In vivo lipid peroxidation and platelet activation in cystic fibrosis.
F(2)-isoprostanes are bioactive peroxidation products of arachidonic acid whose urinary excretion provides an index of lipid peroxidation in vivo. We tested the hypothesis that formation of F(2)-isoprostanes is altered in patients with cystic fibrosis and contributes to platelet activation and pulmonary dysfunction in this setting. The urinary excretion of immunoreactive 8-iso-prostaglandin F(2alpha) (PGF(2alpha)) was significantly (p = 0.0001) higher in 36 patients with cystic fibrosis than in 36 age-matched healthy subjects: 618 +/- 406 versus 168 +/- 48 pg/mg creatinine. The urinary excretion of immunoreactive 11-dehydro-thromboxane B(2) (TXB(2)), an index of in vivo platelet activation, was also significantly (p = 0.0001) higher in patients than in control subjects: 2,440 +/- 1,453 versus 325 +/- 184 pg/mg creatinine. The excretion rate of 8-iso-PGF(2alpha) was correlated with that of 11-dehydro-TXB(2) (rho = 0.51; p = 0.0026) and inversely related to FEV(1) (rho = -0.40; p = 0.0195). Urinary 8-iso-PGF(2alpha) excretion was largely unaffected during cyclooxygenase inhibition with low-dose aspirin, nimesulide, or ibuprofen, consistent with a noncyclooxygenase mechanism of F(2)-isoprostane formation in cystic fibrosis. Increased vitamin E supplementation (from 200 to 600 mg/d) was associated with statistically significant (p = 0.005) reductions in urinary 8-iso-PGF(2alpha) and 11-dehydro-TXB(2) excretion, by 42% and 29%, respectively. We conclude that enhanced lipid peroxidation is an important feature of cystic fibrosis and may contribute to persistent platelet activation and pulmonary dysfunction via generation of bioactive isoeicosanoids. Our results provide a rationale for reassessing the adequacy of vitamin E supplementation in this setting.
Ciabattoni
G
G
Department of Pharmacology, Catholic University School of Medicine, Rome, Italy.
Davì
G
G
Collura
M
M
Iapichino
L
L
Pardo
F
F
Ganci
A
A
Romagnoli
R
R
Maclouf
J
J
Patrono
C
C
D000293:Adolescent; D000328:Adult; D002648:Child; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D028441:F2-Isoprostanes; D005260:Female; D005838:Genotype; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology*; D008168:Lung / Q000503:physiopathology; D008297:Male; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000008:administration & dosage; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000652:urine; D014810:Vitamin E / Q000008:administration & dosage
D016861:Cyclooxygenase Inhibitors; D028441:F2-Isoprostanes; D013449:Sulfonamides; D014810:Vitamin E; C075750:8-epi-prostaglandin F2alpha; D013929:Thromboxane B2; C049235:11-dehydro-thromboxane B2; D015237:Dinoprost; C012655:nimesulide; D007052:Ibuprofen