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Taurine Ameliorates Particulate Matter-Induced Emphysema by Switching on Mitochondrial NADH Dehydrogenase Genes

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Taurine Ameliorates Particulate Matter-Induced Emphysema by Switching on Mitochondrial NADH Dehydrogenase Genes Taurine ameliorates particulate matter-induced PNAS PLUS emphysema by switching on mitochondrial NADH dehydrogenase genes Xiaobo Lia,1, Hongbao Yangb,1, Hao Suna, Runze Lua, Chengcheng Zhanga, Na Gaoa, Qingtao Menga, Shenshen Wua, Susanna Wangc, Michael Aschnerd, Jiong Wue, Boping Tangf, Aihua Gug, Steve A. Kayc,2, and Rui Chena,h,2 aKey Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China; bCenter for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China; cDepartment of Neurology, University of Southern California, Los Angeles, CA 90089; dDepartment of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461; eDepartment of Life Science, Zhejiang Technology University, Hangzhou 310018, China; fJiangsu Key Laboratory for Bioresources of Saline Soils, Jiangsu Synthetic Innovation Center for Coastal Bioagriculture, Yancheng Teachers University, Yancheng 224002, China; gState Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China; and hInstitute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou 511436, China Contributed by Steve A. Kay, September 26, 2017 (sent for review July 13, 2017; reviewed by Mien-Chie Hung and Wang Min) Chronic obstructive pulmonary disease (COPD) has been linked to enhanced oxidative stress are capable of triggering an essential particulate matter (PM) exposure. Using transcriptomic analysis, degradation process known as autophagy (12). we demonstrate that diesel exhaust particles, one of the major The role of autophagy in pulmonary disorders can be either sources of particulate emission, down-regulated genes located in deleterious or protective, depending on the stimuli (13). In cig- mitochondrial complexes I and V and induced experimental COPD in arette-smoke–induced COPD, autophagy is critical in mediating a mouse model. 1-Nitropyrene was identified as a major toxic compo- apoptosis and cilia shortening in airway epithelia (14, 15). Auto- nent of PM-induced COPD. In the panel study, COPD patients were phagy, in turn, accelerates lung aging and emphysema and con- found to be more susceptible to PM than individuals with normal lung tributes to COPD pathogenesis by promoting epithelial cell death function due to an increased inflammatory response. Mechanistically, (16, 17). An autophagy-related pathway has been identified as exposure to PM in human bronchial epithelial cells led to a decline in essential for airborne ultrafine particle-induced inflammation and MEDICAL SCIENCES CCAAT/enhancer-binding protein alpha (C/EBPα), which triggered ab- pulmonary damage both in vitro and in vivo (18). However, the errant expression of NADH dehydrogenase genes and ultimately led to critical physiological functions of autophagy in the pathogenesis of enhanced autophagy. ATG7-deficient mice, which have lower auto- PM-induced COPD have yet to be delineated. phagy rates, were protected from PM-induced experimental COPD. Here, we investigated changes in gene expression profiles in Using metabolomics analysis, we further established that treatment human bronchial epithelial (HBE) cells and COPD-like lesions in with taurine and 3-methyladenine completely restored mitochondrial mouse models upon exposure to DEP to evaluate the molecular gene expression levels, thereby ameliorating the PM-induced emphy- pathogenesis associated with air-pollution–induced COPD. Further- sema. Our studies suggest a potential therapeutic intervention for the more, we undertook a panel study to ascertain which component of C/EBPα/mitochondria/autophagy axis in PM-induced COPD. Significance particulate matter | chronic obstructive pulmonary disease | mitochondria | autophagy | taurine Exposure to high levels of particulate matter (PM) poses a major threat to human health. Cigarette smoke is the most hronic obstructive pulmonary disease (COPD), one of the common irritant that causes chronic obstructive pulmonary Cleading causes of death worldwide (1), is characterized by disease (COPD); however, at least one-fourth of patients with emphysema and small airway wall remodeling (2). The patho- COPD are nonsmokers, and their disease is largely attributed to genesis of COPD is related to chronic environmental stress and is air pollution. The occurrence of pollution episodes in China has associated with inflammatory host immune response (3). Cigarette raised an emergent question of how PM leads to the patho- smoke is the most common irritant that causes COPD; however, at genesis of COPD. In this paper, we show that deregulation of least one-fourth of patients with COPD are nonsmokers; thus the mitochondrial NADH dehydrogenase gene expression levels disease may be attributed to air pollution, chemical fumes, or dust plays a key role in the aggravation of COPD during air pollutant exposure (4). In China, severe air pollution has become a major exposure, which can be rescued by taurine and 3-MA treat- threat to public health, exacerbating the detrimental effects on ments in both mammalian cells and animals. respiratory health. It is noteworthy that in certain highly polluted regions daily concentrations of particulate matter (PM) commonly Author contributions: R.C. designed research; X.L., H.Y., H.S., R.L., C.Z., Q.M., and S. Wu reach levels in the range of 150–500 μg/m3 (5). performed research; S.A.K. contributed new reagents/analytic tools; N.G., S. Wu, J.W., The respiratory system is a primary target of inhaled PM. B.T., A.G., and S.A.K. analyzed data; and X.L., S. Wang, M.A., and S.A.K. wrote the paper. Although the relationship between air pollution and pulmonary Reviewers: M.-C.H., University of Texas MD Anderson Cancer Center; and W.M., Yale University School of Medicine. function is established (6), considerable variability exists in the reduction in pulmonary function of patients following exposure The authors declare no conflict of interest. to air pollution containing diverse components (7, 8). Diesel This open access article is distributed under Creative Commons Attribution-NonCommercial- NoDerivatives License 4.0 (CC BY-NC-ND). exhaust particles (DEP), one of the major sources of PM emis- Data deposition: The microarray datasets reported in this paper have been deposited in sion, are typically composed of a carbonaceous core coupled with the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (acces- a complex mixture of more than 40 toxic adsorbed components sion no. GSE82335). (9). DEP exposure results in the reduction of mitochondrial 1X.L. and H.Y. contributed equally to this work. biogenesis, oxidative phosphorylation, and ATP synthesis, lead- 2To whom correspondence may be addressed. Email: [email protected] or rui.chen@seu. ing to increased oxidative stress as well as inflammatory re- edu.cn. sponses, all of which play important roles in the pathogenesis of This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. COPD (10, 11). Furthermore, mitochondrial dysfunction and 1073/pnas.1712465114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1712465114 PNAS Early Edition | 1of10 Downloaded by guest on September 28, 2021 DEP best associated with COPD. Notably, we also show that confirmed by transmission electron microscopy analysis in HBE switching on mitochondrial NADH dehydrogenase genes alleviates cells. Swollen mitochondria (SI Appendix, Fig. S4C, white arrow) experimental COPD, highlighting a potential therapeutic target for and autophagosomes (SI Appendix, Fig. S4C, black arrow) were PM-induced COPD. observed in the cytoplasm of 1-NP–treated HBE cells. Our re- sults suggested that, among the five most abundant components Results of DEP, 1-NP was the major one that triggered mitochondrial Overview of mRNA Microarray Profiles. Airway epithelial cells are inhibition in pulmonary cells. the primary defense of organisms against inhaled pathogen and chemicals. Therefore, the mRNA of HBE cells was evaluated PM Exposure Increases Levels of Inflammatory Mediators in COPD with a RNA microarray to determine alterations in gene tran- Patients. To assess the health risk following air pollution expo- scription in response to DEP exposure. DEP exposure exerted sure, we assessed 1-NP metabolite levels in the urine of subjects specific transcriptional effects leading to a significantly increased from three different Chinese cities and found that the urinary 6- expression of 313 genes and a decreased expression of 489 genes, OHNP and 8-OHNP levels were significantly increased in sub- with a cutoff of two or more fold changes (FCs) and P < 0.05 (SI jects living in cities with moderate air pollution compared with Appendix, Fig. S1A). A gene ontology (GO) enrichment analysis those experiencing better air quality (SI Appendix,TableS4). classified transcriptional differences between the control and Subsequently, lung function and levels of inflammatory mediators treatment groups. Notably, genes encoding proteins necessary and their association with 1-NP exposure were assessed in healthy for mitochondrial function were differentially expressed in the individuals and COPD patients. Daily air pollution index and air two groups (SI Appendix, Fig. S1 B–D). pollutant concentrations during a consecutive 7-d-observation Then the down-regulated genes were annotated with the Kyoto period are shown in SI Appendix,TableS5. Notably, this period Encyclopedia
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