Blood Oxidative Stress Biomarkers in Patients with Familial Mediterranean Fever (FMF)

Abstract

Interest in the relationship between oxidative stress and inflammation has increased in recent years. Familial Mediterranean fever (FMF) represents a suitable autoinflammatory disease model for investigation of this relationship. We aimed to determine blood oxidative stress biomarkers in patients with FMF in both acute attacks and in attack-free periods, and to evaluate its associations with pyrine mutations and C-reactive protein (CRP) levels. The mean levels of CRP and serum lipid hydroperoxide were higher and serum superoxide dismutase and catalase activities were lower in patients with FMF than in healthy volunteers. Serum lipid hydroperoxide levels were higher and antioxidants were lower in FMF patients during an acute attack than in the attack-free period. Serum lipid hydroperoxide levels were significantly higher, and antioxidants were significantly lower in patients with the M694V homozygote mutations than the other genotypes. Our data imply that higher serum lipid hydroperoxide and lower antioxidant enzyme activities in FMF may indicate inflammation-related ‘oxidative stress’. Our findings also raise interesting questions on oxidative stress and its associations with pyrine mutations in FMF and awaits further investigations.

Zusammenfassung

Das Interesse an der Beziehung zwischen oxidativem Stress und Entzündungsreaktionen ist in den letzten Jahren stark gewachsen. Das familiäre mediterrane Fieber (FMF) stellt ein geeignetes autoinflammatorisches Krankheitsmodell zur Untersuchung dieser Beziehung dar. Ziel war es, Serum-Biomarker für oxidativen Stress bei Patienten mit FMF sowohl im Rahmen akuter Attacken als auch in Attacken-freien Phasen zu untersuchen und deren Assoziation mit Pyrin-Mutationen und C-reaktiven Protein (CRP) Werten zu analysieren. Im Vergleich zu Normalprobanden waren bei FMF Patienten die mittleren Werte von CRP und Lipidhydroperoxid im Serum höher, während für Superoxiddismutase und Katalase-Aktivität niedrigere Werte bei FMF Patienten vorlagen. Serum Lipidhydroperoxid-Werte waren bei FMF Patienten im Rahmen akuter Attacken höher als in Attacken-freien Perioden, während für Antioxidantien niedrigere Werte im Rahmen akuter Attacken im Vergleich zu Attacken-freien Perioden bestanden. Bei Patienten mit homozygoter M694V Mutation waren die Serum Lipidhydroperoxid-Werte signifikant höher und die Antioxidantien-Werte signifikant niedriger als bei Patienten mit anderen Genotypen. Unsere Daten legen nahe, dass höhere Lipidhydroperoxid-Werte und niedrigere Enzymaktivitäten von Antioxidantien entzündungsabhängigen „oxidativen Stress” bei FMF anzeigen. Unsere Ergebnisse bringen zudem interessante Fragen hinsichtlich der Beziehung zwischen oxidativem Stress und Pyrin-Mutationen bei FMF auf, weitere Studien hierzu sollten folgen.

Key words

familial mediterranean fever - superoxide dismutase - catalase - lipid hydroperoxide - pyrine mutations

Schlüsselwörter

familiäres mediterranes Fieber - Superoxiddismutase - Katalase - Lipidhydroperoxid - Pyrin-Mutationen

Literatur

• 1 Terekeci HM, Ulusoy ER, Kucukarslan NM. et al . Familial Mediterranean fever attacks do not alter functional and morphologic tissue Doppler echocardiographic parameters.  Rheumatol Int. 2008;  28 1239-1243
• 2 Terekeci HM, Oktenli C, Ozgurtas T. et al . Increased asymmetric dimethylarginine levels in young men with familial Mediterranean fever (FMF): is it early evidence of interaction between inflammation and endothelial dysfunction in FMF?.  J Rheumatol. 2008;  35 2024-2029
• 3 Musabak U, Sengul A, Oktenli C. et al . Does immune activation continue during an attack-free period in familial Mediterranean fever?.  Clin Exp Immunol. 2004;  138 526-533
• 4 Tunca M, Akar S, Onen F. et al . Turkish FMF Study Group. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study.  Medicine (Baltimore). 2005;  84 1-11
• 5 Centola M, Wood G, Frucht DM. et al . The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators.  Blood. 2000;  95 3223-3231
• 6 Koc B, Oktenli C, Bulucu F. et al . The rate of pyrin mutations in critically ill patients with systemic inflammatory response syndrome and sepsis: A pilot study.  J Rheumatol. 2007;  34 2070-2074
• 7 Balcı-Peynircioglu B, Waite AL, Hu C. et al . Pyrin, product of the MEFV locus, interacts with the proapoptotic protein, Siva.  J Cell Physiol. 2008;  216 595-602
• 8 Emerit I, Arutyunyan R, Sarkisian T. et al . Oxyradical-mediated chromosome damage in patients with familial Mediterranean fever.  Free Radic Biol Med. 1993;  15 265-271
• 9 Ozata M, Mergen M, Oktenli C. et al . Increased oxidative stress and hypozincemia in male obesity.  Clin Biochem. 2002;  35 627-631
• 10 Yesilova Z, Yaman H, Oktenli C. et al . Systemic markers of lipid peroxidation and antioxidants in patients with nonalcoholic Fatty liver disease.  Am J Gastroenterol. 2005;  100 850-855
• 11 Livneh A, Langevitz P, Zemer D. et al . Criteria for the diagnosis of familial Mediterranean fever.  Arthritis Rheum. 1997;  40 1879-1885
• 12 Demirkaya E, Tunca Y, Gok F. et al . A very frequent mutation and remarkable association of R761 H with M694 V mutations in Turkish familial Mediterranean fever patients.  Clin Rheumatol. 2008;  27 729-732
• 13 Karaguezyan KG, Haroutjunian VM, Mamiconyan RS. et al . Evidence of oxidative stress in erythrocyte phospholipid composition in the pathogenesis of familial Mediterranean fever (periodical disease).  J Clin Pathol. 1996;  49 453-455
• 14 Gurbuz M, Yamanel L, Bulucu F. et al . Oxidative stress status in familial Mediterranean fever with or without proteinuria.  Free Radic Biol Med. 2005;  38 271-275
• 15 Lunec J, Halloran SP, White AG. et al . Free radical oxidation (peroxidation) products in serum and synovial fluid in rheumatoid arthritis.  J Rheumatol. 1981;  8 233-245
• 16 Imadaya A, Terasawa K, Tosa H. et al . Erythrocyte antioxidant enzymes are reduced in patients with rheumatoid arthritis.  J Rheumatol. 1988;  15 1628-1631
• 17 Odajima T, Onishi M. Biological significance and mechanisms of reactions and events mediated by myeloperoxidase in the xenobiotic metabolism and disposition pathways of leucocytes.  Med Sci Res. 1998;  26 291-298
• 18 Baskol G, Demir H, Baskol M. et al . Investigation of protein oxidation and lipid peroxidation in patients with rheumatoid arthritis.  Cell Biochem Funct. 2006;  24 307-311
• 19 Ozgocmen S, Sogut S, Ardicoglu O. et al . Serum nitric oxide, catalase, superoxide dismutase, and malondialdehyde status in patients with ankylosing spondylitis.  Rheumatol. Int. 2004;  24 80-83
• 20 Kirkali G, Tunca M, Genc S. et al . Oxidative DNA damage in polymorphonuclear leukocytes of patients with familial Mediterranean fever.  Free Rad Biol Med. 2008;  44 386-393
• 21 Kanayama M, Yamaguchi S, Shibata T. et al . Identification of a serum component that regulates cyclooxygenase-2 gene expression in cooperation with 4-hydroxy-2-nonenal.  J Biol Chem. 2007;  282 24166-24174
• 22 Uchida K. A Lipid-derived endogenous inducer of COX-2: a bridge between inflammation and oxidative stress.  Mol Cells. 2008;  25 347-351
• 23 Zaks N, Shinar Y, Padeh S. et al . Analysis of the three most common MEFV mutations in 412 patients with familial Mediterranean fever.  Isr Med Assoc J. 2003;  5 585-588
• 24 Shinar Y, Livneh A, Langevitz P. et al . Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever.  J Rheumatol. 2000;  27 1703-1707

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