Wei Peng1, Fei Peng2, Yuanlei Lou3, Yong Li4, Ning Zhao1, Qiang Shao1, Jiaquan Chen1, Kejian Qian1, Zhenguo Zeng1, Yian Zhan1, Rong Jiang1, Fen Liu5. 1. Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China. 2. Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China; Department of Critical Care Medicine, Zhongda Hospital, Southeast University, Nanjing, China. 3. Institute of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China. 4. Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China. 5. Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China. Electronic address: liufen9934@163.com.
Abstract
AIM: Acute lung injury (ALI) is characterized by alveolar macrophage overactivation and uncontrolled pulmonary inflammation. Mitochondrial damage-associated molecular patterns (MTDs), one type of damage-associated molecular patterns (DAMPs) released from ruptured mitochondrial, can induce inflammation which participates in the pathogenesis of ALI. Despite the critical role of autophagy in inflammatory response, little is known about its function in MTDs-induced ALI. Herein we have studied how autophagy attenuates MTDs-induced ALI in vitro and in vivo. MAIN METHODS: Exogenous MTDs were injected into mice through tail vein injection or directly treated with cultured alveolar macrophage cell lines to construct MTDs-induced ALI models. Rapamycin and 3-MA were used to regulate autophagy in vivo and in vitro. The expressions of Caspase-1, IL-1β, and their precursor were measured. Inhibition the activation of NLRP3 inflammasome to discover the candidate targets and potential molecular pathways involved in autophagy mitigating the MTDs-induced ALI. KEY FINDINGS: After treatment with MTDs the expression levels of inflammatory cytokines and NLRP3 inflammasome-associated proteins were gradually increased in vitro and in vivo. Most importantly, with autophagy enhanced by rapamycin, all the secretion of inflammation cytokine, the level of lung injury, and the expression level of NLRP3 inflammasome-associated proteins were greatly decreased in MTDs-induced mouse model. MTDs-induced inflammation and lung injury were alleviated by autophagy enhancement. Autophagy can function as an effective way to alleviate inflammation in MTDs-induced ALI by inhibiting NLRP3 inflammasome and may represent a therapeutic target in modulating MTDs-induced inflammatory response.
AIM: Acute lung injury (ALI) is characterized by alveolar macrophage overactivation and uncontrolled pulmonary inflammation. Mitochondrial damage-associated molecular patterns (MTDs), one type of damage-associated molecular patterns (DAMPs) released from ruptured mitochondrial, can induce inflammation which participates in the pathogenesis of ALI. Despite the critical role of autophagy in inflammatory response, little is known about its function in MTDs-induced ALI. Herein we have studied how autophagy attenuates MTDs-induced ALI in vitro and in vivo. MAIN METHODS: Exogenous MTDs were injected into mice through tail vein injection or directly treated with cultured alveolar macrophage cell lines to construct MTDs-induced ALI models. Rapamycin and 3-MA were used to regulate autophagy in vivo and in vitro. The expressions of Caspase-1, IL-1β, and their precursor were measured. Inhibition the activation of NLRP3 inflammasome to discover the candidate targets and potential molecular pathways involved in autophagy mitigating the MTDs-induced ALI. KEY FINDINGS: After treatment with MTDs the expression levels of inflammatory cytokines and NLRP3 inflammasome-associated proteins were gradually increased in vitro and in vivo. Most importantly, with autophagy enhanced by rapamycin, all the secretion of inflammation cytokine, the level of lung injury, and the expression level of NLRP3 inflammasome-associated proteins were greatly decreased in MTDs-induced mouse model. MTDs-induced inflammation and lung injury were alleviated by autophagy enhancement. Autophagy can function as an effective way to alleviate inflammation in MTDs-induced ALI by inhibiting NLRP3 inflammasome and may represent a therapeutic target in modulating MTDs-induced inflammatory response.
Authors: Dong-Ming Wu; Jing Li; Rong Shen; Jin Li; Ye Yu; Li Li; Shi-Hua Deng; Teng Liu; Ting Zhang; Ying Xu; De-Gui Wang Journal: Front Pharmacol Date: 2022-01-18 Impact factor: 5.810