Uma abordagem metodológica para engenharia de groupware aplicada a área de saúde

Tese (doutorado) - Universidade Federal de Santa Catarina, Centro Tecnológico. Programa de Pós-Graduação em Engenharia de ProduçãoEste projeto de tese visa, a partir de um embasamento teórico sobre desenvolvimento de sistemas para grupos de usuários e sobre aspectos do gerenciamento de materiais e equipamentos médicos, adequar e desenvolver um protótipo para um sistema de informação que auxilie a gestão de centros de saúde através da metodologia de Engenharia de Groupware e de Sistemas Workflow

Delayed Goblet Cell Hyperplasia, Acetylcholine Receptor Expression, and Worm Expulsion in SMC-Specific IL-4Rα–Deficient Mice

Interleukin 4 receptor α (IL-4Rα) is essential for effective clearance of gastrointestinal nematode infections. Smooth muscle cells are considered to play a role in the type 2 immune response–driven expulsion of gastrointestinal nematodes. Previous studies have shown in vitro that signal transducer and activator of transcription 6 signaling in response to parasitic nematode infection significantly increases smooth muscle cell contractility. Inhibition of the IL-4Rα pathway inhibits this response. How this response manifests itself in vivo is unknown. In this study, smooth muscle cell IL-4Rα–deficient mice (SM-MHC(Cre)IL-4Rα(−/lox)) were generated and characterized to uncover any role for IL-4/IL-13 in this non–immune cell type in response to Nippostrongylus brasiliensis infection. IL-4Rα was absent from α-actin–positive smooth muscle cells, while other cell types showed normal IL-4Rα expression, thus demonstrating efficient cell-type–specific deletion of the IL-4Rα gene. N. brasiliensis–infected SM-MHC(Cre)IL-4Rα(−/lox) mice showed delayed ability to resolve infection with significantly prolonged fecal egg recovery and delayed worm expulsion. The delayed expulsion was related to a delayed intestinal goblet cell hyperplasia, reduced T helper 2 cytokine production in the mesenteric lymph node, and reduced M3 muscarinic receptor expression during infection. Together, these results demonstrate that in vivo IL-4Rα–responsive smooth muscle cells are beneficial for N. brasiliensis expulsion by coordinating T helper 2 cytokine responses, goblet hyperplasia, and acetylcholine responsiveness, which drive smooth muscle cell contractions

On the behaviour of lung tissue under tension and compression

Lung injuries are common among those who suffer an impact or trauma. The relative severity of injuries up to physical tearing of tissue have been documented in clinical studies. However, the specific details of energy required to cause visible damage to the lung parenchyma are lacking. Furthermore, the limitations of lung tissue under simple mechanical loading are also not well documented. This study aimed to collect mechanical test data from freshly excised lung, obtained from both Sprague-Dawley rats and New Zealand White rabbits. Compression and tension tests were conducted at three different strain rates: 0.25, 2.5 and 25 min−1. This study aimed to characterise the quasi-static behaviour of the bulk tissue prior to extending to higher rates. A nonlinear viscoelastic analytical model was applied to the data to describe their behaviour. Results exhibited asymmetry in terms of differences between tension and compression. The rabbit tissue also appeared to exhibit stronger viscous behaviour than the rat tissue. As a narrow strain rate band is explored here, no conclusions are being drawn currently regarding the rate sensitivity of rat tissue. However, this study does highlight both the clear differences between the two tissue types and the important role that composition and microstructure can play in mechanical response

The Effect of Interleukin-4 and Amphiregulin on the Proliferation of Human Airway Smooth Muscle Cells and Cytokine Release

Airway smooth muscle (ASM) hyperplasia and angiogenesis are important features associated with airway remodeling. We investigated the effect of IL-4 and amphiregulin, an epidermal growth factor family member, on the proliferation of human ASM cells and on the release of vascular endothelial growth factor (VEGF) and monocyte chemotactic protein (MCP)-1 from human ASM cells. Human ASM cells were growth-arrested for 48 hr and incubated with platelet-derived growth factor (PDGF)-BB, interleukin (IL)-4, amphiregulin, and VEGF to evaluate cell proliferation. The cells were treated with PDGF, IL-4 and amphiregulin to evaluate the release of VEGF, MCP-1. IL-4 suppressed unstimulated and PDGF-stimulated ASM cell proliferation. Amphiregulin stimulated ASM cell proliferation in a dose-dependent manner. VEGF did not have any influence on ASM cell proliferation. IL-4 stimulated VEGF secretion by the ASM cells in a dose-dependent manner and showed added stimulatory effects when co-incubated with PDGF. Amphiregulin did not promote VEGF secretion. IL-4 and amphiregulin showed no stimulatory effects on MCP-1 secretion. The results of this study showed that IL-4 had bifunctional effects on airway remodeling, one was the suppression of the proliferation of the ASM cells and the other was the promotion of VEGF release by the ASM cells, and amphiregulin can promote human ASM cell proliferation

IFN-γ, IL-4 and IL-13 modulate responsiveness of human airway smooth muscle cells to IL-13

© 2008 Moynihan et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Anaphylatoxin C3a receptors in asthma

The complement system forms the central core of innate immunity but also mediates a variety of inflammatory responses. Anaphylatoxin C3a, which is generated as a byproduct of complement activation, has long been known to activate mast cells, basophils and eosinophils and to cause smooth muscle contraction. However, the role of C3a in the pathogenesis of allergic asthma remains unclear. In this review, we examine the role of C3a in promoting asthma. Following allergen challenge, C3a is generated in the lung of subjects with asthma but not healthy subjects. Furthermore, deficiency in C3a generation or in G protein coupled receptor for C3a abrogates allergen-induced responses in murine models of pulmonary inflammation and airway hyperresponsiveness. In addition, inhibition of complement activation or administration of small molecule inhibitors of C3a receptor after sensitization but before allergen challenge inhibits airway responses. At a cellular level, C3a stimulates robust mast cell degranulation that is greatly enhanced following cell-cell contact with airway smooth muscle (ASM) cells. Therefore, C3a likely plays an important role in asthma primarily by regulating mast cell-ASM cell interaction

Oncostatin M promotes STAT3 activation, VEGF production, and invasion in osteosarcoma cell lines

<p>Abstract</p> <p>Background</p> <p>We have previously demonstrated that both canine and human OSA cell lines, as well as 8 fresh canine OSA tumor samples, exhibit constitutive phosphorylation of STAT3, and that this correlates with enhanced expression of matrix metalloproteinase-2 (MMP2). While multiple signal transduction pathways can result in phosphorylation of STAT3, stimulation of the cytokine receptor gp130 through either IL-6 or Oncostatin M (OSM) is the most common mechanism through which STAT3 is activated. The purpose of this study was to evaluate the role of IL-6 and OSM stimulation on both canine and human OSA cell lines to begin to determine the role of these cytokines in the biology of OSA.</p> <p>Methods</p> <p>RT-PCR and Western blotting were used to interrogate the consequences of OSM and IL-6 stimulation of OSA cell lines. OSA cells were stimulated with OSM and/or hepatocyte growth factor (HGF) and the effects on MMP2 activity (gel zymography), proliferation (CyQUANT), invasion (Matrigel transwell assay), and VEGF production (Western blotting, ELISA) were assessed. The small molecule STAT3 inhibitor LLL3 was used to investigate the impact of STAT3 inhibition following OSM stimulation of OSA cells.</p> <p>Results</p> <p>Our data demonstrate that the OSM receptor (OSMR), but not IL-6 or its receptor, is expressed by all human and canine OSA cell lines and canine OSA tumor samples; additionally, OSM expression was noted in all tumor samples. Treatment of OSA cell lines with OSM induced phosphorylation of STAT3, Src, and JAK2. OSM stimulation also resulted in a dose dependent increase in MMP2 activity and VEGF expression that was markedly reduced following treatment with the small molecule STAT3 inhibitor LLL3. Lastly, OSM stimulation of OSA cell lines enhanced invasion through Matrigel, particularly in the presence of rhHGF. In contrast, both OSM and HGF stimulation of OSA cell lines did not alter their proliferative capacity.</p> <p>Conclusions</p> <p>These data indicate OSM stimulation of human and canine OSA cells induces STAT3 activation, thereby enhancing the expression/activation of MMP2 and VEGF, ultimately promoting invasive behavior and tumor angiogenesis. As such, OSM and its receptor may represent a novel target for therapeutic intervention in OSA.</p

Genetic Dissection of the Canq1 Locus Governing Variation in Extent of the Collateral Circulation

<div><h3>Background</h3><p>Native (pre-existing) collaterals are arteriole-to-arteriole anastomoses that interconnect adjacent arterial trees and serve as endogenous bypass vessels that limit tissue injury in ischemic stroke, myocardial infarction, coronary and peripheral artery disease. Their extent (number and diameter) varies widely among mouse strains and healthy humans. We previously identified a major quantitative trait locus on chromosome 7 (<em>Canq1</em>, LOD = 29) responsible for 37% of the heritable variation in collateral extent between C57BL/6 and BALB/c mice. We sought to identify candidate genes in <em>Canq1</em> responsible for collateral variation in the cerebral pial circulation, a tissue whose strain-dependent variation is shared by similar variation in other tissues.</p> <h3>Methods and Findings</h3><p>Collateral extent was intermediate in a recombinant inbred line that splits <em>Canq1</em> between the C57BL/6 and BALB/c strains. Phenotyping and SNP-mapping of an expanded panel of twenty-one informative inbred strains narrowed the <em>Canq1</em> locus, and genome-wide linkage analysis of a SWRxSJL-F2 cross confirmed its haplotype structure. Collateral extent, infarct volume after cerebral artery occlusion, bleeding time, and re-bleeding time did not differ in knockout mice for two vascular-related genes located in <em>Canq1</em>, <em>IL4ra</em> and <em>Itgal</em>. Transcript abundance of 6 out of 116 genes within the 95% confidence interval of <em>Canq1</em> were differentially expressed >2-fold (p-value<0.05÷150) in the cortical <em>pia mater</em> from C57BL/6 and BALB/c embryos at E14.5, E16.5 and E18.5 time-points that span the period of collateral formation.</p> <h3>Conclusions</h3><p>These findings refine the <em>Canq1</em> locus and identify several genes as high-priority candidates important in specifying native collateral formation and its wide variation.</p> </div

Neutrophil Extracellular Traps Directly Induce Epithelial and Endothelial Cell Death: A Predominant Role of Histones

Neutrophils play an important role in innate immunity by defending the host organism against invading microorganisms. Antimicrobial activity of neutrophils is mediated by release of antimicrobial peptides, phagocytosis as well as formation of neutrophil extracellular traps (NET). These structures are composed of DNA, histones and granular proteins such as neutrophil elastase and myeloperoxidase. This study focused on the influence of NET on the host cell functions, particularly on human alveolar epithelial cells as the major cells responsible for gas exchange in the lung. Upon direct interaction with epithelial and endothelial cells, NET induced cytotoxic effects in a dose-dependent manner, and digestion of DNA in NET did not change NET-mediated cytotoxicity. Pre-incubation of NET with antibodies against histones, with polysialic acid or with myeloperoxidase inhibitor but not with elastase inhibitor reduced NET-mediated cytotoxicity, suggesting that histones and myeloperoxidase are responsible for NET-mediated cytotoxicity. Although activated protein C (APC) did decrease the histone-induced cytotoxicity in a purified system, it did not change NET-induced cytotoxicity, indicating that histone-dependent cytotoxicity of NET is protected against APC degradation. Moreover, in LPS-induced acute lung injury mouse model, NET formation was documented in the lung tissue as well as in the bronchoalveolar lavage fluid. These data reveal the important role of protein components in NET, particularly histones, which may lead to host cell cytotoxicity and may be involved in lung tissue destruction