RESUMO
Small-vessel vasculitis is a life-threatening autoimmune disease that is frequently associated with anti-neutrophil cytoplasmic antibodies (ANCAs). Conventional immunotherapy including steroids and cyclophosphamide can cause serious adverse events, limiting the efficacy and safety of treatment. Eicosapentaenoic acid (EPA), a key component of fish oil, is an omega-3 polyunsaturated fatty acid widely known to be cardioprotective and beneficial for vascular function. We report two elderly patients with systemic ANCA-associated vasculitis (AAV) in whom the administration of EPA in concert with steroids safely induced and maintained remission, without the use of additioal immunosuppressants. To explore the mechanisms by which EPA enhances the treatment of AAV, we employed SCG/Kj mice as a spontaneous murine model of AAV. Dietary enrichment with EPA significantly delayed the onset of crescentic glomerulonephritis and prolonged the overall survival. EPA-derived anti-inflammatory lipid mediators and their precursors were present in the kidney, plasma, spleen, and lungs in the EPA-treated mice. Furthermore, a decrease in ANCA production and CD4/CD8-double negative T cells, and an increase in Foxp3(+) regulatory T cells in the lymph nodes of the kidney were observed in the EPA-treated mice. These clinical and experimental observations suggest that EPA can safely support and augment conventional therapy for treating autoimmune small-vessel vasculitis.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Modelos Animais de Doenças , Ácido Eicosapentaenoico/uso terapêutico , Imunomodulação/efeitos dos fármacos , Idoso , Animais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Western Blotting , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Proliferação de Células , Células Cultivadas , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Camundongos , Camundongos Endogâmicos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVE: Caffeic acid phenethyl ester (CAPE), a natural flavonoid, specifically blocks activation of nuclear factor-kappaB (NF-kappaB). We examined the effects of oral CAPE supplementation on atherogenesis in apolipoprotein E-deficient (apoE-/-) mice. METHODS AND RESULTS: Ten-week-old male apoE-/- mice were supplemented orally with CAPE (30 mg/kg body weight) for 12 weeks. At the end of administration, atherosclerosis progression, NF-kappaB activity, gene expression profiling by microarray analysis, and oxidative stress were studied. Treatment of apoE-/- mice with CAPE significantly reduced aortic atherosclerosis, NF-kappaB activity, and expression of NF-kappaB-related genes in the aorta. Moreover, expression of other gene clusters such as basic transcription factors, growth factors, cytokines, cell adhesion proteins, and extracellular matrix were also significantly reduced by treatment with CAPE. Plasma isoprostane level in apoE-/- mice was also significantly reduced by CAPE. CONCLUSIONS: In apoE-/- mice, oral CAPE supplementation attenuates the atherosclerotic process. This may be attributable to direct inhibition of NF-kappaB in the lesion and reduction of systemic oxidative stress. In apoE-/- mice, oral caffeic acid phenethyl ester (CAPE) supplementation attenuates the atherosclerotic process and reduces NF-kappaB activity and expression of NF-kappaB-related genes in the aorta. This may be attributable to direct inhibition of NF-kappaB in the lesion and reduction of systemic oxidative stress.