Transcriptomics Underlying Pulmonary Ozone Pathogenesis Regulated by Inflammatory Mediators in Mice

Abstract

Ozone (O3) is the predominant oxidant air pollutant associated with airway inflammation, lung dysfunction, and the worsening of preexisting respiratory diseases. We previously demonstrated the injurious roles of pulmonary immune receptors, tumor necrosis factor receptor (TNFR), and toll-like receptor 4, as well as a transcription factor NF-κB, in response to O3 in mice. In the current study, we profiled time-dependent and TNFR- and NF-κB-regulated lung transcriptome changes by subacute O3 to illuminate the underlying molecular events and downstream targets. Mice lacking Tnfr1/Tnfr2 (Tnfr-/-) or Nfkb1 (Nfkb1-/-) were exposed to air or O3. Lung RNAs were prepared for cDNA microarray analyses, and downstream and upstream mechanisms were predicted by pathway analyses of the enriched genes. O3 significantly altered the genes involved in inflammation and redox (24 h), cholesterol biosynthesis and vaso-occlusion (48 h), and cell cycle and DNA repair (48–72 h). Transforming growth factor-β1 was a predicted upstream regulator. Lack of Tnfr suppressed the immune cell proliferation and lipid-related processes and heightened epithelial cell integrity, and Nfkb1 deficiency markedly suppressed lung cell cycle progress during O3 exposure. Common differentially regulated genes by TNFR and NF-κB1 (e.g., Casp8, Il6, and Edn1) were predicted to protect the lungs from cell death, connective tissue injury, and inflammation. Il6-deficient mice were susceptible to O3-induced protein hyperpermeability, indicating its defensive role, while Tnf-deficient mice were resistant to overall lung injury caused by O3. The results elucidated transcriptome dynamics and provided new insights into the molecular mechanisms regulated by TNFR and NF-κB1 in pulmonary subacute O3 pathogenesis.

Single-Walled vs. Multi-Walled Carbon Nanotubes: Influence of Physico-Chemical Properties on Toxicogenomics Responses in Mouse Lungs

“…WGCNA can be used to find clusters of highly correlated genes, which allows for the identification of key modules [ 24 ]. In this study, WGCNA was conducted to identify gene modules whose expression pattern was found in the in vivo pulmonary toxicity induced by different substances such as polycyclic aromatic hydrocarbons, cigarette smoke, diesel exhaust, ozone, particulate matter, bleomycin, radiation, and nanomaterials, among others ( Table S2 ) [ 10 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 ]. Once modules were identified from those publicly available transcriptomic datasets, the biological functions of each module were determined, and GSEA was conducted to ...…”

Plasma sterols and vitamin D are correlates and predictors of ozone-induced inflammation in the lung: A pilot study

“…Prior to our study, transcriptomic studies conducted in rodents identified increased expression of cholesterol biosynthesis genes in the lung beginning 12–24 hours following O 3 exposure [ 30 – 33 ] suggesting important roles for this pathway in O 3 responses. In the sputum samples, we observed a significant decrease in several cholesterol precursors between asthmatics and non-asthmatics ( Fig 2 ).…”

“…Lipidomic and metabolomic studies have primarily identified changes in arachidonic acid metabolites and polyunsaturated fatty acids following O 3 exposure [23,26,28,29]. However, recent transcriptomic studies in rodents have identified upregulation of cholesterol biosynthesis pathway genes in the lung following O 3 exposure [30][31][32][33]. Cholesterol is the major neutral lipid component of airway surface liquid and important precursor to hormones demonstrated to modulate O 3 responses (i.e.…”

Alpha-lipoic acid, apocynin or probiotics influence glutathione status and selected inflammatory parameters in C57/BL6 mice when combined with a low-fat diet

“…Vieira et al [ 24 ] report that elevated collagen levels in the lungs of OVA-challenged C57BL/6 mice were reduced by anti-TNF-α treatment. TNF-α has been found to mediate O 3 -induced lung inflammation and airway hyper-reactivity (AHR) [ 25 , 26 ], and its inhibition by adiponectin can reduce AHR [ 27 ]. It was also found that adiponectin was down-regulated in a mouse model of sensitized and challenged mice [ 28 ].…”