Hypoxia-inducible Factor and Target Gene Expression Are Decreased in Patients with Sepsis

Abstract

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.