified that USP11 deficiency remarkably reinforced tight junction in the endothelial cells and alleviated TGF-β1 to inhibit fibrosis of fibroblast cells. The present study preliminarily showed that USP11-knockout mitigated RIPF via reinforcement endothelial barrier function.
Keywords:
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
Notes on contributors
Yiting Tang
Yingting Tang, PhD candidate, her research interest is the biological effects of ionizing radiation.
Qian Yuan
Qian Yuan, MD, her research field is Radiation Medicine.
Congzhao Zhao
Congzhao Zhao, MD, his research field is Radiation Medicine.
Ying Xu
Ying Xu, MD, her research interest is the biological effects of ionizing radiation.
Qi Zhang
Yang Jiao, Jianping Cao, Qi Zhang, PhD, are Professors of State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University.
Lili Wang
Lili Wang, PhD, MD, her research field is Radiation Oncology, is a Professor of the Department of Radiotherapy, The First Affiliated Hospital of Soochow University.
Zhiqiang Sun
Judong Luo, Zhiqiang Sun, PhD, MD, are Professors of Department of Radiotherapy, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University.
Jianping Cao
Yang Jiao, Jianping Cao, Qi Zhang, PhD, are Professors of State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University.
Judong Luo
Judong Luo, Zhiqiang Sun, PhD, MD, are Professors of Department of Radiotherapy, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University.
Yang Jiao
Yang Jiao, Jianping Cao, Qi Zhang, PhD, are Professors of State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University.