Mechanisms of the acute effects of inhaled ozone in humans

• Published in: Biochimica et biophysica acta Vol. 1860; no. 12; pp. 2771 - 2781
• Main Author: Bromberg, Philip A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2016
• Subjects: Acute effects; Administration, Inhalation; air; air pollution; Airway; Alveolar Epithelial Cells - drug effects; Alveolar Epithelial Cells - immunology; Alveolar Epithelial Cells - pathology; bronchoconstriction; cations; cholesterol; Cholesterol - immunology; Cholesterol - metabolism; Cytokines - genetics; Cytokines - immunology; depolymerization; eicosanoids; Eicosanoids - immunology; Eicosanoids - metabolism; epithelial cells; epithelium; Gene Expression Regulation; Human; Humans; hyaluronic acid; hydrocarbons; hydrophilicity; hydrophobicity; Inflammation; interleukin-6; interleukin-8; Isoprostanes - immunology; Isoprostanes - metabolism; ligands; lipid peroxidation; Lipid Peroxidation - drug effects; Lipids; lung function; macrophages; Macrophages, Alveolar - drug effects; Macrophages, Alveolar - immunology; Macrophages, Alveolar - pathology; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - immunology; nitrogen oxides; ozonation; Ozone; Ozone - administration & dosage; phospholipids; Phospholipids - immunology; Phospholipids - metabolism; Pneumonia - chemically induced; Pneumonia - genetics; Pneumonia - immunology; Pneumonia - pathology; Respiratory System - drug effects; Respiratory System - immunology; Respiratory System - pathology; Toll-like receptor 4; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - immunology; transcriptional activation; TRPM Cation Channels - genetics; TRPM Cation Channels - immunology; Human; Ozone; Lipids; Inflammation; Acute effects; Airway
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2016.07.015

Ambient air ozone (O3) is generated photochemically from oxides of nitrogen and volatile hydrocarbons. Inhaled O3 causes remarkably reversible acute lung function changes and inflammation. Approximately 80% of inhaled O3 is deposited on the airways. O3 reacts rapidly with CC double bonds in hydrophobic airway and alveolar surfactant-associated phospholipids and cholesterol. Resultant primary ozonides further react to generate bioactive hydrophilic products that also initiate lipid peroxidation leading to eicosanoids and isoprostanes of varying electrophilicity. Airway surface liquid ascorbate and urate also scavenge O3. Thus, inhaled O3 may not interact directly with epithelial cells. Acute O3–induced lung function changes are dominated by involuntary inhibition of inspiration (rather than bronchoconstriction), mediated by stimulation of intraepithelial nociceptive vagal C-fibers via activation of transient receptor potential (TRP) A1 cation channels by electrophile (e.g., 4-oxo-nonenal) adduction of TRPA1 thiolates enhanced by PGE2-stimulated sensitization. Acute O3-induced neutrophilic airways inflammation develops more slowly than the lung function changes. Surface macrophages and epithelial cells are involved in the activation of epithelial NFkB and generation of proinflammatory mediators such as IL-6, IL-8, TNFa, IL-1b, ICAM-1, E-selectin and PGE2. O3-induced partial depolymerization of hyaluronic acid and the release of peroxiredoxin-1 activate macrophage TLR4 while oxidative epithelial cell release of EGFR ligands such as TGFa or EGFR transactivation by activated Src may also be involved. The ability of lipid ozonation to generate potent electrophiles also provides pathways for Nrf2 activation and inhibition of canonical NFkB activation. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu. •O3 causes acute respiratory morbidity, functional decrements and inflammation•O3 effects are mediated largely by products of its reaction with unsaturated lipids•O3-induced lung function decrements involve activation of unmyelinated sensory nerves•O3 induces inflammation through activation of macrophage and epithelial receptors•Acute lung effects of O3 are normally reversible but many health concerns remain