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MBD2 serves as a viable target against pulmonary fibrosis by inhibiting macrophage M2 program.

ABSTRACT: Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. Herein we demonstrated that lungs originated from different types of PF patients including coronavirus disease 2019, systemic sclerosis associated interstitial lung disease and idiopathic pulmonary fibrosis, and mice following bleomycin (BLM)-induced PF are characterized by the altered methyl-CpG-binding domain 2 (MBD2) expression in macrophages. Depletion of Mbd2 in macrophages protected mice against BLM-induced PF. Mbd2 deficiency significantly attenuated transforming growth factor ?1 (TGF-?1) production and reduced M2 macrophage accumulation in the lung following BLM induction. Mechanistically, Mbd2 selectively bound to the Ship promoter in macrophages, by which it repressed Ship expression and enhanced PI3K/Akt signaling to promote macrophage M2 program. Therefore, intratracheal administration of liposomes loaded with Mbd2 siRNA protected mice from BLM-induced lung injuries and fibrosis. Together, our data support that MBD2 could be a viable target against pulmonary fibrosis in clinical settings.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7775789 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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MBD2 serves as a viable target against pulmonary fibrosis by inhibiting macrophage M2 program.

Wang Yi Y Zhang Lei L Wu Guo-Rao GR Zhou Qing Q Yue Huihui H Rao Li-Zong LZ Yuan Ting T Mo Biwen B Wang Fa-Xi FX Chen Long-Min LM Sun Fei F Song Jia J Xiong Fei F Zhang Shu S Yu Qilin Q Yang Ping P Xu Yongjian Y Zhao Jianping J Zhang Huilan H Xiong Weining W Wang Cong-Yi CY

Science advances 20210101 1

Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. Here, we demonstrated that lungs originating from different types of patients with PF, including coronavirus disease 2019, systemic sclerosis-associated interstitial lung disease, and idiopathic PF, and from mice following bleomycin (BLM)-induced PF are characterized by the altered methyl-CpG-binding domain 2 (MBD2) expression in macrophages. Depletion of Mbd2 in macrophages protecte ...[more]

PMID: 33277324

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Project description:Background: The beneficial effects of parasympathetic stimulation in pulmonary arterial hypertension (PAH) have been reported. However, the specific mechanism has not been completely clarified. Donepezil, an oral cholinesterase inhibitor, enhances parasympathetic activity by inhibiting acetylcholinesterase, whose therapeutic effects in PAH and its mechanism deserve to be investigated. Methods: The PAH model was established by a single intraperitoneal injection of monocrotaline (MCT, 50 mg/kg) in adult male Sprague-Dawley rats. Donepezil was administered via intraperitoneal injection daily after 1 week of MCT administration. At the end of the study, PAH status was confirmed by echocardiography and hemodynamic measurement. Testing for acetylcholinesterase activity and cholinergic receptor expression was used to evaluate parasympathetic activity. Indicators of pulmonary arterial remodeling and right ventricular (RV) dysfunction were assayed. The proliferative and apoptotic ability of pulmonary arterial smooth muscle cells (PASMCs), inflammatory reaction, macrophage infiltration in the lung, and activation of bone marrow-derived macrophages (BMDMs) were also tested. PASMCs from the MCT-treated rats were co-cultured with the supernatant of BMDMs treated with donepezil, and then, the proliferation and apoptosis of PASMCs were evaluated. Results: Donepezil treatment effectively enhanced parasympathetic activity. Furthermore, it markedly reduced mean pulmonary arterial pressure and RV systolic pressure in the MCT-treated rats, as well as reversed pulmonary arterial remodeling and RV dysfunction. Donepezil also reduced the proliferation and promoted the apoptosis of PASMCs in the MCT-treated rats. In addition, it suppressed the inflammatory response and macrophage activation in both lung tissue and BMDMs in the model rats. More importantly, donepezil reduced the proliferation and promoted the apoptosis of PASMCs by suppressing M2-macrophage activation. Conclusion: Donepezil could prevent pulmonary vascular and RV remodeling, thereby reversing PAH progression. Moreover, enhancement of the parasympathetic activity could reduce the proliferation and promote the apoptosis of PASMCs in PAH by suppressing M2-macrophage activation.

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MBD2 serves as a viable target against pulmonary fibrosis by inhibiting macrophage M2 program.

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MBD2 serves as a viable target against pulmonary fibrosis by inhibiting macrophage M2 program.

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