Neutrophil release of myeloperoxidase in systemic vasculature of obese women may put them at risk for preeclampsia.

Obesity is a risk factor for preeclampsia, but the reason for this risk is unknown. Neutrophils infiltrate into systemic blood vessels of both obese and preeclamptic women. Neutrophils are a major source of myeloperoxidase (MPO), which is associated with hypertension. We tested the hypothesis that systemic vasculature of both obese and preeclamptic women will have a significant presence of MPO as a result of neutrophil infiltration. We found that immunohistochemical staining of MPO was significantly greater in subcutaneous fat blood vessels of obese women than overweight women, which was significantly greater than normal weight women. Expression of MPO was significantly greater in maternal blood vessels of preeclamptic women than normal pregnant or normal nonpregnant women. In general, when vessels of overweight or normal pregnant women were stained it was primarily for leukocytes in the lumen and not infiltrated into the vessel. In contrast, in obese and preeclamptic women staining was present for leukocytes in the lumen, flattened, and adhered to the endothelium and infiltrated into the vessel wall. There was also extensive diffuse staining for MPO in vessels of obese and preeclamptic women. In conclusion, both obese and preeclamptic women have increased presence of MPO in systemic vasculature as a result of neutrophil infiltration. We speculate that obese women may be at risk of preeclampsia because their vasculature is already prone to hypertension.

Preeclampsia is associated with alterations in DNA methylation of genes involved in collagen metabolism.

Maternal vascular dysfunction is a hallmark of preeclampsia. A recently described vascular phenotype of preeclampsia involves increased expression of matrix metalloproteinase-1 (MMP-1) in endothelial cells, vascular smooth muscle, and infiltrating neutrophils. In contrast, the expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) and collagen type Iα 1 is either reduced or not changed in the vessels, suggesting an imbalance in vessel collagen degradation and synthesis in preeclampsia. In the present study, we explored the possible contribution of DNA methylation to the altered expression of genes involved in collagen metabolism. We assayed the differences in DNA methylation in omental arteries from normal pregnant and preeclamptic women, and determined whether reduced DNA methylation increases the expression of MMP-1 in cultured vascular smooth muscle cells and a neutrophil-like cell line, HL-60. Several MMP genes, including MMP1 and MMP8, were significantly less methylated in preeclamptic omental arteries, whereas TIMP and COL genes either were significantly more methylated or had no significant change in their DNA methylation status compared with normal pregnancy. Experimentally induced DNA hypomethylation increased MMP-1 expression in cultured vascular smooth muscle cells and MMP-1 cells. Our findings suggest that epigenetic regulation contributes to the imbalance in genes involved in collagen metabolism in blood vessels of preeclamptic women.

IL-5 receptor α levels in patients with marked eosinophilia or mastocytosis.

BACKGROUND: IL-5 plays a central role in the development and maintenance of eosinophilia (EO) and eosinophil activation in a wide variety of eosinophilic disorders. Although IL-5, IL-3, and GM-CSF can modulate the expression of IL-5 receptor α (IL-5Rα) on eosinophils in vitro, little is known about soluble and surface IL-5Rα levels in vivo. OBJECTIVE: To assess soluble and surface IL-5Rα levels in patients with EO and/or mastocytosis. METHODS: Surface IL-5Rα expression was assessed by flow cytometry in blood and/or bone marrow from subjects with EO (n = 39) and systemic mastocytosis (n = 8) and from normal volunteers (n = 28). Soluble IL-5Rα (sIL-5Rα) level was measured in a cohort of 177 untreated subjects and correlated with EO, eosinophil activation, and serum tryptase and cytokine levels. RESULTS: IL-5Rα expression on eosinophils inversely correlated with EO (r = -0.48; P < .0001), whereas serum levels of sIL-5Rα increased with the eosinophil count (r = 0.56; P < .0001) and serum IL-5 (r = 0.40; P < .0001) and IL-13 (r = 0.29; P = .004) levels. Of interest, sIL-5Rα level was significantly elevated in patients with systemic mastocytosis without EO. Although sIL-5Rα levels correlated with serum tryptase levels in these patients, eosinophil activation, assessed by CD69 expression on eosinophils and serum eosinophil-derived neurotoxin levels, was increased compared with that in normal subjects. CONCLUSIONS: These data are consistent with an in vivo IL-5Rα regulatory pathway in human eosinophils similar to that described in vitro and involving a balance between soluble and surface receptor levels. This may have implications with respect to the use of novel therapeutic agents targeting IL-5 and its receptor in patients with EO and/or mastocytosis.