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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMS German Medical Science; VOL: 8; DOC20 /20100908/
    Publication Date: 2010-09-09
    Description: Objective: Ischemic heart disease is the leading cause of death worldwide. The complement system plays a major role in inflammation and tissue injury following myocardial ischemia and reperfusion (MI/R) injury. Systemic C5 inhibition in clinical studies has resulted in mixed results and the role of earlier complement components (e.g., C3a), upstream from C5 cleavage, has not been elucidated for MI/R injury. Therefore, we evaluated the role of C5 or C3a in a mouse model of MI/R injury.Methods: We performed experimental MI/R with 30 min of ischemia and 4 hr of reperfusion in 8-12 wk old C57BL/6 (WT) mice. Systemic C5 or C3a inhibition was performed with an anti-C5 monoclonal antibody (BB5.1) 30 min prior to reperfusion or with a C3a receptor antagonist (C3aRA). Since the C3aRA induces neutropenia that resolves within 120 min, we administered C3aRA at two different time points in two separate groups: 30 min prior to reperfusion within the neutropenic time frame and 120 min prior to reperfusion, when the neutropenia had resolved, but C3aRA remained active. Following MI/R, cardiac function was assessed via echocardiography, serum troponin I concentrations were measured as an index of myocardial cell death and myocardial inflammation was determined via myocardial polymorphonuclear leukocyte (PMN) infiltration.Results: In wild type mice, MI/R significantly decrease myocardial ejection fraction and increased serum troponin I levels and myocardial PMN infiltration compared to sham-operated animals. Systemic C5 inhibition, 30 min prior to reperfusion, significantly protected mice from MI/R injury, confirming an important role for C5 in murine MI/R injury.Treatment with the C3aRA, 30 min prior to reperfusion (i.e., within the neutropenic time frame), protected mice significantly from MI/R related injury. In contrast, administration of the C3aRA 120 min prior to reperfusion, when the neutropenia had resolved, but C3aRA remained active, did not prevent MI/R injury.Conclusions: These results confirm an important role for C5 cleavage in murine MI/R injury. At the same time, they suggest a minimal role for C3a, since neutropenia rather than C3a receptor antagonism appears to be responsible for C3aRA related amelioration in MI/R injury. While C5 inhibition in the clinical setting of MI/R does not appear to be therapeutic, our results raise the possibility that inhibition of either C5a or C5b-9 may be more advantageous than inhibition of C3a or complete inhibition of C5 in humans.
    Description: Einleitung: Die koronare Herzerkrankung ist weltweit die führende Todesursache. Das Komplementsystem spielt eine wichtige Rolle bei der Entzündungsreaktion und dem Gewebeschaden nach myokardialer Ischämie und Reperfusion (MI/R). Die Inhibition des Komplementfaktors C5 hatte in klinischen Studien unterschiedliche Ergebnisse gezeigt, und die Rolle von Komplementfaktoren, die oberhalb der C5-Spaltung in der Komplementkaskade liegen (z.B. C3a), wurde für MI/R nicht erforscht. Daher untersuchten wir die Rolle von C5 und C3a in einem MI/R-Mausmodell.Methoden: Wir führten in 12 Wochen alten C57BL/6 (WT)-Mäusen experimentell MI/R mit 30 min Ischämie und 4 h Reperfusion durch. Systemische Inhibition der Komplementfaktoren C5 oder C3a wurde mittels eines anti-C5 monoklonalen Antikörpers (BB5.1) 30 min vor der Reperfusion oder mit einem C3a-Rezeptorantagonist (C3aRA) durchgeführt. Da der C3aRA eine Neutropenie induziert, die innerhalb von 〈TextGroup〉 120 min 〈/TextGroup〉 abgeklungen ist, verabreichten wir den C3aRA in zwei unterschiedlichen Versuchsgruppen zu zwei Zeitpunkten: 30 min vor der Reperfusion, innerhalb der Neutropenie, und 120 min vor der Reperfusion, wenn die Neutropenie abgeklungen war, aber der C3aRA noch aktiv war. Nach MI/R untersuchten wir die kardiale Funktion mittels Echokardiographie, bestimmten die Serumkonzentration von Troponin I als Zeichen myokardialen Zelluntergangs und die myokardiale Infiltration mit Polymorphonukleären Zellen (PMN) als Maß myokardialer Inflammation. Ergebnisse: WT-Mäuse hatten nach MI/R im Vergleich zu sham-operierten Mäusen signifikant reduzierte Ejektionsfraktionen, während Troponin I und die myokardiale PMN-Infiltration signifikant erhöht waren. Systemische C5-Inhibierung 30 min vor der Reperfusion schützte Mäuse signifikant vor MI/R-Schädigung und bestätigt damit eine wichtige Rolle von C5 in MI/R im Mausmodell. Eine Behandlung mit dem C3aRA 30 min vor der Reperfusion, während der neutropenischen Phase, schützte die Mäuse signifikant vor MI/R-Schädigung. Eine Verabreichung des C3aRA 120 min vor der Reperfusion, wenn die Neutropenie abgeklungen war, aber der C3aRA noch aktiv war, verhinderte allerdings keine MI/R-Schädigung.Fazit: Diese Ergebnisse bestätigen eine wichtige Rolle für C5 bei MI/R im Mausmodell. Die durch den C3aRA verursachte Neutropenie, und nicht der C3a-Rezeptorantagonismus, scheint für die Abschwächung des MI/R-Schadens verantwortlich zu sein. Damit scheint C3a bei MI/R im Mausmodell nur eine untergeordnete Rolle zu spielen. Da die Inhibition des Komplementfaktors C5 in klinischen Studien nicht erfolgreich war, sprechen unsere Ergebnisse dafür, dass die Inhibition von C5a oder C5b-9 in klinischen Studien erfolgversprechender sein könnte als die Inhibition von C3a oder eine komplette Inhibition von C5.
    Keywords: ischemia ; reperfusion ; I/R ; cardiac ; myocardial ; heart ; ischemic heart disease ; C5 ; C3a ; complement ; Ischämie ; Reperfusion ; I/R ; kardial ; myokardial ; Herz ; koronare Herzerkrankung ; C5 ; C3a ; Komplement ; ddc: 610
    Language: English
    Type: article
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  • 2
    Keywords: CLINICAL-TRIAL ; MARKERS ; C-REACTIVE PROTEIN ; NATIONAL-HEALTH ; CARDIOVASCULAR-DISEASE ; PHYSICAL-ACTIVITY ; METAANALYSIS ; NUTRITION EXAMINATION SURVEY ; ENDOMETRIAL CANCER-RISK ; LIFE-STYLE INTERVENTION
    Abstract: Obese and sedentary persons have increased risk for cancer; inflammation is a hypothesized mechanism. We examined the effects of a caloric restriction weight loss diet and exercise on inflammatory biomarkers in 439 women. Overweight and obese postmenopausal women were randomized to 1-year: caloric restriction diet (goal of 10% weight loss, N = 118), aerobic exercise (225 min/wk of moderate-to-vigorous activity, N = 117), combined diet + exercise (N = 117), or control (N = 87). Baseline and 1-year high-sensitivity C-reactive protein (hs-CRP), serum amyloid A (SAA), interleukin-6 (IL-6), leukocyte, and neutrophil levels were measured by investigators blind to group. Inflammatory biomarker changes were compared using generalized estimating equations. Models were adjusted for baseline body mass index (BMI), race/ethnicity, and age. Four hundred and thirty-eight (N = 1 in diet + exercise group was excluded) were analyzed. Relative to controls, hs-CRP decreased by geometric mean (95% confidence interval, P value): 0.92 mg/L (0.53-1.31, P 〈 0.001) in the diet and 0.87 mg/L (0.51-1.23, P 〈 0.0001) in the diet + exercise groups. IL-6 decreased by 0.34 pg/mL (0.13-0.55, P = 0.001) in the diet and 0.32 pg/mL (0.15-0.49, P 〈 0.001) in the diet + exercise groups. Neutrophil counts decreased by 0.31 x 10(9)/L (0.09-0.54, P = 0.006) in the diet and 0.30 x 10(9)/L (0.09-0.50, P = 0.005) in the diet + exercise groups. Diet and diet + exercise participants with 5% or more weight loss reduced inflammatory biomarkers (hs-CRP, SAA, and IL-6) compared with controls. The diet and diet + exercise groups reduced hs-CRP in all subgroups of baseline BMI, waist circumference, CRP level, and fasting glucose. Our findings indicate that a caloric restriction weight loss diet with or without exercise reduces biomarkers of inflammation in postmenopausal women, with potential clinical significance for cancer risk reduction.
    Type of Publication: Journal article published
    PubMed ID: 22549948
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