Abstract
OBJECTIVE: Angiogenic factors have been implicated in the pathophysiology of sepsis. In experimental models of sepsis (endotoxemia and/or cecal ligation puncture), there is increased expression of vascular endothelial growth factors (VEGF) and the administration of exogenous soluble VEGF receptor (sVEGFR)-1, an antagonist to VEGF, reduces morbidity and mortality. Moreover, a dramatic elevation in sVEGFR-1 has been demonstrated in human sepsis. Although a balance between angiogenic and anti-angiogenic factors is essential for feto-placental development, the changes of angiogenic factors during pregnancy in the context of infection have never been explored. Angiogenic factors also play crucial roles in the pathophysiology of preeclampsia (PE). This study was conducted to determine if maternal plasma concentrations of placental growth factor (PlGF), sVEGFR-2, and soluble endoglin (sEng) change in pregnancies complicated by acute pyelonephritis (AP) compared with normal pregnancy and PE. STUDY DESIGN: A case-control study was conducted in patients with AP, normal pregnant (NP) women, and patients with PE (n=36 for each group) matched for gestational age. AP was diagnosed in the presence of fever (temperature >or=38 degrees C), clinical signs of infection, and a positive urine culture for microorganisms. Plasma concentrations of PlGF, sVEGFR-2, and sEng were determined by ELISA. The results of plasma sVEGFR-1 concentrations have previously been reported, but were included in this study to provide a complete picture of the angiogenic/anti-angiogenic profiles. Serum concentrations of interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, interferon (IFN)-gamma, granulocyte macrophage colony stimulating factor, and tumor necrosis factor (TNF) were also determined using high sensitivity multiplexed immunoassays in patients with AP and NP. RESULTS: AP was associated with a lower median plasma concentration of PlGF and sVEGFR-2 than NP (both p<0.001). There were no significant differences in the median plasma concentrations of sEng and sVEGFR-1 between AP and NP (p=0.7 and 0.5, respectively). In contrast, there was a 5-fold decrease of the median plasma concentration of PlGF, and an 8-10-fold increase of the median plasma concentrations of sVEGFR-1 and sEng in PE compared with those in AP (all p<0.001). No significant difference in the median plasma concentration of sVEGFR-2 was observed between patients with PE and AP (p=0.5). Pregnant women with AP had median plasma concentrations of IL-6, IL-7, IL-8, IL-10, IFN-gamma, and TNF-alpha significantly higher than those in NP women (all p<0.001, except IL-7 p=0.004). CONCLUSION: AP is associated with changes in the profile of angiogenic and anti-angiogenic factors. Although some of these changes resemble those in PE (decreased PlGF and sVEGFR-2), the magnitude of the changes of PlGF is much higher in PE. We conclude that despite high plasma inflammatory cytokine concentrations, acute systemic inflammation in pregnancy has a different angiogenic/anti-angiogenic profile than that of PE.