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

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-1?, 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.

SUBMITTER: Li F

PROVIDER: S-EPMC6249848 | biostudies-other | 2018 Nov

REPOSITORIES: biostudies-other

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

Li Feng F Xu Mengmeng M Wang Muyun M Wang Lei L Wang Hanying H Zhang Hai H Chen Yuqing Y Gong Jicheng J Zhang Junfeng Jim JJ Adcock Ian M IM Chung Kian Fan KF Zhou Xin X

Respiratory research 20181122 1

<h4>Background</h4>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.<h4>Methods</h4>C57/BL6 mice were exposed to ozone (2.5 ppm, 3 h) or filtered air twice a week over 6 weeks. MitoTEMPO (20 mg ...[more]

PMID: 30466433

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Project description:Crystalline cellulose nanocrystals (CNCs) have emerged as novel materials for a wide variety of important applications such as nanofillers, nanocomposites, surface coatings, regenerative medicine and potential drug delivery. CNCs have a needle-like structure with sizes in the range of 100-200 nm long and 5-20 nm wide and a mean aspect ratio 10-100. Despite the great potential applicability of CNCs, very little is known about their potential immunogenicity. Needle-like materials have been known to evoke an immune response in particular to activate the (NOD-like receptor, pyrin domain-containing 3)-inflammasome/IL-1? (Interleukin 1?) pathway. In this study we evaluated the capacity of unmodified CNC and its cationic derivatives CNC-AEM (aminoethylmethacrylate)1, CNC-AEM2, CNC-AEMA(aminoethylmethacrylamide)1 and CNC-AEMA2 to stimulate NLRP3-inflammasome/IL-1? pathway and enhance the production of mitochondrial reactive oxygen species (ROS). Mouse macrophage cell line (J774A.1) was stimulated for 24 h with 50 µg/mL with unmodified CNC and its cationic derivatives. Alternatively, J774A1 or PBMCs (peripheral blood mononuclear cells) were stimulated with CNC-AEMA2 in presence or absence of LPS (lipopolysaccharide). IL-1? secretion was analyzed by ELISA, mitochondrial function by JC-1 staining and ATP content. Intracellular and mitochondrial reactive oxygen species (ROS) were assessed by DCF-DA (2',7'-dichlorodihydrofluorescein diacetate) and MitoSOX, respectively. Mitochondrial ROS and extracellular ATP were significantly increased in cells treated with CNC-AEMA2, which correlates with the strongest effects on IL-1? secretion in non-primed cells. CNC-AEMA2 also induced IL-1?secretion in LPS-primed and non-primed PBMCs. Our data suggest that the increases in mitochondrial ROS and ATP release induced by CNC-AEMA2 may be associated with its capability to evoke immune response. We demonstrate the first evidence that newly synthesized cationic cellulose nanocrystal derivative, CNC-AEMA2, has immunogenic properties, which may lead to the development of a potential non-toxic and safe nanomaterial to be used as a novel adjuvant for vaccines.

Dataset Information

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

Publications

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

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