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.
Coffey
M J
MJ
Department of Internal Medicine, Taubman Center, University of Michigan, Ann Arbor, USA.
Wheeler
C S
CS
Gross
K B
KB
Eschenbacher
W L
WL
Sporn
P H
PH
Peters-Golden
M
M
D000293:Adolescent; D000328:Adult; D001094:Arachidonate 5-Lipoxygenase / Q000187:drug effects / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology*; D002478:Cells, Cultured; D015777:Eicosanoids / Q000096:biosynthesis; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism; D010126:Ozone / Q000009:adverse effects*; D012129:Respiratory Function Tests
D015777:Eicosanoids; D016718:Arachidonic Acid; D010126:Ozone; D001094:Arachidonate 5-Lipoxygenase