Complement activation and plasma levels of C4b-binding protein in critical limb ischemia patients
Complement activation and plasma levels of C4b-binding protein in critical limb ischemia patients
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DOI：
10.1016/j.jvs.2008.12.033
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发表时间：
2009-07-01
影响因子：
4.3
通讯作者：
Blom, Anna M.
中科院分区：
文献类型：
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作者：
Martin, Myriam;Gottsater, Anders;Blom, Anna M.
目的：严重肢体缺血(CLI)是一种外周动脉疾病，表现为腿部血流量急剧减少、静息疼痛、创面无法愈合和动脉粥样硬化导致的坏疽。严重的组织坏死与晚期CLI相关，患者预后较差。坏死性和凋亡性细胞激活补体和结合补体抑制物C4b结合蛋白(C4BP)。C4BP的主要异构体由7个相同的α链和1个β链组成，这里称为C4BP(β)，而在炎症时，通常不那么丰富的异构体上调，完全由a链组成。测定C4BP的α链包括两种异构体，称为总C4BP(TOT)。这项研究的假设是补体激活水平和C4BP水平可以预测疾病的严重程度，它们的测量可能具有临床优势。这是一项前瞻性的单中心研究，研究对象为259名连续入住血管疾病二级转诊中心的CLI患者。干预措施包括评估可溶末梢补体复合体(C5b-9)、C4BP(TOT)和C4BP(β)的血脂水平，炎性介质肿瘤坏死因子-α、白细胞介素6、8-异前列腺素F-2α、超敏C反应蛋白、新喋呤、血浆同型半胱氨酸和血浆内皮素-1，以及对激活蛋白C和踝部血压的抵抗力。所有数据都与219名当前健康个体的年龄匹配人群控制组进行了比较。数据以平均值+/-结构方程/中位数表示。系统性补体激活(1.17+/-0.06/1.13AU/mLvs 0.69+/-0.07/0.59AU/mLvs0.69+/-0.07/0.59AU/mLP<；0001)，坏疽患者C4BP水平更高(1.33+/-0.11/1.28AU/mLvs1.1+/-0.08/1.0AU/mLvs1.1+/-0.08/1.0AU/mLvs.0264)，C4BP水平也升高(421+/-28.6/386mU/mLvs341+/-10.8/318mU/mLC4BP(TOT)，P=0.0248；374+/-25.4/332微克/毫升对305+/-9.5/285微克/毫升对C4BP(β)，P=.0581)。CLI患者血浆C4BP水平显著高于健康对照组(351+/-8.1/322 mU/mLvs297+/-8.0/288 mU/mLC4BP(TOT)，P=0.0001；314+/-7.0/287 mU/mLvs265+/-7.0/263 mU/mLC4BP(β)，P=0.004)，并与白介素6(P-TOT/β=0.0048/.0019)、高敏C反应蛋白(P<；白细胞(P-TOT/β=.0086/.0043)、血小板计数(P-TOT/β=.0001)、低密度脂蛋白/高密度脂蛋白(P-TOT=.0151)和高密度脂蛋白(P-TOT/β=.0047/.0177)，而与肿瘤坏死因子-α无关。这一知识结合已发现的与其他生物标志物的相关性，有助于了解该病的病理生理学。(《血管外科杂志》2009；50：100-6。)
Objective: Critical limb ischemia (CLI) is a peripheral arterial disease manifested by drastically diminished blood flow to the legs, pain at rest, nonhealing wounds, and gangrene caused by atherosclerosis. Significant tissue necrosis is associated with late stage CLI and the patients have a poor prognosis. Necrotic and apoptotic cells activate complement and bind complement inhibitor C4b-binding protein (C4BP). The major isoform of C4BP is composed of seven identical alpha-chains and one beta-chain, here termed C4BP(beta) whereas upon inflammation a normally less abundant isoform is upregulated that is exclusively composed of a-chains. Measuring the alpha-chains of C4BP includes both isoforms and is termed total C4BP (C4BP(tot)). The hypothesis of this study was that levels of complement activation and C4BP are predictive for the severity of the disease and that their measurement might be of clinical advantage.Methods. This was a prospective, single-center study of 259 consecutive patients with CLI admitted to a secondary referral center for vascular diseases. Interventions included evaluation of soluble terminal complement complexes (C5b-9), C4BP(tot) and C4BP(beta) lipid levels, the inflammatory mediators tumor necrosis factor-alpha, interleukin-6, 8-iso-prostaglandin F-2 alpha, high-sensitivity C-reactive protein, neopterin, plasma homocysteine, and plasma endothelin-1 in plasma as well as resistance to activated protein C and ankle blood pressure. All data were compared with an age-matched population based control group of 219 currently healthy individuals.Results. The data are presented as mean +/- SEM/median. CLI patients showed systemic complement activation (1.17 +/- 0.06/1.13 AU/mL vs 0.69 +/- 0.07/0.59 AU/mL in healthy controls, P < .0001), which was even higher in patients with gangrene (1.33 +/- 0.11/1.28 AU/mL vs 1.1 +/- 0.08/1.0 AU/mL, P = .0264), who also showed increased C4BP levels (421 +/- 28.6/386 mu g/mL vs 341 +/- 10.8/318 mu g/mL for C4BP(tot) P = .0248; 374 +/- 25.4/332 mu g/mL vs 305 +/- 9.5/285 mu g/mL for C4BP(beta), P = .0581). C4BP plasma levels were significantly elevated in CLI patients in comparison to healthy controls (351 +/- 8.1/322 mu g/mL vs 297 +/- 8.0/288 mu g/mL for C4BP(tot), P = .0001; 314 +/- 7.0/287 mu g/mL vs 265 +/- 7.0/263 mu g/mL for C4BP(beta) P = .0004) and correlated to levels of interleukin-6 (P-tot/beta = .0048/.0019), high-sensitivity C-reactive protein (P < .0001), leukocyte (P-tot/beta = .0086/.0043) and platelet count (P = .0001), LDL/HDL ratio (P-tot = .0151) and HDL (P-tot/beta = .0047/.0177), but not to tumor necrosis factor-alpha.Conclusions: Increased complement activation and C4BP plasma levels are related to the degree of tissue necrosis and disease severity of critical limb ischemia. This knowledge in combination with the found correlations to other biomarkers is useful for understanding the pathophysiology of the disease. (J Vasc Surg 2009;50:100-6.)