William L. Eschenbacher

Increased 5-lipoxygenase metabolism in the lungs of human subjects exposed to ozone

The environmental pollutant ozone, at sufficiently high levels, is known to induce pulmonary inflammation with resultant airway obstruction in normal subjects. Eicosanoids comprise one group of mediators released from alveolar macrophages which are involved in the pathogenesis of inflammatory lung diseases. We compared the effects of 2-h exposures to 0.4 ppm ozone and filtered air on pulmonary function and eicosanoid levels in bronchoalveolar lavage fluid in 11 normal healthy volunteers. Subjects were exposed to a 6-fold increase in minute ventilation using an adjusted work load on a cycle ergometer. All subjects complained of cough and dyspnea, and demonstrated increased airway obstruction, and increased specific airway resistance following ozone exposure as compared to air exposure. Bronchoalveolar lavage cell count demonstrated a 9-fold increase in the number of neutrophils with a lesser reduction in the number of alveolar macrophages following ozone exposure. Notably, bronchoalveolar lavage fluid leukotriene (LT) C4 (8-fold) and to a lesser extent LTB4 (1.5-fold) levels were higher following ozone exposure compared to air control, with no change in prostaglandins. In a subset of four subjects, alveolar macrophage arachidonic acid metabolism was studied in vitro following separate in vivo exposures to both ozone and air. Alveolar macrophages obtained following ozone exposure released more 5-lipoxygenase (1.5-fold) metabolites, with no change in cyclooxygenase metabolites, than did cells obtained following air exposure. These observations document activation of the 5-lipoxygenase pathway in the lung following ozone exposure, and suggest that alveolar macrophages may participate in the generation of LT, whose actions promote airway inflammation and obstruction.

Ozone-Induced Lung Function Changes in Normal and Asthmatic Subjects and the Effect of Indomethacin

Abstract We performed a two-part study to determine 1) the effect of 0.4 ppm of ozone on subjects with already increased airways responsiveness (asthmatics), and 2) whether indomethacin could alter the pulmonary effects of ozone in normal subjects. After 2 hours of ozone exposure, both the normal and asthmatic subjects had significant, reversible falls in lung function (FE1, FVC, FEV1%, IC) with greater decreases in FWV1-and FEV1% for the asthmatics. Both groups also had increases in airways responsiveness to methacholine after the ozone exposure but the asthmatics had increases in responsiveness after exercise in air alone. The results of the second part of the study showed that pretreatment with indomethacin partially prevented the ozone-induced changes in lung function for normal subjects. Indomethacin did not prevent the ozone-induced increase in airways responsiveness.