Polychlorinated dibenzo-p-dioxins and the human immune system: 4 studies on two Spanish families with increased body burdens of highly chlorinated PCDDs.

The consequences of exposure of people to highly chlorinated polychlorodibenzo-p-dioxins (PCDDs) are much less known than those of TCDD. We report on levels of PCDDs (and PCDFs) in 13 members of two families poisoned by contaminated cooking oil. Originally, all persons displayed chloracne as an early symptom. Persisting hexa- and higher chlorinated PCDDs could be analysed many years after exposure. Highest values found in blood lipids were: OCDD 660,000 pg/g; HpCDD 58,000 pg/g; HxCDDs: 3500 pg/g. None of the participants exhibited increased TCDD levels at the time of study. During a period of 6 years, HpCDD and OCDD disappeared from the blood lipids much faster in persons exposed as children or young adults, than from lipids of their parents. Surface receptors on blood lymphocytes of the members of the two families and the proliferative capacity of these blood cells in the presence of typical stimulants were analysed. Even in family members with the highest body burdens of hexa- to octachlorinated PCDDs we could not detect pronounced changes from a reference population with respect to the immunological markers. Minor deviations of levels of some receptors in a few, but not all, highly exposed persons suggested a similar trend to those reported in previous studies of persons with body burdens of > or =3000 pg TCDD/g blood lipids. An increase in the number of total blood lymphocytes in some subjects exposed as children may have similarity with highly TCDD-exposed children in Seveso.

Soluble vascular endothelial growth factor receptor-1 (sFLT-1) mediates downregulation of FLT-1 and prevents activated neutrophils from women with preeclampsia from additional migration by VEGF.

Neutrophil activation and increased migration is associated with preeclampsia and is resolved after delivery. Preeclampsia is an inflammatory disorder where altered levels of vascular endothelial growth factor (VEGF) and the circulating soluble fms-like tyrosine kinase 1 (sFlt-1) have a pathogenic role. VEGF, by binding to FLT-1, induces leukocytic chemotaxis. We studied expression and function of FLT-1 in maternal neutrophils during preeclampsia and normal pregnancies. Analysis of maternal neutrophils showed the relationship between FLT-1 expression and week of gestation. Preeclamptic women express lower FLT-1 and sFLT-1 in neutrophils. In contrast, serum levels of sFLT-1 in patients with preeclampsia are increased and, therefore, inhibit upregulation of FLT-1 in neutrophils by neutralizing VEGF. VEGF-dependent FLT-1 expression is regulated by changing FLT-1-promoter activity. Promoter activity is decreased by sFLT-1. In vitro experiments demonstrated that migration of neutrophils is regulated by VEGF via FLT-1 and excess of sFLT-1. Thus, VEGF-dependent migration of neutrophils is decreased during preeclampsia as a consequence of excess circulating sFlt1. But, they still increase migration by fMLP and, therefore, migration of neutrophils from preeclamptic women is highly activated when compared with the normotensive group. In conclusion, besides being involved in inducing an antiangiogenic state in the serum, excess of sFLT-1 seems to prevent activated neutrophils from women with preeclampsia from additional migration by VEGF. We provide evidence that neutrophils may be involved in the pathophysiology of pregnancy-related hypertensive disorders.

Detection of angiotensin II in supernatants of stimulated mononuclear leukocytes by matrix-assisted laser desorption ionization time-of-flight/time-of-flight mass analysis.

Angiotensin II (Ang II) is the major vasoactive component of the renin-angiotensin system. Several components of the renin-angiotensin system have been demonstrated in different tissues. Whereas the roles of tissue and renal renin-angiotensin system have been studied in detail, much less is known on whether the corpuscular elements of circulating blood contribute to Ang II production. Here we examined whether, in addition to vasculature, blood cells also contribute to the circulating Ang II levels. Mononuclear leukocytes were obtained from healthy subjects and were incubated. The resulting supernatant was chromatographed using different chromatographic methods. The vasoconstrictive effects of aliquots of the resulting fractions were tested. Each fraction with a vasoconstrictive effect was analyzed by mass spectrometry. In one fraction with a strong vasoconstrictive effect, Ang II was identified. Mononuclear lymphocytes produced Ang II in amounts sufficient to stimulate Ang II type 1 receptors. Moreover, in mononuclear leukocytes, renin as well as angiotensin-converting enzyme mRNA expression was detectable by RT-PCR. These findings demonstrate that mononuclear leukocytes are a source of Ang II. Ang II secretion by these cells may play a significant role in humoral vascular regulation. In conclusion, the isolation of Ang II in supernatants of mononuclear leukocytes adds a further physiological source of Ang II to the current view of angiotensin metabolism. The quantitative role of lymphocyte-derived Ang II secretion compared with the other sources of Ang II should be defined further, but the release found under the present conditions is at least sufficient to elicit vasoconstrictive effects.