Theranostics 2023; 13(6):1826-1842. doi:10.7150/thno.82069 This issue Cite

Research Paper

Inhibition of Th17 cells by donepezil ameliorates experimental lung fibrosis and pulmonary hypertension

Yuan Guo1,2, Ziyu He2, Zhu Chen3, Fengling Chen2, Chengming Wang2, Wanlu Zhou1, Jie Liu1, Hao Liu1, Ruizheng Shi1✉

1. Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
2. Department of Cardiovascular Medicine, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou 412007, Hunan, China.
3. Hunan Key Laboratory of Biomedical Nanomaterials and Devices, Hunan University of Technology, Zhuzhou 412007, Hunan, China.

Citation:
Guo Y, He Z, Chen Z, Chen F, Wang C, Zhou W, Liu J, Liu H, Shi R. Inhibition of Th17 cells by donepezil ameliorates experimental lung fibrosis and pulmonary hypertension. Theranostics 2023; 13(6):1826-1842. doi:10.7150/thno.82069. https://www.thno.org/v13p1826.htm
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Abstract

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Rationale: Pulmonary hypertension (PH) secondary to lung fibrosis belongs to WHO Group III, one of the most common subgroups of PH; however, it lacks effective treatment options. Cholinesterase inhibitor donepezil (DON) has been shown to effectively improve Group I PH. However, its effects on Group III PH are unknown.

Methods: A lung fibrosis-induced PH mouse model was constructed using a single intratracheal instillation of bleomycin (BLM), after which DON was administered daily. Pulmonary artery and right ventricle (RV) remodeling were evaluated at the end of the study. Lung tissue in each group was analyzed using RNA sequencing, and the results were further verified with datasets from patients with PH. The mechanisms underlying DON-induced effects on PH were verified both in vivo and in vitro.

Results: DON effectively improved pulmonary artery and RV remodeling in the BLM-induced mouse model. Transcriptomic profiles of lung tissue indicated that the expression of inflammatory and fibrotic genes was significantly changed in this process. In the animal model and patients with PH, T helper 17 lymphocytes (Th17) were the most common inflammatory cells infiltrating the lung tissue. DON significantly inhibited lung fibroblast activation; thus, preventing lung fibrosis and reducing the inflammatory response and Th17 cell infiltration in the BLM-induced lung tissue. In addition, Th17 cells could activate lung fibroblasts by secreting IL17A, and DON-mediated inhibition of Th17 cell differentiation was found to depend on the α7nAchR-JAK2-STAT3 pathway.

Conclusion: DON can alleviate lung fibrosis and PH in an experimental mouse model. It inhibited pro-inflammatory Th17 cell differentiation, which is dependent on a cholinergic receptor pathway, thereby regulating fibroblast activation.

Keywords: pulmonary hypertension, fibrosis, inflammatory response, T helper 17 cells


Citation styles

APA
Guo, Y., He, Z., Chen, Z., Chen, F., Wang, C., Zhou, W., Liu, J., Liu, H., Shi, R. (2023). Inhibition of Th17 cells by donepezil ameliorates experimental lung fibrosis and pulmonary hypertension. Theranostics, 13(6), 1826-1842. https://doi.org/10.7150/thno.82069.

ACS
Guo, Y.; He, Z.; Chen, Z.; Chen, F.; Wang, C.; Zhou, W.; Liu, J.; Liu, H.; Shi, R. Inhibition of Th17 cells by donepezil ameliorates experimental lung fibrosis and pulmonary hypertension. Theranostics 2023, 13 (6), 1826-1842. DOI: 10.7150/thno.82069.

NLM
Guo Y, He Z, Chen Z, Chen F, Wang C, Zhou W, Liu J, Liu H, Shi R. Inhibition of Th17 cells by donepezil ameliorates experimental lung fibrosis and pulmonary hypertension. Theranostics 2023; 13(6):1826-1842. doi:10.7150/thno.82069. https://www.thno.org/v13p1826.htm

CSE
Guo Y, He Z, Chen Z, Chen F, Wang C, Zhou W, Liu J, Liu H, Shi R. 2023. Inhibition of Th17 cells by donepezil ameliorates experimental lung fibrosis and pulmonary hypertension. Theranostics. 13(6):1826-1842.

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