Am. J. Respir. Crit. Care Med., Volume 162, Number 4, October 2000, 1195-1201

In Vivo Lipid Peroxidation and Platelet Activation in Cystic Fibrosis

GIOVANNI CIABATTONI, GIOVANNI DAVÌ, MIRELLA COLLURA, LUCIANA IAPICHINO, FRANCESCA PARDO, ANTONINA GANCI, ROSSANA ROMAGNOLI, JACQUES MACLOUF, and CARLO PATRONO

Department of Pharmacology, Catholic University School of Medicine, Rome, Italy; Department of Medicine and Aging and Department of Biomedical Sciences, University of Chieti "G. D'Annunzio" School of Medicine, Chieti, Italy; Cystic Fibrosis Center, Di Cristina Hospital, Palermo, Italy; and INSERM U348, Hôpital Lariboisière, Paris, France

F₂-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 F₂-isoprostanes is altered in patients with cystic fibrosis and contributes to platelet activation and pulmonary dysfunction in this set-ting. The urinary excretion of immunoreactive 8-iso-prostaglandin F₂ (PGF₂) 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 B₂ (TXB₂), 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-PGF₂ was correlated with that of 11-dehydro-TXB₂ (rho = 0.51; p = 0.0026) and inversely related to FEV₁ (rho = 0.40; p = 0.0195). Urinary 8-iso-PGF₂ excretion was largely unaffected during cyclooxygenase inhibition with low-dose aspirin, nimesulide, or ibuprofen, consistent with a noncyclooxygenase mechanism of F₂-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-PGF₂ and 11-dehydro-TXB₂ 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.

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