Mechanisms of the acute effects of inhaled ozone in humans

Ambient air ozone (O-3) is generated photochemically from oxides of nitrogen and volatile hydrocarbons. Inhaled O-3 causes remarkably reversible acute lung function changes and inflammation. Approximately 80% of inhaled O-3 is deposited on the airways. O-3 reacts rapidly with C=C 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 O-3. Thus, inhaled O-3 may not interact directly with epithelial cells. Acute O-3-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) Al cation channels by electrophile (e.g., 4-oxo-nonenal) adduction of TRPA1 thiolates enhanced by PGE(2)-stimulated sensitization. Acute O-3-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-lb, ICAM-1, E-selectin and PGE(2). O-3-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. (C) 2016 Published by Elsevier B.V.