RESUMO
Ongoing low-grade chronic inflammation represents a pathogenetic background for age-related diseases. In this report, we tested the hypothesis that endogenous anti-inflammatory mechanisms may become less efficient with age, resulting in increased susceptibility to inflammatory disorders. Using previously validated ELISA assays, we evaluated urinary levels of the anti-inflammatory, pro-resolution, arachidonic acid (AA) metabolite, lipoxin (LX)A(4) and of the pro-inflammatory cysteinyl leukotrienes (cysLTs) in volunteers aged from 26 to over 100 years. (i) LXA(4) excretion was decreased in elderly people, resulting in a profound unbalance of the LXA(4)/cysLTs ratio, which may be considered an index of the endogenous anti-inflammatory potential. A significant inverse correlation was denoted between age and the LXA(4)/cysLTs ratio (rho = -0.41, P = 0.0026). We conclude that aging is associated with a switch in arachidonic acid metabolism that prevents formation of key 'stop signals' of the inflammatory reaction. This may contribute to promote the development of disease in elderly.
Assuntos
Envelhecimento/metabolismo , Anti-Inflamatórios não Esteroides/urina , Lipoxinas/urina , Adulto , Ácido Araquidônico/metabolismo , Feminino , Humanos , Leucotrienos/urina , Masculino , Pessoa de Meia-IdadeRESUMO
Microalbuminuria is a predictor of adverse outcome in hypertension.We evaluated in vivo platelet activation, by urinary 11-dehydrothromboxane (TX)B2 and plasma P-selectin, in hypertensives with or without microalbuminuria, and its possible association with oxidative stress, by urinary 8-iso-prostaglandin (PG)F2alpha and endothelial dysfunction. Sixty essential hypertensive patients, with (n=30) or without (n=30) microalbuminuria, and 30 controls were studied. Endothelial function was assessed by nitric oxide products, intercellular adhesion molecule (ICAM)-1, and asymmetric dimethylarginine (ADMA) levels. Urinary 11-dehydro-TXB2 excretion was higher in microalbuminuric (median 805 pg/mg creatinine) compared to nonmicroalbuminuric patients or controls (414 and 291 pg/mg, respectively; P<0.0001). Plasma P-selectinwas significantly higher in patients with microalbuminuria (median 136 ng/ml) as compared to those without microalbuminuria or controls (85 and 65 ng/ml; P<0.0001). Urinary 8-iso-PGF2alpha excretion was also enhanced in microalbuminuric (median 279 pg/mg creatinine) compared to nonmicroalbuminuric patients or controls (157 and 146 pg/mg, respectively; P<0.0001). A significant impairment in endothelial function was found in microalbuminuric patients, with decreased nitric oxide and increased ICAM-1 and ADMA levels. Multivariate regression analysis showed that urinary 8-iso-PGF2alpha excretion (beta=0.49; P<0.0001) and microalbuminuria (beta=0.36; P<0.001) were independently related to 11-dehydro-TXB2 in hypertensives. Vitamin E supplementation (900 mg daily for 1 month) in 10 hypertensives with microalbuminuria was associated with normalization in median 11-dehydro-TXB2 and 8-iso-PGF2alpha. We conclude that lipid peroxidation is a major determinant of persistent platelet activation in hypertensive patients with microalbuminuria.
Assuntos
Endotélio/metabolismo , Hipertensão/fisiopatologia , Peroxidação de Lipídeos/fisiologia , Selectina-P/sangue , Ativação Plaquetária/fisiologia , Prostaglandinas A/urina , Tromboxano B2/análogos & derivados , Idoso , Albuminúria , Arginina/análogos & derivados , Arginina/metabolismo , Biomarcadores/sangue , Biomarcadores/urina , Progressão da Doença , Endotélio/efeitos dos fármacos , Endotélio/patologia , Feminino , Humanos , Hipertensão/sangue , Hipertensão/urina , Molécula 1 de Adesão Intercelular/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Estresse Oxidativo/fisiologia , Tromboxano B2/urina , Vitamina E/administração & dosagemRESUMO
OBJECTIVES: To investigate the rate of platelet thromboxane (TX) biosynthesis and its determinants in Alzheimer's disease. METHODS AND RESULTS: A cross-sectional comparison of urinary 11-dehydro-TXB(2) and 8-iso-prostaglandin (PG)F(2alpha) (markers of in vivo platelet activation and lipid peroxidation, respectively), plasma Vitamin E, C-reactive protein (CRP), tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, was carried-out in 44 Alzheimer patients and 44 matched controls. To investigate the cyclooxygenase (COX)-isoform involved in TXA(2) biosynthesis, nine Alzheimer patients were treated with low-dose aspirin (100mg/d) or rofecoxib (25mg/d) for 4 days. Urinary 11-dehydro-TXB(2) and 8-iso-PGF(2alpha) were significantly higher in Alzheimer patients than in controls (Median: 1983.5 versus 517.5pg/mg creatinine and 938.5 versus 304.0pg/mg creatinine, p<0.0001, respectively), with a significant correlation between the two metabolites (rho=0.75, p<0.0001). An inverse correlation was observed between Vitamin E and both urinary metabolites (8-iso-PGF(2alpha): R(s)=-0.51, p=0.0004; 11-dehydro-TXB(2): R(s)=-0.44, p=0.0026) in Alzheimer patients. No difference was found in CRP, TNF-alpha and IL-6 levels between the two groups. Urinary 11-dehydro-TXB(2) was significantly reduced by aspirin, but not by rofecoxib, consistently with a COX-1-mediated TXA(2) biosynthesis. 8-iso-PGF(2alpha) excretion was not modified by either COX-inhibitor, consistently with its oxygen radical-catalyzed formation. CONCLUSIONS: Platelet activation is persistently enhanced in Alzheimer's disease. This is related, at least in part, to increased lipid peroxidation associated with inadequate levels of Vitamin E.