Summary
Background
The allergic inflammatory reaction is characterized by leucocyte adherence and infiltration processes which are controlled by the expression of adhesion molecules on the surface of ...vascular endothelium. One of the main mediators implicated in allergic reactions is represented by histamine. Histamine is a potent activator of endothelial cells (EC): it induces the expression of P‐selectin on the surface of endothelium and the secretion of IL‐6 and IL‐8.
Objectives
Loratadine (L), a histamine H1‐antagonist, and one of its active metabolites, descarboxyethoxyloratadine (DCL), were studied at different concentrations for their ability to reduce the histamine‐induced activation of human umbilical vein EC (HUVEC).
Methods
HUVEC were stimulated in the presence of histamine at 10‐6M, 10‐5M and 10‐4M. We assessed by ELISA the expression of P‐selectin on EC surface, as well as cytokine production in EC supernatants of 24 h culture.
Results
Our results showed that for a 10‐4 M‐histamine stimulation, L and DCL have a similar inhibitory effect on P‐selectin expression (IC50= 13 × 10‐9 M and 23 × 10‐9 M, respectively). L and DCL inhibited significantly IL‐6 and IL‐8 secretion induced by histamine with a more powerful efficiency of the active metabolite. For the dose of 10‐4 M histamine, a 50% inhibition of IL‐6 secretion was obtained for a dose of DCL equal to 2.6 × 10‐12 M whereas the same magnitude of effects were only reached for a higher concentration of L (0.3 × 10‐6 M). Similar results were obtained for IL‐8 (IC50 = 0.2 × 10‐6M for L and 10‐9 M for DCL). Analysis of IL‐8 mRNA expression by RT‐PCR was in accordance with these data.
Conclusions
These results demonstrate that both L and DCL are active to reduce the histamine‐induced activation of EC. Interestingly, DCL seems to be effective at lesser concentrations especially to inhibit cytokine secretion.
Background: We have shown previously that the late airways response (LAR) can be transferred by ovalbumin-primed CD4
+ T lymphocytes in Brown Norway rats. This response is associated with an increase ...of eosinophils and high expression of T
H2 cytokines (IL-4 and IL-5) in bronchoalveolar lavage (BAL) fluid.
Objective: In this study we hypothesized that the inhibition of IL-4 or IL-5 production in the CD4
+ cells transferred to a naive animal could decrease the LAR and prevent airway eosinophilia in response to antigen challenge.
Methods: CD4
+ cells, purified from the cervical lymph nodes of ovalbumin-sensitized rats, were maintained in culture for 6 hours with medium alone or with 10 μg/mL IL-4 antisense (AS), IL-5 AS, or control AS oligodeoxynucleotide. Then the cells were administrated intraperitoneally to naive rats, which were challenged 2 days later by a 5% ovalbumin aerosol. The lung resistance was measured for 8 hours, and then BAL was performed. Cytospin preparations from BAL cells were assessed for the presence of eosinophils by immunocytochemistry for major basic protein and for IL-4, IL-5, and IFN-γ expression.
Results: In rats injected with IL-4 AS–treated T cells, LAR, eosinophils, and IL-4 and IL-5 expression were significantly decreased compared with the other groups. Only IL-5 expression in BAL fluid was slightly decreased consequent to the transfer of IL-5 AS–treated T cells.
Conclusion: This study demonstrates that, in the CD4
+ T cell–driven LAR, the early production of IL-4, but not IL-5, by the transferred CD4
+ cells is essential for the development of the LAR. (J Allergy Clin Immunol 1999;104:205-14.)
A congenital brain tumor is a tumor detected before birth or during the first two months of life. The frequency of congenital brain tumors is extremely low - 0.34 per 1 million newborns, and no more ...than 1.5% of all neoplasms of the central nervous system in children, but the rapid growth of the tumor and the destruction of normal brain tissue give them a fatal prognosis. Purpose - to expand knowledge on the possibilities of antenatal diagnosis and the features of the management of the early neonatal period of congenital mіalformations based on the clinical observation of fetal brain teratoma. An overview of literature sources is provided on the prevalence of pathology, histological structure (teratomas, neuroepithelial and mesenchymal tumors), features of the clinical course that distinguish them from childhood tumors - mainly supratentorial localization, lack of growth restriction due to the mobility of the bones of the skull, prognosis and tactics of pregnancy and childbirth . Ultrasound examination is the main method of diagnosis of brain tumors, which are visualized in the form of a solid or cystic calcified formation or not, and manifestations of hypervascularization can also be absent or present. The features of the structure and development of the teratoma, which contains cells of all 3 germ layers and has properties of rapid destructive growth, are also described. Hydrocephalus accompanying congenital brain tumors can be caused both by compression of the ventricular system and intracranial hemorrhages. Thanks to modern diagnostic capabilities, most cases are detected in terms of possible termination of pregnancy, in the case of childbirth with such a pathology, in 60% of cases, a cesarean section is used. The given clinical case shows the possibilities of antenatal diagnosis of a brain tumor and even clearly establishing the depth of the lesion, at the same time as the lack of treatment options. The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.
CD8 super(+)T cells can suppress allergen-induced late airway responses (LARs) and airway inflammation. To test the hypothesis that the suppression of LARs and airway eosinophilia by CD8 super(+)T ...cells is IFN- gamma mediated, we tested the effects of adoptively transferred CD8 super(+)T cells, in which IFN- gamma synthesis was inhibited by an antisense (AS) oligodeoxynucleotide (ODN), on the airway responses of a rat model of allergic asthma. CD8 super(+)T cells were harvested from the cervical lymph nodes of ovalbumin (OVA)-sensitized Brown Norway rats for administration to other actively sensitized syngeneic rats. CD8 super(+)T cells (2 x 10 super(6)) were incubated for 6 hours with 2 mu mol/L AS ODN or sense ODN and were injected intraperitoneally into recipients; inhibition of IFN- gamma expression in vitro by AS ODN was shown by means of flow cytometry. Two days later, rats were challenged with aerosolized OVA. OVA-induced LAR and bronchoalveolar lavage (BAL) fluid eosinophilia were suppressed by sense treated CD8 super(+)T cells. IFN- gamma expression in BAL cells was elevated in these animals. IFN- gamma expression in BAL cells was at control levels in recipients of AS ODN-treated CD8 super(+)cells, confirming the success of the AS treatment in vivo. BAL eosinophilia was also largely restored in the AS ODN treatment group. In contrast, the CD8 super(+)T cell-induced suppression of the LAR was not significantly affected by AS ODN pretreatment. These results indicate that CD8 super(+)T cells inhibit airway eosinophilia through secretion of IFN- gamma but may suppress the LAR by means of other mechanisms.
The blockade of alpha4 integrins with a monoclonal antibody (TA-2) decreases late airway responses (LR) in ovalbumin (OVA)-sensitized and challenged rats. In this study, we used a model of CD4+ ...cell-driven LR to test the hypothesis that alpha4-integrin blockade involves interference with T-cell activation in the inhibition of LR. Purified CD4+ cells from OVA-sensitized rats were transferred to unsensitized recipients, which received either TA-2 or a control antibody (cAb), and were OVA-challenged. A sham-challenged group was also studied. LR, calculated from pulmonary resistance after challenge, were reduced in the TA-2 group compared with the cAb group (p = 0.015). Total cell counts, macrophages, neutrophils, and lymphocytes in bronchoalveolar lavage (BAL), and CD3+ cells in airway sections, were unaffected. The cAb group had higher numbers of cells expressing interleukin-5 (IL-5) mRNA (55.2 +/- 3.39 cells/1,000, mean +/- SEM) and major basic protein (MBP) (6.2 +/- 0.4/100 cells) in bronchoalveolar lavage (BAL), than the TA-2 group (25.37 +/- 2.41 IL-5+ and 2.7 +/- 0.2 MBP+) and the sham group (12.37 +/- 0.96 IL-5+, 1.7 +/- 0.1 MBP+). Interferon gamma (IFN-gamma) mRNA+ cells were downregulated in both OVA-challenged groups, compared with the sham group. Our results suggest that the attenuation of LR and eosinophilia by alpha4-integrin blockade may involve interference with CD4+ cell activation and IL-5 expression.
L'endothélium participe activement au développement de la réaction inflammatoire notamment par l'expression de molécules d'adhérence et la sécrétion de cytokines, en particulier de chimiokines. La ...sévérité de l'asthme allergique est liée en grande partie à la réaction inflammatoire chronique présente au niveau des bronches. Afin de préciser les mécanismes de recrutement des leucocytes dans l'asthme allergique, nous avons étudié l'implication de l'endothélium dans cette pathologie et les interactions aboutissant à cette stimulation. En plus de l'augmentation de la vasoperméabilité classiquement observée au cours de la réaction allergique, nous avons mis en évidence une augmentation de l'expression de molécules d'adhérence sur l'endothélium de la muqueuse bronchique issue de patients asthmatiques. Concernant les mécanismes d'activation de l'endothélium, l'implication des macrophages alvéolaires, des lymphocytes T, des mastocytes et des éosinophiles a été successivement étudiée. Ces différentes cellules effectrices, dans le contexte d'une réaction allergique, sont capables, selon différentes modalités, d'augmenter l'expression de molécules d'adhérence et la sécrétion de chimiokines par les cellules endothéliales. Les principaux médiateurs intervenant dans ces interactions sont l'interleukine (IL)-1β et le facteur nécrosant des tumeurs (TNF); l'IL-4 et l'histamine interviennent également. Dans le cadre d'un état de mal asthmatique caractérisé par une réaction inflammatoire très importante, la sécrétion d'IL-1β et de TNF a été observée, suggérant fortement l'implication de ces cytokines dans le développement de l'inflammation. Plus récemment, nous avons cloné et séquencé une molécule appelée molécule spécifique de l'endothélium (ESM)-1 qui pourrait inhiber l'adhérence des leucocytes et donc leur migration. Cette découverte ainsi que l'étude des interactions endothélium — cellules inflammatoires ont permis d'identifier de nouvelles cibles pour une approche thérapeutique.
The endothelium participates actively in the development of the inflammatory response, in particular by expressing adhesion molecules and by secreting chimiokines and other cytokines. The severity of allergic asthma is determined in large part by the chronic inflammatory response in the bronchial tree. To elucidate the mechanisms of leukocyte recruitment in allergic asthma, we conducted a study of the endothelium and its interactions with inflammatory cells. In addition to the increase in blood vessel permeability that is a classic feature of the allergic response, we found increased expression of adhesion molecules on bronchial mucosa endothelium from asthma patients. The potential role of alveolar macrophages, T lymphocytes, mastocytes, and cosinophils in activation of the endothelium was investigated. In the course of an allergic response, each of these effector cell types can enhance, via various modalities, adhesion molecule expression and chimiokine secretion by the endothelial cells. The main mediators of these interactions are interleukin-1β (IL-1β) and tumor necrosis factor (TNF); IL-4 and histamine are also involved. In status asthmaticus, a condition characterized by extreme inflammation, IL-1β and TNF were secreted, suggesting that these cytokines are involved in the development of the inflammation. We have recently cloned and sequenced a molecule called endothelium-specific molecule-1, which may inhibit the adhesion, and therefore the migration, of leukocytes. This discovery and data from studies of endothelium-inflammatory cell interactions have identified new targets for the treatment of asthma.
Eosinophil differentiation is thought to occur by the action of interleukin (IL)-5 on CD34(+) progenitor cells. The allergen-induced increase in eosinophil numbers in isolated airway preparations in ...vitro, and detection of increased numbers of circulating CD34(+) cells in atopic subjects, led us to the hypothesis that the eosinophil infiltration of the airway in asthma may result from local mucosal differentiation, in addition to recruitment from the bone marrow. We examined CD34(+) cell numbers by immunohistochemistry and IL-5 receptor alpha (IL-5Ralpha) messenger RNA (mRNA) expression by in situ hybridization in bronchial biopsies from atopic asthmatic patients, and from atopic and nonatopic control subjects. CD34(+) cell numbers were increased in the airway in atopic asthmatic and atopic nonasthmatic subjects. In contrast, CD34(+)/ IL-5Ralpha mRNA+ cells were increased in asthmatic subjects when compared with both atopic and nonatopic control subjects. Airway numbers of CD34(+)/IL-5Ralpha mRNA+ cells were correlated to airway caliber in asthmatic subjects and to eosinophil numbers. These findings support the concept that eosinophils may differentiate locally in the airway in asthma.
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