Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen and Universität Duisburg-Essen, Essen, Germany.
Anesthesiology. 2013 Jun;118(6):1426-36. doi: 10.1097/ALN.0b013e31828baa67.
Hypoxia-inducible factor-1 (HIF-1) is a molecular key player in response to hypoxemic/inflammatory conditions prevailing in sepsis. In a prospective observational study, we tested the hypotheses that sepsis affects HIF-1α messenger ribonucleic acid (mRNA) expression (primary hypothesis) and also (secondary hypotheses) the expression of the HIF-1α target genes adrenomedullin and β2-integrins. Furthermore, we tested that lipopolysaccharide administration increases HIF-1α mRNA and protein in naive and endotoxin-tolerant monocytes.
In 99 patients with sepsis and 48 healthy volunteers, leukocyte HIF-1α mRNA expression (real-time polymerase chain reaction), cytokine concentrations (enzymelinked immunosorbent assay), and intracellular distribution of HIF-1α protein (immunofluorescence staining) were assessed. In vitro, HIF-1α mRNA expression and protein were measured in naive or endotoxin-tolerant (48 h; 0.05 ng/ml lipopolysaccharide) monocytes, with/without additional lipopolysaccharide (6h; 1 μg/ml).
In comparison to healthy volunteers, HIF-1α mRNA expression (-67%; P = 0.0001) and HIF-1α protein positive cells (-66.7%; P = 0.01) were decreased in sepsis. mRNA expression of adrenomedullin (-75%), CD11a (-85%), and CD11b (-86%; all P = 0.0001) was also decreased. In contrast, interleukin 6 (P = 0.0001), interleukin 10 (P = 0.0001), and tumor necrosis factor-α (P = 0.0002) concentrations were increased. Of note, HIF-1α mRNA expression was inversely associated with illness severity (Simplified Acute Physiology Score II; r = -0.29; P = 0.0001). In vitro, acute lipopolysaccharide administration of naive monocytic cells increased HIF-1α mRNA expression, whereas HIF-1α mRNA and protein (-60%; P = 0.001) were decreased in endotoxin-tolerant cells, which still up regulated cytokines.
In sepsis, HIF-1α mRNA expression was suppressed and inversely associated with illness severity. While acute lipopolysaccharide administration increased HIF-1α mRNA expression, prolonged stimulation suppressed HIF-1α expression. The clinical implications of decreased HIF-1α may include maladaption to tissue hypoxia or depressed immune function.
缺氧诱导因子-1（HIF-1）是应对脓毒症中缺氧/炎症条件的分子关键因子。在一项前瞻性观察研究中，我们检验了以下假设：脓毒症会影响 HIF-1α 信使核糖核酸（mRNA）表达（主要假设），以及 HIF-1α 靶基因肾上腺髓质素和β2-整合素的表达（次要假设）。此外，我们还测试了脂多糖给药是否会增加幼稚和内毒素耐受单核细胞中的 HIF-1α mRNA 和蛋白。
在 99 例脓毒症患者和 48 例健康志愿者中，通过实时聚合酶链反应（real-time polymerase chain reaction）检测白细胞 HIF-1α mRNA 表达、细胞因子浓度（酶联免疫吸附测定）和 HIF-1α 蛋白的细胞内分布（免疫荧光染色）。在体外，用/不用额外的脂多糖（6 小时；1μg/ml），测量幼稚或内毒素耐受（48 小时；0.05ng/ml 脂多糖）单核细胞中的 HIF-1α mRNA 表达和蛋白。
与健康志愿者相比，脓毒症患者的 HIF-1α mRNA 表达（-67%；P=0.0001）和 HIF-1α 蛋白阳性细胞（-66.7%；P=0.01）减少。肾上腺髓质素（-75%）、CD11a（-85%）和 CD11b（-86%；均 P=0.0001）的 mRNA 表达也减少。相反，白细胞介素 6（P=0.0001）、白细胞介素 10（P=0.0001）和肿瘤坏死因子-α（P=0.0002）的浓度增加。值得注意的是，HIF-1α mRNA 表达与疾病严重程度呈负相关（简化急性生理学评分 II；r=-0.29；P=0.0001）。在体外，急性脂多糖给药增加了幼稚单核细胞中的 HIF-1α mRNA 表达，而内毒素耐受细胞中的 HIF-1α mRNA 和蛋白（-60%；P=0.001）减少，但其仍能上调细胞因子。
在脓毒症中，HIF-1α mRNA 表达受到抑制，并与疾病严重程度呈负相关。虽然急性脂多糖给药增加了 HIF-1α mRNA 表达，但长期刺激会抑制 HIF-1α 表达。HIF-1α 减少的临床意义可能包括对组织缺氧的适应不良或免疫功能抑制。
