Shu-Yan Gao1, Xue Zhou2, You-Jie Li3, Wei-Li Liu2, Ping-Yu Wang3, Min Pang3, Shu-Yang Xie4, Chang-Jun Lv5. 1. Department of Clinical Medicine, Binzhou Medical University, Yantai 264003, China; Key Laboratory of Tumour Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong 264003, China. 2. Department of Clinical Medicine, Binzhou Medical University, Yantai 264003, China. 3. Key Laboratory of Tumour Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong 264003, China. 4. Department of Clinical Medicine, Binzhou Medical University, Yantai 264003, China; Key Laboratory of Tumour Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong 264003, China. Electronic address: shuyangxie@aliyun.com. 5. Department of Clinical Medicine, Binzhou Medical University, Yantai 264003, China. Electronic address: changjun_lv@163.com.
Abstract
AIMS: This study aimed to investigate the pathogenesis mechanisms of bleomycin (BLM)-induced pulmonary fibrosis (PF) in Sprague-Dawley rats and explore the anti-fibrotic role of arsenic trioxide (As2O3) in preventing PF. MAIN METHODS: Intratracheal instillation of BLM was performed to establish PF rat models. The treatment group was treated with As2O3 (0.4 mg/kg/day). Morphological changes were observed by hematoxylin-eosin and Masson staining. Related proteins were determined by immunohistochemistry, immunofluorescence, and Western blot. MicroRNA detection was performed by quantitative real-time polymerase chain reaction. KEY FINDINGS: As a novel miRNA in PF, miR-98 decreased in the fibrotic lung tissues. Based on microRNA analysis software, we found that Stat3-3'-UTR is targeted by miR-98. Then, we found that Stat3 was activated with PF development and the expression of Stat3 and p-Stat3 was significantly increased in BLM-induced PF at day 28 compared with saline-treated rats. Our results showed that both Stat3 and p-Stat3 were significantly decreased in miR-98-treated A549 cells compared with that in mu-98-treated cultures or untreated controls. The fibrotic marker α-SMA was upregulated, whereas E-cadherin was inhibited in fibrotic lung tissues. The ratio of apoptotic factors Bax/Bcl-2 increased with the development of fibrosis. Furthermore, As2O3 treatment prevented lung interstitial thickening and inhibited the collagen type I and hydroxyproline, thereby preventing the development of PF. As2O3 also significantly down-regulated α-SMA but increased E-cadherin and miR-98 levels. SIGNIFICANCE: The study revealed that arsenic trioxide prevented rat PF by up-regulation of miR-98 and inhibition of its downstream Stat3 signals.
AIMS: This study aimed to investigate the pathogenesis mechanisms of bleomycin (BLM)-induced pulmonary fibrosis (PF) in Sprague-Dawley rats and explore the anti-fibrotic role of arsenic trioxide (As2O3) in preventing PF. MAIN METHODS: Intratracheal instillation of BLM was performed to establish PF rat models. The treatment group was treated with As2O3 (0.4 mg/kg/day). Morphological changes were observed by hematoxylin-eosin and Masson staining. Related proteins were determined by immunohistochemistry, immunofluorescence, and Western blot. MicroRNA detection was performed by quantitative real-time polymerase chain reaction. KEY FINDINGS: As a novel miRNA in PF, miR-98 decreased in the fibrotic lung tissues. Based on microRNA analysis software, we found that Stat3-3'-UTR is targeted by miR-98. Then, we found that Stat3 was activated with PF development and the expression of Stat3 and p-Stat3 was significantly increased in BLM-induced PF at day 28 compared with saline-treated rats. Our results showed that both Stat3 and p-Stat3 were significantly decreased in miR-98-treated A549 cells compared with that in mu-98-treated cultures or untreated controls. The fibrotic marker α-SMA was upregulated, whereas E-cadherin was inhibited in fibrotic lung tissues. The ratio of apoptotic factors Bax/Bcl-2 increased with the development of fibrosis. Furthermore, As2O3 treatment prevented lung interstitial thickening and inhibited the collagen type I and hydroxyproline, thereby preventing the development of PF. As2O3 also significantly down-regulated α-SMA but increased E-cadherin and miR-98 levels. SIGNIFICANCE: The study revealed that arsenic trioxide prevented rat PF by up-regulation of miR-98 and inhibition of its downstream Stat3 signals.
Authors: Mesias Pedroza; Thuy T Le; Katherine Lewis; Harry Karmouty-Quintana; Sarah To; Anuh T George; Michael R Blackburn; David J Tweardy; Sandeep K Agarwal Journal: FASEB J Date: 2015-08-31 Impact factor: 5.191