Journal Article

Roles of mitochondrial ROS and NLRP3 inflammasome in multiple ozone-induced lung inflammation and emphysema

Gong, Jicheng, Chung, Kian Fan, Xu, Mengmeng, Zhang, Junfeng(Jim), Adcock, Ian M., Chen, Yuqing, Li, Feng, Wang, Lei, Wang, Hanying, Zhou, Xin, Wang, Muyun, Zhang, Hai

2018

Overview

Background Mitochondrial damage leading to oxidant stress may play an important role in the pathogenesis of airflow obstruction and emphysema. NLPR3 inflammasome can be activated by mitochondrial ROS (mtROS) and other stimuli. We examined the importance of mtROS and NLRP3 inflammasome and their interactions in multiple ozone-induced lung inflammation and emphysema. Methods C57/BL6 mice were exposed to ozone (2.5 ppm, 3 h) or filtered air twice a week over 6 weeks. MitoTEMPO (20 mg/kg), an inhibitor of mtROS, and VX765 (100 mg/kg), an inhibitor of caspase-1 activity, were administered by intraperitoneal or intragastric injection respectively 1 h prior to each ozone exposure for 6 weeks. Results Ozone-exposed mice had increased bronchoalveolar lavage (BAL) total cells and levels of IL-1β, KC and IL-6, augmented lung tissue inflammation scores, enhanced oxidative stress with higher serum 8-OHdG concentrations, emphysema with greater mean linear intercept (Lm), airway remodeling with increased airway smooth muscle mass and airflow limitation as indicated by a reduction in the ratio of forced expiratory volume at 25 and 50 milliseconds to forced vital capacity (FEV 25 /FVC, FEV 50 /FVC). Both MitoTEMPO and VX765 reduced lung inflammation scores, cytokine levels, oxidative stress and increased mitochondrial fission proteins. VX765 also attenuated emphysema, airway remodeling and airflow limitation. MitoTEMPO inhibited the increased expression of mitochondrial complex II and IV and of NLPR3 while VX765 inhibited the expression and activity of NLRP3 and caspase-1 pathway in the lung. Conclusions Both mtROS and NLRP3 inflammasome play a role in ozone-induced lung inflammation while only NLRP3 is involved in ozone-induced emphysema.

• Publisher: BioMed Central,BioMed Central Ltd,Nature Publishing Group,BMC
• Subject: 8-Hydroxydeoxyguanosine / Air flow / Alveoli / Animals / Bronchus / Caspase / Caspase-1 / Chronic obstructive pulmonary disease / Cigarettes / Compliance / Cytokines / Electron transport / Emphysema / Emphysema - chemically induced / Emphysema - metabolism / Exposure / Gene expression / Genetic aspects / IL-1β / Inflammasomes / Inflammation / Inhibitors / Interleukin 6 / Laboratory animals / Lavage / Ligands / Lung diseases / Lung inflammation / Lungs / Male / Medicine / Medicine & Public Health / Mice / Mice, Inbred C57BL / Mitochondria / Mitochondria - physiology / Mitochondrial DNA / Mitochondrial ROS / Muscles / NLR Family, Pyrin Domain-Containing 3 Protein - metabolism / NLRP3 / NLRP3 inflammasome / Oxidants / Oxidative stress / Oxidative Stress - drug effects / Oxidative Stress - physiology / Oxidizing agents / Ozone / Ozone - administration & dosage / Ozone - toxicity / Pathogenesis / Pathogens / Pneumology/Respiratory System / Pneumonia - chemically induced / Pneumonia - metabolism / Proteins / Reactive oxygen species / Reactive Oxygen Species - metabolism / Respiratory tract / Risk factors / Senescence / Smooth muscle / Variance analysis