Aggregates In Lungs Research Articles

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Preeclampsia Is Associated With the Presence of Transcriptionally Active Placental Fragments in the Maternal Lung

Preeclampsia is associated with increased levels of the circulating antiangiogenic factor sFlt-1 and with an excessive shedding of placenta-derived multinucleated syncytial aggregates into the maternal circulation. However, it remains unclear whether these aggregates are transcriptionally active in the maternal organs and can, therefore, contribute to the systemic manifestations of preeclampsia. In this study, we measured placental soluble fms-like tyrosine kinase-1 (sFlt-1) mRNA levels in preeclamptic- and control placentas and performed RNA in situ hybridization to localize the main placental expression site of sFlt-1 mRNA. Because the maternal lung is the first capillary bed that circulating syncytial aggregates traverse, we studied the presence and persistence of placental material in lungs of preeclamptic and control subjects. To confirm the placental origin of these aggregates in maternal lungs, immunohistochemistry for the placenta-specific marker hCG (human chorionic ghonadotropin) and Y chromosome in situ hybridization were performed. Using human placental tissue, we found that syncytial knots are the principal site of expression of the antiangiogenic factor sFlt-1. In addition, autopsy material obtained from women with preeclampsia (n=9) showed significantly more placenta-derived syncytial aggregates in the lungs than in control subjects (n=26). Importantly, these aggregates still contained the antiangiogenic factor sFlt-1 after their entrapment in the maternal lungs. The current study confirms the important role of syncytial knots in placental sFlt-1 mRNA production. In addition, it shows a significant association between preeclampsia and larger quantities of sFlt-1 containing syncytial aggregates in maternal lungs, suggesting that the transfer of syncytial aggregates to the maternal compartment may contribute to the systemic endothelial dysfunction that characterizes preeclampsia.

OP005. Preeclampsia is associated with the presence of transcriptionally active placental fragments in the maternal lung

Preeclampsia is associated with increased levels of the circulating anti-angiogenic factor sFlt-1 as well as with an excessive shedding of placenta-derived multinucleated syncytial aggregates into the maternal circulation. However, it remains unclear whether these aggregates are transcriptionally active in the maternal organs and can therefore contribute to the systemic manifestations of preeclampsia. We hypothesized that in preeclampsia, syncytial knots are the primary placental site of sFlt-1 production and that increased numbers of sFlt-1-containing syncytial aggregates are retained in the maternal lungs. In this study, we measured placental sFlt-1 mRNA levels in preeclamptic- and control placentas and performed RNA in situ hybridization to localize the main placental expression site of sFlt-1 mRNA. Because the maternal lung is the first capillary bed that circulating syncytial aggregates traverse, we studied the presence and persistence of placental material in lungs of preeclamptic women and control subjects. To confirm the placental origin of suspected syncytial aggregates in these lungs, immunohistochemistry for the placenta-specific marker hCG and Y-chromosome in situ hybridization were performed. Using human placental tissue, we found that syncytial knots are the principal site of expression of the anti-angiogenic factor sFlt-1. In addition, in autopsy material obtained from women with preeclampsia (n=9), we observed significantly more placenta-derived syncytial aggregates in the lungs than in control subjects (n=26). Importantly, these placental aggregates still contained the anti-angiogenic factor sFlt-1 following their entrapment in the maternal lungs. The current study confirms the important role of syncytial knots in placental sFlt-1 mRNA production. Additionally, it shows a significant association between preeclampsia and larger quantities of sFlt-1 containing syncytial aggregates in maternal lungs, suggesting that the transfer of syncytial aggregates to the maternal compartment may contribute to the systemic endothelial dysfunction that characterizes preeclampsia.

Role of HGF/SF and c-Met in morphogenesis and metastasis of epithelial cells.

We have analysed the role of hepatocyte growth factor/scatter factor (HGF/SF) in the process of morphogenesis and metastasis of epithelial (carcinoma) cells. HGF/SF induces various morphogenic responses in epithelial cells that derive from different tissues when these are grown in three-dimensional gels, e.g. branching tubules in kidney, breast, and prostate epithelial cells, crypt-like structures with brush border in colon epithelial cells, and alveolar-like aggregates in lung and pancreas cells. Epithelial cells are thus able to form complex structures in vitro which resemble the structures formed in the organ they originate from. We also examined the response of human breast carcinoma cells to HGF/SF in vivo. MDA MB 435 cells transfected with HGF/SF were injected into the mammary fat pad of nude mice, where they form tumours which spontaneously metastasize to the lungs. We found that expression of HGF/SF promoted metastasis whereas expression of the cell adhesion molecule E-cadherin was inhibitory. Moreover, expression of E-cadherin reconstituted the ability of the cells to form complex structures in response to HGF/SF in vitro. These data demonstrate that the different responses to HGF/SF depend on the state of the epithelial cells: morphogenesis requires epithelial differentiation and cell polarity, whereas metastasis is observed when the cells have lost their epithelial characteristics. Moreover, we have recently identified Gab-1 as a direct-binding substrate of the c-Met receptor. Gab-1 binds to c-Met phosphorylated on tyrosine residues, but not to a number of other tyrosine kinases from different subfamilies. A newly identified proline-rich domain of Gab-1 is responsible for the binding to the bidentate docking site in c-Met. Expression of Gab-1 in epithelial cells is sufficient to induce c-Met-specific cellular responses which include the formation of branching tubules. Thus, Gab-1 seem to correspond to the substrate of the c-Met receptor tyrosine kinase that mediates the epithelial morphogenesis.

Histologic, neurologic, and immunologic effects of methylmercury in captive great egrets.

Captive great egret (Ardea albus) nestlings were maintained as controls or were dosed with methylmercury chloride at low (0.5), and high doses (5 mg/kg, wet weight) in fish. Low dosed birds were given methylmercury at concentrations comparable to current exposure of wild birds in the Everglades (Florida, USA). When compared with controls, low dosed birds had lower packed cell volumes, dingy feathers, increased lymphocytic cuffing in a skin test, increased bone marrow cellularity, decreased bursal wall thickness, decreased thymic lobule size, fewer lymphoid aggregates in lung, increased perivascular edema in lung, and decreased phagocytized carbon in lung. High dosed birds became severely ataxic and had severe hematologic, neurologic, and histologic changes. The most severe lesions were in immune and nervous system tissues. By comparing responses in captive and wild birds, we found that sublethal effects of mercury were detected at lower levels in captive than in wild birds, probably due to the reduced sources of variation characteristic of the highly controlled laboratory study. Conversely, thresholds for more severe changes (death, disease) occurred at lower concentrations in wild birds than in captive birds, probably because wild birds were exposed to multiple stressors. Thus caution should be used in applying lowest observed effect levels between captive and wild studies.

The Distribution of a Rabbit Thymic Antigen and Membrane Immunoglobulins in Lymphoid Tissue, with Special Reference to Mucosal Lymphocytes

Abstract We have examined rabbit lymphocytes from several tissue sources for membrane immunoglobulins with antisera specific for α, µ and γ heavy chains, as well as with an antiserum specific for a rabbit thymus lymphocyte antigen (RTLA). Among lymphocytes from bronchus-associated lymphoid tissue (BALT), Peyer's patches, thoracic duct, and gut mucosa exclusive of Peyer's patches, α and µ predominated with roughly equal percentages of each being found. The distribution of cells with γ receptors was approximately half that of either of the two other classes. In splenic lymphocytes, µ predominated, followed, respectively, in numbers by γ and α. Detection of RTLA on almost all thymus lymphocytes (94%), most thoracic duct lymphocytes (72%), and lower numbers of peripheral blood lymphocytes (44%), Peyer's patch lymphocytes (17%), and splenic lymphocytes (20%) indicated a similar distribution of this antigen between the lymphoid organs as has been found for the mouse thymus lymphocyte-specific antigens. Low numbers of RTLA-bearing lymphocytes were detected in both the BALT (18%) and the gut mucosa (11%). An unexpected finding was the number of “null” cells among the gut mucosa populations, bearing neither thymic nor heavy chain markers. These results in toto support the view that lymphoid aggregates in lung and gut may both contain precursor populations of B cells destined for IgA production.

Increased incidence of lymphoreticular aggregates in lungs of children found unexpectedly dead.

A quantitative study was carried out of the number of lymphoreticular aggregates in standard sections of the lungs of 316 children. Of these, 128 showed no recognizable lung disease, 104 of whom presented as sudden unexpected death. The number of lymphoreticular aggregates was higher in the unexpected than in the expected child deaths. As lymphoreticular aggregates are nonspecific indicators of previous antigenic stimulation, it follows that many of the children in the unexpected death group had been subject to a greater amount of such stimulation.

PERIVASCULAR REACTIONS IN LUNG AND LIVER FOLLOWING INTRAVENOUS INJECTION OF STREPTOCOCCI INTO PREVIOUSLY SENSITIZED ANIMALS

Intravenous inoculation of small doses of non-hemolytic streptococci into previously sensitized rabbits is usually followed by the appearance of perivascular cellular aggregates in lung and liver. The characteristic cell in these aggregates is moderately large, with vesicular nucleus, prominent nucleoli, clumped chromatin, and basophilic cytoplasm. In addition, the lesions contain small lymphocytes and granulocytes. This lesion is easily differentiated by architecture and cell content from normally occurring lymphoid aggregates, and from spontaneous rabbit hepatic cirrhosis. This mononuclear response does not occur when the intravenous dose is large enough to cause death of the animal within 24 hours. In spleen and lymph nodes the characteristic basophilic cells, which normally occur in these organs, are present in increased numbers. Following intravenous treatment alone, or sensitization without intravenous treatment, the lesions occur much less frequently, and when present are smaller and more sparsely found. Inasmuch as in the present series of experiments this lesion was not found in normal animals, and infrequently in those treated by the intravenous route alone, it is suggested that the preliminary sensitization serves to enhance the animal's reactivity to the antigen. In this way a small dose of bacteria is capable of eliciting the cellular phenomenon, which in unsensitized animals appears only when larger doses of antigen are administered over longer periods of time. Too large a dose of antigen, however, results in shock and cell death rather than proliferation.