Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 200030, People's Republic of China.
Department of Respiratory Medicine, Shanghai First People's Hospital, Shanghai Jiaotong University, No.100, Haining Road, Shanghai, 200080, China.
Respir Res. 2018 Nov 22;19(1):230. doi: 10.1186/s12931-018-0931-8.
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.
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.
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/FVC, FEV/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.
Both mtROS and NLRP3 inflammasome play a role in ozone-induced lung inflammation while only NLRP3 is involved in ozone-induced emphysema.
导致氧化应激的线粒体损伤可能在气流阻塞和肺气肿的发病机制中起重要作用。NLPR3 炎性小体可被线粒体 ROS（mtROS）和其他刺激物激活。我们研究了 mtROS 和 NLRP3 炎性小体及其相互作用在多次臭氧诱导的肺炎症和肺气肿中的重要性。
C57/BL6 小鼠每周两次暴露于臭氧（2.5ppm，3 小时）或过滤空气中，共 6 周。mtROS 抑制剂 MitoTEMPO（20mg/kg）和 caspase-1 活性抑制剂 VX765（100mg/kg）分别于每次臭氧暴露前 1 小时通过腹腔内或胃内注射给药，共 6 周。
臭氧暴露的小鼠支气管肺泡灌洗液（BAL）总细胞数和白细胞介素-1β、KC 和白细胞介素-6 水平增加，肺组织炎症评分增加，氧化应激增强，血清 8-OHdG 浓度升高，肺气肿表现为平均线性截距（Lm）增加，气道重塑表现为气道平滑肌质量增加，用力呼气量在 25 毫秒和 50 毫秒时与用力肺活量的比值（FEV/FVC，FEV/FVC）降低，气流受限。MitoTEMPO 和 VX765 均降低了肺炎症评分、细胞因子水平、氧化应激和增加的线粒体分裂蛋白。VX765 还减轻了肺气肿、气道重塑和气流受限。MitoTEMPO 抑制了线粒体复合物 II 和 IV 以及 NLPR3 的表达增加，而 VX765 抑制了 NLRP3 和半胱天冬酶-1 通路在肺中的表达和活性。
mtROS 和 NLRP3 炎性小体均在臭氧诱导的肺炎症中发挥作用，而只有 NLRP3 参与臭氧诱导的肺气肿。
