Many factors influence the inflammatory responses in rat trachea, including inflammatory mediators released from nerve fibers, histamine released by mast cells and endotoxin from the cell walls of bacteria. The inflammatory responses include plasma extravasation, subepithelial edema, and hypersecretion of secretory cells. But the mechanism of inflammation mediated by these factors was not completely understood. In the present study, a high dose of histamine was administered intravenously to induce the inflammation in rat airway. India ink was also injected as a tracer to label the leaky blood vessels in different time points. To investigate the serous cell secretion and subepithelial edema formation, the treacheal tissue was processed for histological study. Electron microcopy was carried out to investigate the ultrastructure of serous cells. To investigate the mechanism of histamine effect, the muscarinic receptor antagonist atropine (1 mg/ml/kg) or histamine H1 receptor antagonist mepyramine (10 mg/ml/kg) was injected 15 min before histamine injection. Five minutes after histamine, plasma leakage and serous cell secretion were extensive. The area density of India ink-labeled leaky vessels was 17.24 % ¡Ó 2.03 %. Saline, the vehicle of histamine, produced only a little extravasation. Mepyramine inhibited the histamine-induced plasma extravasation and serous cell degranulation significantly but atropine had no effect. The results suggest that histamine-induced serous cell degranulation is mainly through histamine H1 receptors but not through cholinergic muscarinic receptors in rat trachea.

No description available.

Neutrophil extravasation into tissues is an essential process required for the inflammatory response. Upon receiving an inflammatory cue, neutrophils begin accumulating on the luminal surface of the endothelium. Neutrophil recruitment is initiated by selectin-mediated tethering and rolling of neutrophils along the endothelial monolayer, followed by integrin-mediated firm adhesion. Adherent neutrophils then traverse the endothelium in a process known as transendothelial migration. The events mediating the rolling and adhesion steps are well characterised, but research into the molecular mechanisms regulating transendothelial migration is an area of intense focus. A previous study conducted in our laboratory found that the activation of endothelial extracellular signal-regulated kinase (ERK) 1/2 was required for neutrophil transmigration. Furthermore, it was found that endothelial ERK was activated in response to a soluble protein produced by fMLP- or IL-8-stimulated neutrophils. In the present study, the soluble ERK-activating neutrophil protein was identified as annexin A1, which was selected as a possible candidate following mass spectrometry analysis of proteins secreted from activated neutrophils. Annexin A1 antibodies (Abs) were found to block endothelial ERK activation induced by conditioned medium harvested from stimulated neutrophils. Annexin A1 Abs were additionally able to inhibit neutrophil transmigration across human umbilical vein endothelial cell (HUVEC) monolayers in an in vitro transmigration assay. Following the purification of recombinant annexin A1, it was demonstrated that it could activate endothelial ERK in a similar manner to neutrophil conditioned medium. Upon further investigation, ERK activation was found to be induced by a truncated form of annexin A1 present in the protein preparation rather than the full length protein. Calpain I, a calcium dependent protease that is activated upon neutrophil stimulation and is known to cleave annexin A1 within the N-terminal domain, was shown to process full length inactive recombinant annexin A1 into an unidentified product that could activate endothelial ERK. A calpain I inhibitor was also found to prevent stimulated neutrophils from secreting an ERK-activating protein, thus further suggesting a role for calpain I in this process. As full length annexin A1 has been reported to signal through the formyl peptide receptor (FPR) family, a pan-FPR antagonist was incubated with endothelial cells and was found to inhibit ERK activation induced by neutrophil conditioned medium, indicating that pro-inflammatory annexin A1 is also a FPR ligand. Endothelial projections termed “transmigratory cups” form around neutrophils during extravasation, of which ICAM-1 is a major component. Using an assay that examined transmigratory cups during neutrophil transmigration, it was found that annexin A1 Abs could inhibit neutrophil adhesion and transmigration through HUVEC monolayers by interfering with transmigratory cup formation around neutrophils, as shown by monitoring ICAM-1 during the process. Quantification of transmigrating neutrophils highlighted that the majority of neutrophils were emigrating via a transcellular pathway, which is in opposition to many in vitro studies where paracellular transmigration predominates. The results generated from this study identified a novel pro-inflammatory role for annexin A1 in neutrophil transendothelial migration. Preliminary experiments suggested that the pro-inflammatory annexin A1 responsible for endothelial ERK activation was a truncated form. Calpain I appears to be a likely candidate responsible for the generation of this uncharacterised, truncated annexin A1 product, however further experiments are required to confirm this hypothesis. Pro-inflammatory annexin A1 represents a new target for the treatment of inflammatory disorders. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1374554 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2009

Le mélanome cutané est l'un des cancers les plus agressifs et mortel capables de dissémination métastatique à distance. L’intravasation cellules tumorales dans le vaisseau sanguin dans les tumeurs primaires et l'extravasation sont des étapes importantes dans la formation de métastases. Ces étapes impliquent la perturbation de la barrière endothéliale par des cellules tumorales afin de faciliter leur migration transendothéliale et la colonisation métastatique. Cependant, le processus par lequel les cellules tumorales modulent l'intégrité des jonctions vasculaires est encore mal compris. Afin de déterminer les facteurs de perméabilité sécrétés par les cellules métastatiques, nous avons identifié la protéine matricielle SPARC comme un facteur critique contribuant à la perméabilité vasculaire et l'extravasation des cellules tumorales. Nous montrons que SPARC sécrété par les cellules de mélanome induit une perméabilité vasculaire via l'ouverture des jonctions intercellulaires des monocouches endothéliales et entraîne la migration transendothéliale de cellules de mélanome. In vivo, l’extinction de SPARC mène à une diminution drastique dans la colonisation à court et long terme des poumons et de la perméabilité des capillaires pulmonaires. A l’inverse, sa surexpression augmente les capacités d’extravasation et les métastases. / Cutaneous melanoma is one of the most aggressive cancers capable of distant and lethal metastatic spread. Tumor cell intravasation into blood vessel at primary tumor sites and subsequent extravasation are critical steps in the formation of metastases. These steps entail disruption of the endothelial barrier by tumor cells to facilitate their transendothelial passage and metastatic seeding. However, the way by which tumor cells modulate vascular junction integrity is still poorly understood. In an attempt to determine permeability factors secreted by metastatic cells, we identified the matricellular protein SPARC as a critical signaling factor that contributes to elevated vascular permeability and tumor cell extravasation. We show that SPARC released by melanoma cells enhances vascular leakiness by inducing opening of intercellular junctions of endothelial monolayers and drives melanoma cell transendothelial migration. In vivo vascular permeability and metastatic assays demonstrate that SPARC deficiency abrogates tumor-induced permeability of lung capillaries and prevents extravasation from blood vessels and metastasis, whereas overexpression of SPARC increases the lung metastatic potential of melanoma cells. Mechanistically, SPARC-induced endothelial gap formation and transmigration is dependent on vascular cell adhesion molecule (VCAM1) and p38 MAPK signaling pathway in endothelial cells. Importantly, blocking VCAM1 impedes melanoma cell extravasation. The clinical relevance of our findings is highlighted by the high levels of SPARC detected in tumor cells from human pulmonary melanoma lesions.

¡iAbstract¡j Neurogenic inflammation is an acute inflammatory tissue response, that is mediated by sensory axon reflex. Accompanied with neurogenic inflammation, plasma extravasation, occurs in the eyes, esophagus, bladder, joints, the tip of tongue, and the respiratory tract of the mammal. Recently, many studies have investigated the neurogenic inflammation by electrical stimulation of nerves and intravascular injection of irritants. Upon stimulation, the sensory nerve endings in mucosa can release neuropeptides such as substance P, that causes formation of the venular endothelial gaps, plasma extravasation and tissue edema in various organs. Substance P also cause smooth muscle contraction and mucus secretion in the respiratory tract. Neurogenic plasma extravasation has been studied extensively in the trachea, and bronchi, but rarely in the esophagus. It is known that a plexus of substance P-immunoreactive axons exists in the mucosal and submucosal layers. They play an important role in releasing substance P to act on the receptors of the venular endothelium through diffusion. Based on plasma extravasation and other studies related to the respiratory tract, the purpose of the present study was to investigate neurogenic inflammatory response in the esophagus of the digestive tract. In this study, capsaicin (90 µg/ml/kg) and substance P (3 µg/ml/kg) were used as the irritant and inflammatory mediator, respectively to reduce neurogenic inflammation in the esophagus. India ink was used to label the affected venules. The magnitude of the neurogenic inflammation was expressed as area density of India ink-labeled leaky venules. Histopathological changes in the esophageal tissue were studied under the light microscope. The result of this study indicated that capsaicin at the dose of (90 µg/ml/kg) and substance P at the dose of (3 µg/ml/kg) caused similar magnitude of inflammation in the esophagus. India ink-labeled venules distributed like a network in the mucosal tissue and in connective tissue of the submucosal layer. The upper, middle and lower parts of esophagus exhibited the same degree of inflammatory response, that was similar to that in the lower respiratory tract as the previous studies reported. These results suggest that nerve branches from the vagal trunk send sensory axons to innervate both the esophagus and airways.

No description available.

No description available.

Busca-se em pesquisas e estudos avaliar a capacidade de adaptação e selamento entre a conexão implante/intermediário de diferentes sistemas de implantes odontológicos. Observou-se recentemente que implantes com abutments retidos com parafusos, diversos fenômenos como afrouxamento e fratura do parafuso, rotação e fratura do abutment com penetração bacteriana nas câmaras internas dos implantes, acontece como conseqüência da desadaptação interface implante/abutment. É descrito ao nível desta região um pequeno espaço microgap, fator relevante para remodelamento da crista óssea e longevidade da saúde dos tecidos moles periimplantares. O propósito do estudo foi investigar o extravasamento da solução do corante azul de Evan em três tipos de implantes e seus respectivos intermediários, durante um período de seis (6) dias, a cada vinte e quatro (24) horas, com intervalo em cento e vinte (120) horas, através da agitação proporcionada por uma mesa agitadora. Para tal, foram utilizados trinta (30) implantes, dez (10) de cada tipo, com seus respectivos intermediários protéticos, minipilares, sendo o Grupo Um (1) de implantes Hexágono Externo (HE), Grupo dois (2) de Hexágono Interno (HI) e Grupo três (3) de Cone Morse (CM). No interior de cada implante foi pipetado volume ou quantidade proporcional ao seu espaço interno uma solução de corante azul de Evan. Após a colocação do corante no interior dos implantes, os abutments ou intermediários foram acoplados e aparafusados com torque de vinte (20) Ncm, através do torquímetro de Gauge (Tohnichi), e estes depositados individualmente em micro tubos de cor âmbar na condição de intermediários voltados para baixo. Segui/se imediatamente a colocação de (1)ml de água deionizada. A seguir os tubos foram fechados hermeticamente e posicionados numa mesa suporte para microtubos e foram armazernados por 24 horas, sem agitação. Posteriormente foram agitados por 10 minutos com movimentos uniformes em mesa agitadora e a partir deste momento iniciou/se a coleta de uma pequena quantidade de água de cada micro tubo onde por sua vez estas amostras foram analisadas por absorbância através do método de fotometria, espectrofotometria, onde mostraram o extravasamento da solução do corante azul de Evan nos sistemas de implantes usados. Do inicio da coleta das amostras no tempo de (24 horas) até a condição no terceiro dia ou setenta e duas horas, os três sistemas não mostraram/se alterações estatisticamente significantes. A partir do tempo quarto dia ou 96 h., no sistema do grupo Cone Morse, revelou diferenças estatisticamente significantes entre o grupo HE e HI. Os resultados foram tabulados e o teste estatístico Anova há dois critérios e aplicados a eles o teste Tukey comparação entre todos, com o nível de significância de p<0.05. Os resultados do teste de vinte e quatro (24); quarenta e oito (48), setenta e duas (72), não havendo diferenças estatisticamente significantes, ao passo que no período de noventa e seis (96) e cento e quarenta e quatro(144) horas, mostrou a solução do corante de azul de Evan do sistema CM, o xtravasamento estatisticamente significante maior do que nos grupos HE e HI. Conclui/se, portanto, que houve extravasamento nos três sistemas na condição inicial. No tempo 96 houve um maior extravasamento do sistema CM perpetuando até o final do experimento, mostrando-se estaticamente diferente em relação aos sistemas HE e HI. / Research and studies seek to evaluate the capacity of adaptation and sealing between the implant-intermediate connections of different dental implant systems. It has recently been observed that in implants with screw-retained abutments, various phenomena, such as screw4 loosening and fracture, rotation and fracture of the abutment with bacterial penetration into the internal chambers of the implants have occurred as a result of maladaptatation at the implant-abutment interface. At the level of this region, a small space known as a microgap is described, and is a relevant factor in remodeling of the crestal bone and peri-implant soft tissue health in the long term. The purpose of this study was to investigate the extravasation of Evans blue dye solution in three types of implants and their respective intermediates during a period of six (6) days, every twenty-four (24) hours, with an interval in one hundred and wenty (120) hours, by means of agitation provided by an agitating table. To do this, thirty (30) implants were used, ten (10) of each type, with their respective prosthetic intermediates and mini-abutments, divided into groups as follows: Group One (1) External Hexagon implants (EH), Group Two (2) Internal Hexagon (IH) and Group three (3) Morse Cone (MC). Into the interior of each implant, Evans blue dye solution was inserted with a pipette in a volume or quantity proportional to its internal space. After the dye was put into the implants, the abutments or intermediates were coupled and the screws tightened to a torque of twenty (20) Ncm, with a Gauge torque meter (Tohnichi), and they were individually deposited in amber-colored microtubes positioned so that the intermediates faced downwards. This was immediately followed by the placement of (1)ml of deionized water. Next, the tubes were hermetically closed and placed on a table with a microtube holder and stored for 24 hours, without agitation. Afterwards they were agitated for 10 minutes on an agitating table making uniform movements and from then on, a small quantity of water began to be collected from each microtube, where in turn these samples were analyzed by absorbance method of photometry, spectrophotometry, in which they showed the extravasation of the Evans blue dye solution in the implant system used. From the beginning of sample collection at the time of (24hours) until the condition on the third day or at seventy-two hours, the three systems showed no statistically significant alterations. From the fourth day, or at the time of 96 h., in the Morse Cone Group system, statistically significant differences were revealed between Group EH and IH. The results were tabulated and the ANOVA statistical test for two criteria and the Tukey test were applied for comparison among all the groups, with a level of significance of p<0.05. The results of the twenty-four-hour (24); forty-eight (48), seventy-two hour tests (72), there were no statistically significant differences, whereas in the period of ninety-six (96) and one hundred and forty-four (144) hours, showed the Evans blue dye solution extravasation from the MC system to be greater with statistical significance than in Groups EH and IH. It was therefore concluded that there was extravasation in the three systems in the initial condition. At the time of 96 there was greater extravasation from the MC system, which was perpetuated up to the end of the experiment, showing it to differ statistically in comparison with the EH and IH systems.

Os pacientes submetidos ao tratamento antineoplásico necessitam de um acesso venoso que permita a infusão segura das drogas quimioterápicas, evitando assim o risco do extravasamento. O extravasamento quimioterápico é definido como o escape de drogas do vaso sanguíneo para os tecidos circunjacentes, e seus efeitos tóxicos locais variam podendo causar dor, necrose tissular ou descamação do tecido. A morbidade depende do tipo da droga, da quantidade extravasada, da sua concentração, da localização do extravasamento, das condições do paciente e do intervalo entre o fato, seu reconhecimento e o tratamento. A prática baseada em evidências é uma abordagem que capacita os profissionais buscarem a melhor evidência para o cuidado, respeitando a opinião dos pacientes e seus familiares. O presente estudo é uma revisão integrativa da literatura, que teve como objetivo buscar e avaliar as evidências disponíveis na literatura sobre as intervenções eficazes frente ao extravasamento de drogas quimioterápicas vesicantes, em cateteres periféricos, prevenindo e minimizando lesões no paciente adulto oncológico. Para a seleção dos artigos utilizamos a base de dados Medline, e a amostra constituiui-se de 16 artigos. As medidas de prevenção do extravasamento são consideradas mais eficazes e recomendadas. Para o manejo do extravasamento das drogas doxorrubicina e epirrubicina é recomendado aplicação de gelo local, os antídotos dimetilsulfoxide tópico e dexrazoxane intravenoso, intervenção cirúrgica se houver persistência dos sintomas ou para grande quantidade de droga extravasada. Para o extravasamento de mitomicina C, gelo local e intervenção cirúrgica em lesões detectadas após 48 horas; para mecloretamina é indicado gelo e o antídoto tiossulfato de sódio. Para o manejo da vinorelbine é recomendado calor local e o antídoto hialuronidase por via subcutânea. As evidências extraídas dos estudos analisados podem auxiliar a implementação de cuidados de enfermagem eficazes relacionados ao extravasamento das drogas vesicantes contribuindo assim com a melhoria da assistência à saúde. / Patients submitted to antineoplastic chemotherapy need a venous access that allows for the safe infusion of chemotherapeutic drugs, thus avoiding the risk of chemotherapeutic extravasation. Chemotherapeutic extravasation is defined as the escape of drugs from the blood vessel to surrounding tissues. Its local toxic effects vary and can cause pain, tissue necrosis or flaking. Morbidity depends on the type of drug, the extravasated quantity, its concentration, the location of the extravasation, the patient s conditions and the interval between the fact and its recognition and treatment. Evidence-based practice is an approach that trains professionals to look for the best evidence for care, respecting the opinions of patients and their relatives. This study is an integrative literature review that aimed to look for and assess available evidence in literature about effective interventions in case of extravasation of vesicant chemotherapeutic drugs, in peripheral catheters, minimizing skin injuries of adult cancer patients. To select the articles, we used the database Medline, and the sample consisted of 16 articles. Extravasation prevention measures are considered as the most effective and recommended measures. To handle the extravasation of doxorubicin and epirubicin, the local application of ice is recommended, the antidotes topic dimethyl sulphoxide and intravenous dexrazoxane, and surgical intervention if the symptoms persist or if a large quantity of the drug has extravasated. For the extravasation of mitomycin C, local ice and surgical intervention in injuries detected after 48 hours; for mecloretamine, ice is indicated, as well as the antidote sodium thiosulphate. To handle vinorelbine, local heat is recommended, as well as the subcutaneous application of the antidote hyaluronidase. The evidence extracted from the analyzed studies can support the implementation of effective nursing care related to the extravasation of vesicant drugs, thus contributing to the improvement of nursing care.

Cigarette smoke's influence on cancer has primarily been a subject of epidemilogic and tumorigenic studies. There have been no proper investigations with interests focused on how cigarette smoke affects the cellular mechanics of metastasis. Gathering an understanding of how smoke influences metastatic invasion could be vital in regulating or possibly eliminatings cancer's ability to initiate new tumor growth sites. This project focuses on cigarette smoke's influence on cellular mechanics of endothelial cells, and the invasive potential of cancer against a fully active endothelium. It is already known that cigarette smoke has a carcinogenic effect, but it is hypothesized that the cigarette smoke causes the endothelium to exhibit pro-invasive characteristics. Cancer cells are often ignorant to extra-cellular stimuli. It is suspected that there will be a less pronounced degradation of cellular mechanics of cancerous cells than endothelial cells when exposed to similar concentrations of cigarette smoke.