Prophylactic treatment with novel phosphodiesterase type 5 inhibitor CPD1 protects rats from bleomycin-induced pulmonary fibrosis_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

LIU Xiaoqing , CAI Huajian , QIU Haoheng , YANG Jianqin , YU Aini , LI Limei , ZHAO Zijian ,  MU Yunping ,  LI Fanghong

The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong 510006, P. R. China;

Corresponding author：

MU Yunping, Email: muyunping2018@gdut.edu.cn; LI Fanghong, Email: fli@gdut.edu.cn

Keywords：

Phosphodiesterase type 5 inhibitors; CPD1; pulmonary fibrosis; alveolar epithelial cells; bleomycin

DOI：

10.7507/1671-6205.202307008

Video：

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Objective To investigate the preventive therapeutic effects of CPD1, a novel phosphodiesterase 5 inhibitor, on lung pathological phenotype and interstitial fibrosis of lung in pulmonary fibrosis model rats caused by bleomycin (BLM). Methods Rats were randomly divided into a sham surgery group (n=10), a model group (n=14), a CPD1 treatment group (n=13), and a nintedanib positive control drug treatment group (n=13). Pulmonary fibrosis model was constructed by slowly instilling BLM (3 mg/kg) into the left bronchus in the model group and two treatment groups. Two hours after BLM infusion, the rats were treated with CPD1 (20 mg·kg^–1·d^–1), or positive control drug nintedanib (50 mg·kg^–1·d^–1) by intragastric administration, respectively, for 2 weeks. To observe the effect of CPD1 treatment on pathological structural damage, collagen deposition, and the expression of fibronectin (Fn), α-smooth muscle actin (α-SMA), Collagen Ⅰ, and E-cadherin (E-Cad) in the affected lung tissues of unilateral pulmonary fibrosis rats. Moreover, to further observed the effects of CPD1 intervention on the expression of transforming growth factor β1 (TGF-β1) and Smad3 in the cell model of human alveolar basal epithelial A549 cells. Results Compared with the control group, the lung tissue structure was seriously damaged in the BLM group, and with expansion of the alveolar space, collapse of the alveolar lumen. Significant widening of the alveolar septum and thickening of the alveolar wall were observed in the BLM group. There was a marked increase in collagen deposition in the thickened walls of the BLM group. Moreover, the expressions of Fn, α-SMA, Collagen Ⅰ, TGF-β and Smad3 were increased, while the expression of E-Cad significantly decreased in the BLM group (all P<0.05). Compared with the BLM group, the lung tissue damage was significantly improved in the CPD1 group rats. Furthermore, CPD1 inhibit the expression of Fn, α-SMA, Collagen Ⅰ, TGF-β and Smad3, and upregulate the expression of E-Cad (all P<0.05). Conclusions Prophylactic treatment with phosphodiesterase 5 inhibitor CPD1 strongly attenuates BLM-induced pulmonary fibrosis by inhibiting the lung injury and inflammation response via targeting TGF-β/Smad pathway, reducing the deposition of extracellular matrix.

Citation： LIU Xiaoqing, CAI Huajian, QIU Haoheng, YANG Jianqin, YU Aini, LI Limei, ZHAO Zijian, MU Yunping, LI Fanghong. Prophylactic treatment with novel phosphodiesterase type 5 inhibitor CPD1 protects rats from bleomycin-induced pulmonary fibrosis. Chinese Journal of Respiratory and Critical Care Medicine, 2023, 22(11): 796-804. doi: 10.7507/1671-6205.202307008 Copy

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11.	刘傲璐, 任倩, 封文斌, 等. 新型磷酸二酯酶5抑制剂CPD1对单侧输尿管梗阻引起的肾间质纤维化小鼠治疗作用. 中国药理学通报, 2023, 39(1): 147-152.
12.	B Moore B, Lawson WE, Oury TD, et al. Animal models of fibrotic lung disease. Am J Respir Cell Mol Biol, 2013, 49(2): 167-179.
13.	庄永杰, 陈继巧. 一种大鼠单侧肺肺纤维化模型的建立. 中国: CN105148254A (中国专利), 2015-12-16.
14.	Bowe B, Xie Y, Al-Aly Z. Acute and postacute sequelae associated with SARS-CoV-2 reinfection. Nat Med, 2022, 28(11): 2398-2405.
15.	Lamb YN. Nintedanib: a review in fibrotic interstitial lung diseases. Drugs, 2021, 81(5): 575-586.
16.	Gulati S, Luckhardt TR. Updated evaluation of the safety, efficacy and tolerability of pirfenidone in the treatment of idiopathic pulmonary fibrosis. Drug Healthc Patient Saf, 2020, 12: 85-94.
17.	林荣梅, 柴燕玲. 进展性肺纤维化诊治进展. 中国呼吸与危重监护杂志, 2023, 22(1): 66-70.
18.	Rockey DC, Bell PD, Hill JA. Fibrosis--a common pathway to organ injury and failure. N Engl J Med, 2015, 372(12): 1138-1149.
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20.	欧阳小荔, 彭红. 特发性肺纤维化预后的影响因素. 中国呼吸与危重监护杂志, 2021, 20(11): 824-830.

1. Wijsenbeek M, Suzuki A, Maher TM. Interstitial lung diseases. Lancet, 2022, 400(10354): 769-786.
2. Zhao MY, Wang LQ, Wang MZ, et al. Targeting fibrosis, mechanisms and cilinical trials. Signal Transduct Target Ther, 2022, 7(1): 206.
3. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Eng J Med, 2014, 370(22): 2071-2082.
4. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet, 2011, 377(9779): 1760-1769.
5. 万一千, 柯衡明, 陈功, 等. 吡唑并嘧啶酮衍生物及其可药用盐、其制备方法和应用. 中国: ZL 201010501383.2 (中国专利), 2012-12-12.
6. 赵子建, 穆云萍, 李芳红, 等. 一种5型磷酸二酯酶抑制剂的钾盐晶型B及其制备方法和应用. 中国: ZL 201910505948.5 (中国专利), 2022-03-01.
7. 朱惠丹, 柯嘉琪, 王家璐, 等. 新型磷酸二酯酶5抑制剂CPD1对肺动脉高压大鼠血管收缩的影响. 中国药理学通报, 2021, 37(3): 328-337.
8. 刘晓晴, 杨建钦, 王栩林, 等. 新型磷酸二酯酶5抑制剂CPD1对异丙肾上腺素诱导心肌肥厚大鼠心脏的保护作用. 中国药理学通报, 2022, 38(9): 1280-1287.
9. 封文斌, 杨建钦, 陈心慧, 等. 新型磷酸二酯酶5抑制剂CPD1对四氯化碳诱导的肝纤维化小鼠治疗作用. 中国药理学通报, 2023, 39(3): 470-476.
10. 刘傲璐, 李壮, 卢美芝, 等. 新型磷酸二酯酶5抑制剂CPD1对单侧肾缺血再灌注损伤后肾间质纤维化的影响. 生理学报, 2023, 75(1): 1-9.
11. 刘傲璐, 任倩, 封文斌, 等. 新型磷酸二酯酶5抑制剂CPD1对单侧输尿管梗阻引起的肾间质纤维化小鼠治疗作用. 中国药理学通报, 2023, 39(1): 147-152.
12. B Moore B, Lawson WE, Oury TD, et al. Animal models of fibrotic lung disease. Am J Respir Cell Mol Biol, 2013, 49(2): 167-179.
13. 庄永杰, 陈继巧. 一种大鼠单侧肺肺纤维化模型的建立. 中国: CN105148254A (中国专利), 2015-12-16.
14. Bowe B, Xie Y, Al-Aly Z. Acute and postacute sequelae associated with SARS-CoV-2 reinfection. Nat Med, 2022, 28(11): 2398-2405.
15. Lamb YN. Nintedanib: a review in fibrotic interstitial lung diseases. Drugs, 2021, 81(5): 575-586.
16. Gulati S, Luckhardt TR. Updated evaluation of the safety, efficacy and tolerability of pirfenidone in the treatment of idiopathic pulmonary fibrosis. Drug Healthc Patient Saf, 2020, 12: 85-94.
17. 林荣梅, 柴燕玲. 进展性肺纤维化诊治进展. 中国呼吸与危重监护杂志, 2023, 22(1): 66-70.
18. Rockey DC, Bell PD, Hill JA. Fibrosis--a common pathway to organ injury and failure. N Engl J Med, 2015, 372(12): 1138-1149.
19. Jenkins RG, Moore BB, Chambers RC, et al. An Official American Thoracic Society Workshop Report: use of animal models for the preclinical assessment of potential therapies for pulmonary fibrosis. Am J Respir Cell Mol Biol, 2017, 56(5): 667-679.
20. 欧阳小荔, 彭红. 特发性肺纤维化预后的影响因素. 中国呼吸与危重监护杂志, 2021, 20(11): 824-830.

Chinese Journal of Respiratory and Critical Care Medicine

Prophylactic treatment with novel phosphodiesterase type 5 inhibitor CPD1 protects rats from bleomycin-induced pulmonary fibrosis

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