RESUMO
Eosinophil recruitment in asthma is a multistep process, involving both trans-endothelial migration to the lung interstitium and trans-epithelial migration into the airways. While the trans-endothelial step is well studied, trans-epithelial recruitment is less understood. To contrast eosinophil recruitment between these two compartments, we employed a murine kinetics model of asthma. Eosinophils were phenotyped by multicolor flow cytometry in digested lung tissue and bronchoalveolar lavage (BAL) simultaneously, 6 h after each ovalbumin (OVA) challenge. There was an early expansion of tissue eosinophils after OVA challenge followed by eosinophil buildup in both compartments and a shift in phenotype over the course of the asthma model. Gradual transition from a Siglec-F(med) CD11c(-) to a Siglec-F(high) CD11c(low) phenotype in lung tissue was associated with eosinophil recruitment to the airways, as all BAL eosinophils were of the latter phenotype. Secondary microarray analysis of tissue-activated eosinophils demonstrated upregulation of specific integrin and chemokine receptor signature suggesting interaction with the mucosa. Using adhesion assays, we demonstrated that integrin CD11c mediated adhesion of eosinophils to fibrinogen, a significant component of epithelial barrier repair and remodeling. To the best of our knowledge, this is the only report to date dissecting compartmentalization of eosinophil recruitment as it unfolds during allergic inflammation. By capturing the kinetics of eosinophil phenotypic change in both tissue and BAL using flow cytometry and sorting, we were able to demonstrate a previously undocumented association between phenotypic shift of tissue-recruited eosinophils and their trans-epithelial movement, which implicates the existence of a specific mechanism targeting these cells to mucosal airways.
Assuntos
Asma/imunologia , Asma/metabolismo , Antígeno CD11c/metabolismo , Eosinófilos/imunologia , Eosinófilos/metabolismo , Imunofenotipagem , Fenótipo , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Adesão Celular , Quimiotaxia de Leucócito , Modelos Animais de Doenças , Feminino , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , CamundongosRESUMO
Lung inflammation, caused by acute exposure to ozone (O3) - one of the six criteria air pollutants - is a significant source of morbidity in susceptible individuals. Alveolar macrophages (AMØs) are the most abundant immune cells in the normal lung and their number increases following O3 exposure. However, the role of AMØs in promoting or limiting O3-induced lung inflammation has not been clearly defined. Here, we used a mouse model of acute O3 exposure, lineage tracing, genetic knockouts, and data from O3-exposed human volunteers to define the role and ontogeny of AMØs during acute O3 exposure. Lineage tracing experiments showed that 12, 24, and 72 h after exposure to O3 (2 ppm) for 3h all AMØs were tissue-resident origin. Similarly, in humans exposed to FA and O3 (200 ppb) for 135 minutes, we did not observe ~21h post-exposure an increase in monocyte-derived AMØs by flow cytometry. Highlighting a role for tissue-resident AMØs, we demonstrate that depletion of tissue-resident AMØs with clodronate-loaded liposomes led to persistence of neutrophils in the alveolar space after O3 exposure, suggesting that impaired neutrophil clearance (i.e., efferocytosis) leads to prolonged lung inflammation. Moreover, depletion of tissue-resident AMØ demonstrated reduced clearance of intratracheally instilled apoptotic Jurkat cells, consistent with reduced efferocytosis. Genetic ablation of MerTK - a key receptor involved in efferocytosis - also resulted in impaired clearance of apoptotic neutrophils followed O3 exposure. Overall, these findings underscore the pivotal role of tissue-resident AMØs in resolving O3-induced inflammation via MerTK-mediated efferocytosis.
RESUMO
At least three vasopressinergic brain systems are involved in inflammatory reaction. The first one is VP neurons of the bed nucleus of stria terminalis, projecting to antipyretic center in the preoptic forebrain region. The second system is neurons of the parvocellular subnucleus of the hypothalmic paraventricular nucleus. VP from these neurons reaches portal blood through the external zone of the median eminence. VP potentiates the effect of corticotropin releasing hormone on ACTH cells in the anterior pituitary. Synergetic modulation of pituitary-adrenal axis by these neurohormones maintains synthesis and release of glucocorticosteroids. The latter plays crucial role as endogenous immunosuppresants. The third VP system is magnocellular hypothalamic neurons that release vasopressin into general circulation. Systemic VP is capable of compensating the water lost caused by symptoms of inflammation. The review is devoted to analysis of current information concerning physiology and interactions between these systems during acute and chronic inflammation. The special reference has been made on the magnocellular neurons and the role of circulating vasopressin in the renal function regulation.
Assuntos
Inflamação/fisiopatologia , Vasopressinas/fisiologia , Glândulas Suprarrenais/fisiologia , Animais , Encéfalo/fisiologiaRESUMO
The effectiveness and safety of the new Russian drug Rastan® (recombinant human growth hormone) were evaluated in children with growth hormone deficiency (GHD) and Turner's syndrome (TS). An open-labeled clinical study of the drug was performed in 35 children with GHD or TS. The main efficacy criteria were growth changes and yearly calculated height velocity; the secondary criteria were changes in height SDS and IGF-1 and IGFBP-3 levels. Rastan® was subcutaneously injected daily for 6 months; the dose of the drug being 0.033 mg/kg in GHD and 0.05 mg/day in TS. All enrolled 35 patients completed the study. During the study, the patients' growth significantly increased in all the patients (P < 0 0001), in those with GHD (P < 0.0001) and TS (P < 0.0001). Height SDS statistically significantly increased in all the patients (P < 0.0001) and in the GHD (P < 0.0001) and TS (P < 0.0001) groups. Over 6 months of therapy, the average estimated height velocity was 12.4±3.76 cm/year. There were 2-3-fold increases in lower baseline IGF-1 and IGFBR levels. The advene reactions were mild and required no drug discontinuation. Rastan® was effective and well tolerated in patients with GHD or TS.
RESUMO
Expression of antidiuretic hormone V(2)-receptor, water channel protein aquaporin-2, and cytokines interleukin-1b and interleukin-6 was studied in the kidneys of rats with acute inflammation produced by intraperitoneal injection of lipopolysaccharide in a dose of 250 microg/100 g. Reduced expression of aquaporin-2 and V(2)-receptor led to impairment of concentration capacity in the kidneys and decrease in urine osmolarity.