Ciabattoni G, Davì G, Collura M, Iapichino L, Pardo F, Ganci A, Romagnoli R, Maclouf J, Patrono C
Department of Pharmacology, Catholic University School of Medicine, Rome, Italy.
Am J Respir Crit Care Med. 2000 Oct;162(4 Pt 1):1195-201. doi: 10.1164/ajrccm.162.4.9911071.
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.
F(2)-异前列腺素是花生四烯酸的生物活性过氧化产物，其尿排泄量可反映体内脂质过氧化水平。我们检验了以下假设：囊性纤维化患者体内F(2)-异前列腺素的生成发生改变，并导致该情况下的血小板活化和肺功能障碍。36例囊性纤维化患者尿中免疫反应性8-异前列腺素F(2α)（PGF(2α)）的排泄量显著高于36例年龄匹配的健康受试者（p = 0.0001）：分别为618±406和168±48 pg/mg肌酐。作为体内血小板活化指标的免疫反应性11-脱氢血栓素B(2)（TXB(2)）的尿排泄量在患者中也显著高于对照组（p = 0.0001）：分别为2440±1453和325±184 pg/mg肌酐。8-异PGF(2α)的排泄率与11-脱氢TXB(2)的排泄率相关（ρ = 0.51；p = 0.0026），与第一秒用力呼气量（FEV(1)）呈负相关（ρ = -0.40；p = 0.0195）。在用低剂量阿司匹林、尼美舒利或布洛芬抑制环氧化酶期间，尿8-异PGF(2α)排泄量基本不受影响，这与囊性纤维化中F(2)-异前列腺素形成的非环氧化酶机制一致。增加维生素E补充量（从200 mg/d增至600 mg/d）与尿8-异PGF(2α)和11-脱氢TXB(2)排泄量在统计学上显著降低相关（p = 0.005），分别降低了42%和29%。我们得出结论，脂质过氧化增强是囊性纤维化的一个重要特征，可能通过生成生物活性异二十碳烷酸导致持续的血小板活化和肺功能障碍。我们的结果为重新评估这种情况下维生素E补充量的充足性提供了理论依据。
