Ferrari R, Bachetti T, Confortini R, Opasich C, Febo O, Corti A, Cassani G, Visioli O
Cattedra di Cardiologia, Università degli Studi di Brescia, Italy.
Circulation. 1995 Sep 15;92(6):1479-86. doi: 10.1161/01.cir.92.6.1479.
Tumor necrosis factor alpha (TNF-alpha) increases in patients with severe congestive heart failure (CHF) and cachexia. Two naturally occurring modulators of TNF-alpha activity have been identified in human serum. These two soluble proteins are the extracellular domains of the TNF receptors (sTNF-RI and sTNF-RII, respectively). The determination of circulating sTNF-Rs could provide us with some additional information about the activation of this cytokine in CHF.
This study was undertaken to examine the concentration of sTNF-Rs and of bioactive and antigenic TNF-alpha in 37 consecutive patients with various degrees of CHF compared with that of 26 age-matched healthy subjects. Antigenic TNF-alpha increased (from 14.3 +/- 7.08 to 33.5 +/- 13.1 pg/mL, P < .001) in preterminal patients with severe CHF (New York Heart Association [NYHA] class IV). In these patients, sTNF-Rs were also increased (sTNF-RI from 1.17 +/- 0.43 to 4.43 +/- 2.14 ng/mL and sTNF-RII from 2.2 +/- 0.44 to 7.55 +/- 2.28 ng/mL, P < .001). When measured by cytolytic bioassay, TNF-alpha was undetectable (< 100 pg/mL). Addition of 625 pg/mL recombinant human TNF-alpha (rhTNF-alpha), corresponding in the bioassay to 60% of the lethal dose, to the serum of healthy subjects resulted in a significant increase of the expected cytotoxicity (from 625 to 1290 +/- 411 pg/mL, P < .001). Addition of the same dose of rhTNF-alpha to the serum of patients with mild to moderate CHF (NYHA classes II and III) increased the cytotoxicity from 625 to 877 +/- 132 pg/mL, P < .001. In 4 patients with severe CHF (class IV), the expected cytotoxicity was completely inhibited, whereas it was reduced from 625 to 263 +/- 198 pg/mL, P < .001, in the remaining 8 patients. Ten patients died within 1 month of entry into the study. They had the highest level of sTNF-RII (8.18 +/- 1.92 ng/mL). sTNF-RII was a more powerful independent indicator of mortality than TNF-alpha, sTNF-RI, NYHA class, norepinephrine, and atrial natriuretic peptide.
Measurement of sTNF-Rs, in addition to antigenic and bioactive TNF-alpha, is essential for evaluation of the activation of this cytokine in CHF. Both sTNF-Rs increase in preterminal patients with severe CHF and might inhibit the in vitro cytotoxicity of TNF-alpha. Antigenic TNF-alpha also increases in severe CHF. The increased levels of sTNF-RII independently correlate with poor short-term prognosis.
肿瘤坏死因子α（TNF-α）在严重充血性心力衰竭（CHF）和恶病质患者中升高。在人血清中已鉴定出两种天然存在的TNF-α活性调节剂。这两种可溶性蛋白分别是TNF受体的细胞外结构域（sTNF-RI和sTNF-RII）。循环sTNF-Rs的测定可为我们提供有关CHF中这种细胞因子激活的一些额外信息。
本研究旨在检测37例不同程度CHF患者与26例年龄匹配的健康受试者相比，sTNF-Rs以及生物活性和抗原性TNF-α的浓度。重度CHF（纽约心脏协会[NYHA]IV级）的终末期前患者中，抗原性TNF-α升高（从14.3±7.08 pg/mL增至33.5±13.1 pg/mL，P<.001）。在这些患者中，sTNF-Rs也升高（sTNF-RI从1.17±0.43 ng/mL增至4.43±2.14 ng/mL，sTNF-RII从2.2±0.44 ng/mL增至7.55±2.28 ng/mL，P<.001）。通过细胞溶解生物测定法检测时，TNF-α无法检测到（<100 pg/mL）。向健康受试者血清中添加625 pg/mL重组人TNF-α（rhTNF-α），在生物测定中相当于致死剂量的60%，导致预期细胞毒性显著增加（从625增至1290±411 pg/mL，P<.001）。向轻度至中度CHF（NYHA II级和III级）患者血清中添加相同剂量的rhTNF-α，细胞毒性从625增至877±132 pg/mL，P<.001。在4例重度CHF（IV级）患者中，预期细胞毒性完全被抑制，而在其余8例患者中，细胞毒性从625降至263±198 pg/mL，P<.001。10例患者在进入研究后1个月内死亡。他们的sTNF-RII水平最高（8.18±1.92 ng/mL）。与TNF-α、sTNF-RI、NYHA分级、去甲肾上腺素和心房利钠肽相比，sTNF-RII是更强有力的独立死亡指标。
除了抗原性和生物活性TNF-α外，sTNF-Rs的测定对于评估CHF中这种细胞因子的激活至关重要。在重度CHF的终末期前患者中，sTNF-Rs均升高，且可能抑制TNF-α的体外细胞毒性。抗原性TNF-α在重度CHF中也升高。sTNF-RII水平升高与短期预后不良独立相关。
