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

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Title: Roles of mitochondrial ROS and NLRP3 inflammasome in multiple ozone-induced lung inflammation and emphysema
Authors: Li, F
Xu, M
Wang, M
Wang, L
Wang, H
Zhang, H
Chen, Y
Gong, J
Zhang, JJ
Adcock, IM
Chung, KF
Zhou, X
Item Type: Journal Article
Abstract: 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 (FEV25/FVC, FEV50/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.
Issue Date: 22-Nov-2018
Date of Acceptance: 7-Nov-2018
URI: http://hdl.handle.net/10044/1/66295
DOI: https://dx.doi.org/10.1186/s12931-018-0931-8
ISSN: 1465-9921
Publisher: BioMed Central
Journal / Book Title: Respiratory Research
Volume: 19
Copyright Statement: © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Sponsor/Funder: Wellcome Trust
Funder's Grant Number: 093080/Z/10/Z
Keywords: Science & Technology
Life Sciences & Biomedicine
Respiratory System
Mitochondrial ROS
NLRP3 inflammasome
Ozone
Lung inflammation
Emphysema
INJURY
STRESS
DYSFUNCTION
RECEPTOR
LEADS
Emphysema
Lung inflammation
Mitochondrial ROS
NLRP3 inflammasome
Ozone
Animals
Emphysema
Male
Mice
Mice, Inbred C57BL
Mitochondria
NLR Family, Pyrin Domain-Containing 3 Protein
Oxidative Stress
Ozone
Pneumonia
Reactive Oxygen Species
Mitochondria
Animals
Mice, Inbred C57BL
Mice
Pneumonia
Emphysema
Ozone
Reactive Oxygen Species
Oxidative Stress
Male
NLR Family, Pyrin Domain-Containing 3 Protein
Science & Technology
Life Sciences & Biomedicine
Respiratory System
Mitochondrial ROS
NLRP3 inflammasome
Ozone
Lung inflammation
Emphysema
INJURY
STRESS
DYSFUNCTION
RECEPTOR
LEADS
1102 Cardiovascular Medicine And Haematology
1103 Clinical Sciences
Respiratory System
Publication Status: Published
Article Number: ARTN 230
Appears in Collections:National Heart and Lung Institute
Airway Disease
Faculty of Medicine



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