Cyclooxygenase metabolites play a different role in ozone-induced pulmonary function decline in asthmatics compared to normals.
Indomethacin has been used to demonstrate that cyclooxygenase (COX) metabolites of arachidonic acid play a mechanistic role in ozone-induced spirometric decline in normals (Nm). Since the weight of evidence suggests that asthmatics (Asth) do not differ substantially from Nm subjects in the magnitude of their spirometric response to ozone, we sought to determine whether COX metabolites play a similar role in the asthmatic response to ozone. Thirteen (n = 13) Asth and nine (n = 9) Nm volunteers were pretreated with indomethacin or placebo (3 days, 75 mg/day), then exposed for 2 h to 400 ppb ozone or clean air while performing mild intermittent exercise (Vi(min) = 30 L/min.). Baseline changes in spirometry (FVC, FEV(1), FEF(25), FEF(50), FEF(60p), FEF(75)) and soluble markers of COX metabolism (prostaglandin [PG] F2-alpha) were measured from induced sputum samples. Results showed similar reductions in FVC (Asth = 12%, Nm = 10%) and FEV(1) (Asth = 13%, Nm = 11%) in Asth and Nm following ozone. Variables representing small-airways function demonstrated the greatest ozone-induced decline in Asth (FEF(75) = 25%). Indomethacin pretreatment significantly attenuated ozone-induced decreases in FVC and FEV(1) in Nm, but not in Asth. Marked attenuation of ozone-induced decrements in FEF(75) and FEF(60p) was observed in Asth but not in Nm. PGF2-alpha levels were similar in both groups prior to ozone exposure with indomethacin (Asth = 65 pg/ml, Nm = 59 pg/ml), but postexposure levels in Asth were significantly elevated (118 pg/ml) compared to Nm (54 pg/ml). We conclude that COX metabolites, such as PGF2-alpha, play an important but different role in asthmatics than normals with respect to ozone-induced pulmonary function decline. Specifically, COX metabolites contribute to restrictive-type changes in normals and obstructive-type changes in small airways in asthmatics.
Alexis
N
N
Center for Environmental Medicine and Lung Biology, University of North Carolina, Chapel Hill, 104 Mason Farm Rd., Chapel Hill, NC 27599-7310, USA. Neil_Alexis@med.unc.edu
Urch
B
B
Tarlo
S
S
Corey
P
P
Pengelly
D
D
O'Byrne
P
P
Silverman
F
F
D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000503:physiopathology*; D015237:Dinoprost / Q000032:analysis / Q000502:physiology*; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D008297:Male; D010126:Ozone / Q000633:toxicity*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D013183:Sputum / Q000737:chemistry
D010126:Ozone; D015237:Dinoprost; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin