Effects of cyclo-oxygenase inhibition on exhaled eicosanoids in patients with COPD.
BACKGROUND
Leukotriene (LT) B4 concentrations are increased and prostaglandin (PG) E2 concentrations are decreased in exhaled breath condensate (EBC) in patients with chronic obstructive pulmonary disease (COPD). A study was undertaken to investigate the short term effects of cyclo-oxygenase (COX) inhibition on exhaled LTB4 and PGE2 concentrations in patients with COPD and to identify the COX isoform responsible for exhaled PGE2 production.


METHODS
Two studies were performed. A double blind, crossover, randomised, placebo controlled study with ibuprofen (400 mg qid for 2 days), a non-selective COX inhibitor, was undertaken in 14 patients with stable COPD, and an open label study with oral rofecoxib (25 mg once a day for 5 days), a selective COX-2 inhibitor, was undertaken in a different group of 16 COPD patients. EBC was collected before and after drug treatment. Exhaled LTB4 and PGE2 concentrations were measured with specific immunoassays.


RESULTS
All patients complied with treatment as indicated by a reduction in ex vivo serum thromboxane B2 concentrations (ibuprofen) and a reduction in lipopolysaccharide induced increase in ex vivo plasma PGE2 values (rofecoxib) of more than 80%. Exhaled LTB4 was increased after ibuprofen (median 175.5 (interquartile range 128.8-231.5) pg/ml v 84.0 (70.0-98.5) pg/ml, p < 0.001) and exhaled PGE2 was reduced (93.5 (84.0-105-5) pg/ml v 22.0 (15.0-25.5) pg/ml, p < 0.0001). Rofecoxib had no effect on exhaled LTB4 (p = 0.53) or PGE2 (p = 0.23).


CONCLUSIONS
Non-selective COX inhibition decreases PGE2 and increases LTB4 in EBC, whereas selective COX-2 inhibition has no effect on these eicosanoids. PGE2 in EBC is primarily derived from COX-1 activity, and COX inhibition may redirect arachidonic acid metabolism towards the 5-lipoxygenase pathway.
Montuschi
P
P
Department of Pharmacology, Faculty of Medicine, School of Medicine, Catholic University of the Sacred Heart, Largo F Vito 1, 00168 Rome, Italy. pmontuschi@rm.unicatt.it
Macagno
F
F
Parente
P
P
Valente
S
S
Lauriola
L
L
Ciappi
G
G
Kharitonov
S A
SA
Barnes
P J
PJ
Ciabattoni
G
G
D001784:Blood Gas Analysis / Q000379:methods; D018592:Cross-Over Studies; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D015232:Dinoprostone / Q000378:metabolism; D004311:Double-Blind Method; D015777:Eicosanoids / Q000378:metabolism*; D005260:Female; D005541:Forced Expiratory Volume / Q000502:physiology; D006801:Humans; D007052:Ibuprofen / Q000627:therapeutic use*; D007783:Lactones / Q000627:therapeutic use*; D007975:Leukotriene B4 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000378:metabolism; D013183:Sputum / Q000737:chemistry; D013450:Sulfones / Q000627:therapeutic use*; D013929:Thromboxane B2 / Q000378:metabolism; D014797:Vital Capacity / Q000502:physiology
D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; D007975:Leukotriene B4; D013929:Thromboxane B2; D015232:Dinoprostone; D007052:Ibuprofen