Air Quality Guidelines Global Update 2005 - World Health ...

ANNEX 1
system, an increase in the intracellular levels of Ca 2+ and the action of various
kinases. The reaction between ozone and unsaturated fatty acids in ELF and cell
membranes generates a cascade of lipid ozonation products that mediate the activation
of phospholipases and the release of arachidonic acid in the pulmonary
environment (64). Arachidonic acid may be metabolized by two main pathways:
the cyclooxygenase pathway (forming prostaglandins and thromboxanes) and
the lypoxygenase pathway (producing leukotrienes and lipoxins). These mediators
act on the target cells through G-protein coupled receptors and literally participate
in all steps of the inflammatory process. For instance, vasoconstriction
and bronchoconstriction are results of thromboxane A2 and leukotrienes C4,
D4 and E4. Some prostaglandins (PGI2, PGE1, PGE2, PGD2 and prostacyclin)
have a relaxing effect on smooth muscle. Leukotrienes C4, D4 and E4 induce a
marked increase in vascular and epithelial permeability, whereas leukotriene B4,
5-hydroxyeicosatetraenoic acid and lipoxins markedly stimulate chemotaxis and
leukocyte adhesion.
There is growing evidence for the participation of metabolites of arachidonic
acid in the inflammatory process induced by ozone (32,65). In vitro exposure
of bovine tracheal epithelium (66) and human bronchial cells (67) to ozone increases
the metabolism of arachidonic acid through cyclooxygenase and lipoxygenase
pathways in concentrations as low as 0.2 mg/m 3 . Schierhorn et al. (68)
reported that human nasal epithelium, when exposed to ozone in vitro, exhibited
increases of both cyclooxygenase and lipoxygenase products. Inhalation of
0.8 mg/m 3 ozone for two hours significantly increased the concentration of 8-isoprostane,
a prostaglandin-F(2 alpha) isomer that is formed in vivo by free-radical-catalysed
peroxidation of arachidonic acid in healthy persons (69). Administration
of the non-steroidal anti-inflammatory drug ibuprofen (an inhibitor of
cyclooxygenase) blunted the decrement of pulmonary function induced by the
inhalation of ozone (0.8 mg/m 3 for two hours) in normal volunteers without affecting
the numbers of neutrophils in BAL samples (70).
In rats exposed to near-lifetime ozone, Szarek & Valentovic (71) reported that
the cyclooxygenase pathway of the arachidonic acid cascade appears to be the
most important. Coffey et al. (72) reported, however, an increase in BAL fluid
of leukotriene (LT) C4 (8-fold) and to a lesser extent LTB4 (1.5-fold) levels in
healthy volunteers exposed to 0.8 mg/m 3 ozone for two hours, suggesting that
the lipoxygenase pathway may be more important after ozone inhalation than
the cyclooxygenase pathway. Interestingly, cyclooxygenase metabolites may play
a different role in the ozone-induced decline in pulmonary function, depending
on the pre-exposure condition of the lungs. Alexis et al. (73) reported that cyclooxygenase
metabolites contribute to restrictive-type changes in normal people
(probably because of activation of nociceptive receptors in the lungs) and obstructive-type
changes in small airways in asthmatics, an event mostly dependent
on inflammation.
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