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Epidemiology of asthma in primary school children : the Obstructive Lung Disease in Northern Sweden (OLIN) studies thesis VIIIBjerg Bäcklund, Anders January 2008 (has links)
Background: Childhood asthma has increased worldwide, although recent studies report a prevalence plateau in some western countries. Aims: To investigate the prevalence of asthma and the associated risk factor patterns from ages 7-8 to 11-12 with special emphasis on the hereditary component, and further to study prevalence trends at age 7-8 from 1996 to 2006 and the possible determinants of these trends. Methods: The studies involved two cohorts from Kiruna, Luleå and Piteå: one previously identified cohort of 3430 children age 7-8 followed by yearly questionnaires until age 11-12 with 97% yearly participation. Skin-prick tests for allergic sensitisation were performed at ages 7-8 and 11-12 in subsets of 2148 and 2155 children respectively (88% of invited). In 2006 a new cohort of 7-8-year-olds was identified and examined identically. 2585 (96% of invited) and 1700 (90% of invited) participated in the questionnaire and skin-prick tests, respectively. The questionnaire included questions about symptoms of asthma, allergic rhinitis and eczema, and possible risk factors. Results: In the 1996 cohort, from age 7-8 to 11-12 the prevalence of physician-diagnosed asthma increased (5.7%-7.7%, P<0.01) while current wheeze decreased (11.7%-9.4%, P<0.01), and 34.7% reported ever wheee at ≥one occasion. Remission was 10% of which half relapsed during the study. Remission was significantly lower among sensitised children. The strongest risk factors for current asthma at ages 7-8 and 11-12 were allergic sensitisation (OR 5) and family history of asthma (OR 3). Several other significant risk factors, e.g. respiratory infections, damp house and low birth weight, had lost importance at age 11-12. At age 7-8, parental asthma was a stronger risk factor (OR 3-4) than parental rhinitis or eczema (OR 1.5-2). Sibling asthma had no independent effect. Biparental asthma had a multiplicative effect (OR 10). Maternal and paternal asthma was equally important, regardless of the child’s sex and sensitisation status. From 1996 to 2006 the prevalence of current wheeze and asthma at age 7-8 did not increase (P=0.13, P=0.18), while lifetime prevalence of ever wheeze and physician-diagnosed asthma increased (P<0.01, P=0.01). Symptoms of rhinitis and eczema were unchanged, despite 45% increase (P<0.01) in allergic sensitisation. For current asthma the adjusted population attributable fractions of sensitisation and parental asthma increased (35%-41%, 27%-45%). This was however balanced by decreased exposure to infections, maternal smoking and home dampness, resulting in stable asthma prevalence. Stratification by sex revealed that current wheeze increased in boys (P<0.01) but tended to decrease in girls (P=0.37), seemingly due to symptom persistence in males. Several asthma indices followed this pattern. The boy-to-girl ratio in exposure to all studied risk factors increased, which may explain the sex-specific prevalence trends in wheeze. Conclusions: The prevalence of current asthma and wheeze did not increase statistically significantly. However, the risk factor pattern has changed considerably since 1996, which will presumably affect the clinical features of childhood wheeze in this region. Sex-specific trends in wheeze can be explained by changes in exposure, and trends in risk factors should be explored parallel to prevalence trends.
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Health Effects of Childhood Exposure to Environmental Tobacco Smoke in Children followed to AdulthoodPugmire, Juliana January 2011 (has links)
Background A significant proportion of children are exposed to environmental tobacco smoke (ETS) throughout the world. This is mainly because of exposure to parental smoking. It is unknown to what extent the negative effects of ETS on respiratory symptoms track from childhood into adulthood. Methods TESAOD (Tucson Epidemiologic Study of Airway Obstructive Disease) is a large population-based prospective study that was initiated in 1972. Participants were followed prospectively with questionnaires and pulmonary function tests (PFTs) completed about every two years in 12 follow-up surveys up to 1996. Skin prick tests and blood samples for IgE measurements were collected at surveys 1, 6, and 11. We identified subjects who entered the study as children (<15 years old) and were followed to adulthood (>18 years) during the study follow-up. Based on questionnaire data, active asthma, wheeze, cough, and chronic cough (cough for three consecutive months) were coded as never (never reported in childhood or adulthood), incident (never reported in childhood, but ≥ one positive report in adulthood), remittent (≥ one positive report in childhood, but not in adulthood), and persistent (≥ one positive report both in childhood and adulthood). PFTs measurements included forced expiratory volume in 1 second, forced vital capacity, and forced expiratory flow at 25-75%. Parent information on smoking status was collected simultaneously at child visits. ETS exposure status was assessed as “ever” or “never” between birth and 15 years. Results Information on parental ETS exposure in childhood and outcomes in adulthood was available for 444 non-Hispanic white participants (51.4% male) with mean age at initial survey of 7.7 years. Total mean follow-up time was 19.0 years (8.8 years in adulthood). Between birth and 15 years, 53.4% of children were exposed to ETS. After adjusting for sex, age at enrollment, years of follow-up, and personal smoking status (assessed at age 15 and above), combined parental ETS exposure in childhood was significantly associated with persistent wheeze (RR(adj) 1.9, p=0.026), persistent cough (RR(adj) 5.9, p<0.001), and persistent (RR(adj) 3.7, p=0.030) and incident chronic cough (RR(adj) 2.3, p=0.040). Paternal ETS exposure in childhood was associated with persistent wheeze (RR(adj) 2.3, p=0.002), persistent cough (RR(adj) 3.9, p<0.001), persistent (RR(adj) 4.8, p=0.004) and incident chronic cough (RR(adj) 2.2, p=0.031), and persistent asthma (RR(adj) 2.3, p=0.016). Maternal ETS exposure was associated with persistent (RR(adj) 1.9, p=0.029) and incident cough (RR(adj) 2.5, p=0.006). Maternal ETS exposure was associated with an increased percent predicted FVC in adulthood (coefficient, 3.75; p=0.019). No other effects on lung function were seen. There were no effects of ETS exposure on total serum IgE or allergic sensitization. ETS exposure was associated with respiratory symptoms in adulthood among both never and current smokers. Conclusions ETS exposure in childhood has long term health effects on lung function and respiratory symptoms. These effects do not appear to be IgE-mediated. ETS exposure, especially paternal ETS exposure, seems to influence the persistence of respiratory symptoms from childhood to adulthood and to affect women more than men. These effects are independent of personal smoking and also seen in never smokers. Both smoking mothers and fathers should be targeted when attempting to reduce ETS exposure among children.
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Mast Cell Progenitor Trafficking in Allergic Airway InflammationDahlin, Joakim January 2013 (has links)
Mast cell progenitors originate from the bone marrow and migrate to the lungs via the blood. During maturation, these cells acquire granules that contain a potent array of bronchoconstrictive mediators. The number of pulmonary mast cells is augmented in asthmatic patients and in mice with allergic airway inflammation, possibly contributing to airway hyperreactivity. An increase in mast cells is likely due to an increased recruitment of committed mast cell progenitors from the blood. However, until now a committed mast cell progenitor population has not been found in adult peripheral blood. We isolated Lin- c-kithi ST2+ integrin β7hi CD16/32hi progenitors from murine blood and showed that these cells were committed to the mast cell lineage. Based on the expression of FcεRI, these cells were less mature in Th1-prone C57BL/6 mice than in Th2-prone BALB/c mice. Asthma is associated with elevated levels of IgE. Upon exposure to allergens, IgE immune complexes are formed. In a mouse model of allergic airway inflammation, we showed that intranasal administration of IgE immune complexes to antigen-sensitized mice resulted in an increased number of mast cell progenitors compared with antigen administration alone. The increase in mast cell progenitors was independent of the low-affinity IgE receptor CD23. Rather, signaling through the common FcRγ-chain was required to enhance the number of lung mast cell progenitors. Signaling through FcεRI was likely responsible for the increase. However a role for FcγRIV could not be excluded. CD11c+ cells, such as dendritic cells, are important for antigen sensitization. In a mouse model of allergic airway inflammation, these cells are also important for the development of airway hyperreactivity, eosinophilia and Th2 cytokine production in response to antigen challenge. We showed that CD11c+ cells are critical for the recruitment of lung mast cell progenitors and the subsequent increase in mast cells. These CD11c+ cells were needed for the upregulation of endothelial vascular cell adhesion molecule-1 (VCAM-1), which is a prerequisite for the antigen-induced recruitment of lung mast cell progenitors.
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Modeling The Spatiotemporal Dynamics Of Cells In The LungPothen, Joshua Jeremy 01 January 2016 (has links)
Multiple research problems related to the lung involve a need to take into account the spatiotemporal dynamics of the underlying component cells. Two such problems involve better understanding the nature of the allergic inflammatory response to explore what might cause chronic inflammatory diseases such as asthma, and determining the rules underlying stem cells used to engraft decellularized lung scaffolds in the hopes of growing new lungs for transplantation. For both problems, we model the systems computationally using agent-based modeling, a tool that enables us to capture these spatiotemporal dynamics by modeling any biological system as a collection of agents (cells) interacting with each other and within their environment. This allows to test the most important pieces of biological systems together rather than in isolation, and thus rapidly derive biological insights from resulting complex behavior that could not have been predicted beforehand, which we can then use to guide wet lab experimentation.
For the allergic response, we hypothesized that stimulation of the allergic response with antigen results in a response with formal similarity to a muscle twitch or an action potential, with an inflammatory phase followed by a resolution phase that returns the system to baseline. We prepared an agent-based model (ABM) of the allergic inflammatory response and determined that antigen stimulation indeed results in a twitch-like response. To determine what might cause chronic inflammatory diseases where the twitch presumably cannot resolve back to baseline, we then tested multiple potential defects to the model. We observed that while most of these potential changes lessen the magnitude of the response but do not affect its overall behavior, extending the lifespan of activated pro-inflammatory cells such as neutrophils and eosinophil results in a prolonged inflammatory response that does not resolve to baseline. Finally, we performed a series of experiments involving continual antigen stimulation in mice, determining that there is evidence in the cytokine, cellular and physiologic (mechanical) response consistent with our hypothesis of a finite twitch and an associated refractory period.
For stem cells, we made a 3-D ABM of a decellularized scaffold section seeded with a generic stem cell type. We then programmed in different sets of rules that could conceivably underlie the cell's behavior, and observed the change in engraftment patterns in the scaffold over selected timepoints. We compared the change in those patterns against the change in experimental scaffold images seeded with C10 epithelial cells and mesenchymal stem cells, two cell types whose behaviors are not well understood, in order to determine which rulesets more closely match each cell type. Our model indicates that C10s are more likely to survive on regions of higher substrate while MSCs are more likely to proliferate on regions of higher substrate.
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Pharmacological Inhibition of Cyclophilin Ameliorates Experimental Allergic EncephalomyelitisHuang, Zi L 01 January 2016 (has links)
A subset of cyclophilins have been implicated in mechanisms of neuroinflammation and neurodegeneration that contributes to the pathogenesis of Multiple Sclerosis. Mitochondrial dysfunction leading to mitochondrial permeability transition plays a pivotal role in axonal damage and disease progression in Multiple Sclerosis. Cyclophilin D (CypD) is a crucial regulatory component of the mitochondrial permeability transition pore and it was demonstrated that the cyclophilin D knockout animals showed reduced experimental allergic encephalomyelitis (EAE) clinical disease severity and axonal injury. We investigated the effect of N-methyl-4-isoleucine-cyclosporin (NIM811), a non-immunosuppressive and non-selective cyclophilin inhibitor, on the course and severity of EAE. EAE mice treated with NIM811 showed a significant reduction in clinical disease severity compared to vehicle treated mice. FACS analysis performed with the dissociated thoracolumbar spine showed that NIM811 treatment was associated with a reduction in CNS macrophages but does not alter T-helper lineage frequencies. In addition, we demonstrated NIM811’s effect on crude mitochondrial fraction obtained from brain and liver homogenates of both wild type and CypD knockout mice in order to determine drug specificity. Benefits observed from the pharmacological inhibition of cyclophilin may lead to a novel MS therapy but NIM811’s exact mechanism of action has yet to be elucidated.
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Atividade antialérgica e estudos químicos das espécies Bidens gardneri Bak. e Bidens sulphurea (Cav.) Sch. Bip. (Asteraceae) / Anti-allergic activity and chemistry studies from species Bidens gardneri Bak. and Bidens sulphurea (Cav.) Sch. Bip. (Asteraceae)Silva, Denise Brentan da 04 December 2009 (has links)
As análises dos voláteis por SPME/CG-EM das partes aéreas, flores e frutos de Bidens sulphurea e Bidens gardneri permitiram-nos constatar diferenças em suas composições químicas. Porém, em todas as frações analisadas os compostos majoritários foram os sequiterpenos b-cariofileno, germacreno D e biciclogermacreno. Apesar dos constituintes majoritários coincidirem nas frações analisadas das duas espécies, foi possível constatar a presença exclusiva de determinados metabólitos em cada fração. A partir das frações hexânicas, oriundas dos extratos etanólicos de B. sulphurea (partes aéreas e flores) e B. gardneri (partes aéreas), foram identificadas trinta e cinco, dezenove e vinte substâncias por CG-EM, respectivamente. Na fração hexânica das partes aéreas de B. sulphurea (BsfcEt/Hx) foram identificados, como constituintes majoritários, o óxido de cariofileno, espatulenol e _- cariofileno, enquanto que na fração hexânica de suas flores (BsflorEt/Hx) os principais constituintes identificados foram _-amirina e _-sitosterol e na fração hexânica das partes aéreas de B. gardneri (BgfcEt/Hx) foram os metabólitos _-estigmasterol e o trans-fitol. O estudo químico da espécie B. sulphurea (partes aéreas e flores) conduziu ao isolamento de um sesquiterpeno (1), 5 flavonas (2, 10, 13-15), 8 flavonóis (3-8, 11, 16), 1 aurona (9) e 2 chalconas (12, 17). Já o estudo de B. gardneri (partes aéreas) conduziu ao isolamento de 4 ácidos clorogênicos (21, 22, 27, 28), 3 poliacetilenos (18-20), 2 flavonas (25, 27), 3 flavanonas (23, 24, 30) e 2 chalconas (29, 31). Os metabólitos 3-O-_-glicopiranosil-tetradeca- 6(E),12(E)-dieno-8,10-diino-1,14-diol (18), 1-O-_-glicopiranosil-14-hidróxi-tetradeca-6(E), 12(E)-dieno-8,10-diino-3-ona (19), 4-metóxi-7-O-_-glicopiranosil-8,3-diidróxi-flavanona (23), 4-metóxi-7-O-_-(6-acetil)-glicopiranosil-8,3-diidróxi-flavanona (24) e 7-O-_-(6- trans-p-cumaroil)-glicopiranosil-8,34-triidróxi-flavanona (30) estão sendo descritos pela primeira vez na literatura. Enquanto que os flavonóides 3-O-_-xilopiranosil-quercetina (5), 3-O-a-arabinofuranosil-kaempferol (8) e 3-O-b-(6-trans-cafeoil)-galactopiranosil-quercetina (16) estão sendo relatados pela primeira vez na família Asteraceae e as substâncias 4(15)- eudesmeno-1_,6_-diol (1), 6-C-_-glicopiranosil-apigenina (2), 3-O-_-arabinofuranosilquercetina (6), 8-C-_-glicopiranosil-apigenina (13), 6-C-_-glicopiranosil-luteolina (14), 8-C- _-glicopiranosil-luteolina (15), ácido 1-metil-5-O-E-cafeoilquínico (22) e 7-O-_- glicopiranosil-apigenina (25) estão sendo relatadas pela primeira vez no gênero Bidens. Além disso, convém destacar que a partir das substâncias 2-O-_-glicopiranosil-trideca-3(E),11(E)- dieno-5,7,9-triino-1,13-diol (20), 4-metóxi-4-O-_-glicopiranosil-okanina (29) e 4-O-_-(6- trans-p-cumaroil)-glicopiranosil-okanina (31) há poucos relatos na literatura e ainda não foram descritos dados de suas propriedades biológicas. Na avaliação da atividade antialérgica das substâncias isoladas, os flavonóides causaram inibição da liberação de _-hexosaminidase de forma dose-dependente, sendo que as substâncias 11 e 31 foram as mais ativas e apresentaram CI50 de 5,1 ± 1,3 M e 5,8 ± 1,2 M, respectivamente. Dentre os extratos e frações avaliados biologicamente, observou-se que BsfcEt/Hx (maior teor de sesquiterpenos) causou um estímulo da liberação de _-hexosaminidase, enquanto que BsfcEt/Ac foi a fração mais ativa (CI50 = 1,3 ± 1,1g/mL). As análises desta última fração e de BsfcEt/DCM por CLAE-DAD-EM e CLAE-DAD-EM/EM revelaram que seus constituintes majoritários são os flavonóis 3, 4, 6 e 7. / The SPME/GC-MS analyses of aerial parts, flowers and fruits of Bidens sulphurea and Bidens gardneri showed the differences in their chemical compositions. However the sesquiterpenes _-caryophyllene, germacrene D and bicyclogermacrene were identified in all fractions analyzed as major compounds. It was observed the exclusive presence of metabolites in each fraction, in spite of major constituents were equal in fractions analyzed of two species. Thirty-five, nineteen and twenty substances were identified in the hexane fractions from ethanol extracts of B. sulphurea (aerial parts and flowers) and B. gardneri (aerial parts) by GC-MS. The major compounds were caryophyllene oxide, spathulenol and _-caryophyllene in the hexane fraction from aerial parts of B. sulphurea (BsfcEt/Hx), while _-amyrin and _- sitosterol were identified in the hexane fraction of its flowers and _-stigmasterol and transphytol were main constituents identified in the hexane fraction from aerial parts of B. gardneri. The chemical study of species B. sulphurea (aerial parts and flowers) led to the isolation of one sesquiterpene (1), five flavones (2, 10, 13-15), eight flavonols (3-8, 11, 16), one aurone (9) and two chalcones (12, 17). From B. gardneri (aerial parts), four chlorogenic acids (21, 22, 27, 28), three polyacetylenes (18-20), two flavones (25, 27), three flavanones (23, 24, 30) and two chalcones (29, 31) were isolated. The substances 3-O-_-glucopyranosyltetradeca-6(E),12(E)-dien-8,10-diin-1,14-diol(18), 1-O-_-glucopyranosyl-14-hydroxytetradeca-6(E),12(E)-dien-8,10-diin-3-one(19),4-methoxy-7-O_glucopyranosyl-8,3-dihydroxyflavanone (23), 4-methoxy-7-O-_-(6-acetyl)-glucopyranosyl-8,3-dihydroxyflavanone(24) and 7-O-_-(6-trans-p-coumaroyl)-glucopyranosyl-8,34-trihydroxyflavanone(30) are described for the first time in the literature. Whereas the flavonols 3-O-_-xylopyranosyl quercetin (5), 3-O-a-arabinofuranosyl kaempferol (8) and 3-O--(6-transcaffeoyl)-galactopyranosyl quercetin (16) are described for the first time in the Asteraceaeand 4(15)-eudesmene-1_,6_-diol (1), 6-C-_-glucopyranosyl apigenin (2), 3-O-_-arabinofuranosyl quercetin (6), 8-C-_-glucopyranosyl apigenin (13), 6-C-_-glucopyranosylluteolin (14), 8-C-_-glucopyranosyl luteolin (15), 1-methyl-5-O-E-caffeoylquinic acid (22)and 7-O-_-glucopyranosyl apigenin (25) for the first time in the genus Bidens. Moreover,there are few reports of the isolation and there are not studies of biological activities from 2-O-_-glucopyranosyl-trideca-3(E),11(E)-dien-5,7,9-triin-1,13-diol (20), 4-methoxy-4-O-_-glucopyranosyl okanin (29) and 4-O-_-(6-trans-p-coumaroyl)-glucopyranosyl okanin (31).The flavonoids showed inhibition of _-hexosaminidase released with dependent-doseresponse and the substances 11 (IC50 = 5,1 ± 1,3 M) and 31 (IC50 = 5,8 ± 1,2 M) were themost active. The BsfcEt/Hx fraction (highest concentration of sesquiterpenes) induced _-hexosaminidase released, while the BsfcEt/Ac fraction exhibited the lower IC50 (1,3 ±1,1g/mL). The flavonoids 3, 4, 6 and 7 were identified, by HPLC-DAD-MS and HPLCDAD-MS/MS, as major constituents in BsfcEt/Ac and BsfcEt/DCM fractions.
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Participação glutamatérgica nos efeitos induzidos pela anfetamina na resposta inflamatória alérgica pulmonar de camundongos / Glutamatergic involvement in amphetamine-induced effects on pulmonary allergic inflammatory response in miceHamasato, Eduardo Kenji 06 September 2011 (has links)
O objetivo do presente estudo foi avaliar a participação do sistema glutamatérgico nos efeitos induzidos pela anfetamina em camundongos sensibilizados e desafiados com ovalbumina, através do tratamento prévio com MK-801, um antagonista de receptores glutamatérgicos NMDA. Em relação aos animais tratados apenas com anfetamina, observamos que o tratamento prévio com MK-801: 1) reverteu a diminuição no número de leucócitos totais bem como o número de eosinófilos e neutrófilos no lavado broncoalveolar (LBA); 2) reverteu a diminuição da porcentagem de expressão das moléculas L-selectina e ICAM-1 em granulócitos do LBA; 3) reverteu a diminuição das citocinas IL-10 e IL-13 no sobrenadante do LBA; 4) reverteu a diminuição na contração da traquéia; 5) reverteu a desgranulação de mastócitos pulmonares; 6) não alterou a produção de IgE total e IgE-OVA; 7) não reduziu os níveis de corticosterona plasmáticos. Tomados em seu conjunto, quer nos parecer que os efeitos induzidos pela anfetamina implicam na ativação do sistema glutamatérgico via receptores NMDA. Possivelmente, as diferenças dos efeitos do MK-801, da anfetamina ou a combinação de fármacos se devam a uma ativação (modulação) diferenciada sobre o eixo hipotálamo pituitária adrenal (HPA) e/ou sistema nervoso autônomo simpático (SNAS) o que poderia explicar os efeitos opostos observados na resposta inflamatória alérgica pulmonar de camundongos. / The aim of this study was to evaluate the involvement of the glutamatergic system in the effects induced by amphetamine in mice OVA-sensitized and challenged by the pretreatment with MK-801, an NMDA glutamate receptor antagonist. In relation to animals treated only with amphetamine we found that pretreatment with MK-801: 1) reverted the decrease in the total leukocytes and in the total number of eosinophils and neutrophils within the bronchoalveolar lavage fluid (BAL) 2) reverted the decrease in the percentage of expression of adhesion molecules L-selectin and ICAM-1 in BAL granulocytes, 3) reverted the decrease in IL-10 and IL-13 in BAL supernatant and 4) reverted the decrease in methacoline-induced tracheal contraction; 5) reverted the degranulation of mast cells in the lungs; 6) did not alter the production of total IgE and IgE-OVA, 7) did not decrease the plasma levels of corticosterone. Taken together, it seems feasible to suggest that the effects induced by amphetamine requires the participation of the glutamatergic system via NMDA receptors. Possibly, differences in MK-801, amphetamine or MK-801 + amphetamine effects on hypothalamic pituitary adrenal axis (HPA) and/or sympathetic autonomic nervous system (SNAS) might explain the opposite effects now observed for these drugs given alone or in combination in the pulmonary allergic inflammatory response in mice.
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Papel anti-fibrótico de PGE2 e BMP-7 na asma alérgica experimental. / Anti-fibrotic role of PGE2 and BMP-7 in experimental allergic asthma.Stumm, Camila Leindecker 19 June 2012 (has links)
A asma alérgica é uma doença inflamatória crônica das vias aéreas que envolve ativação de fibroblastos pulmonares. Esta ativação é induzida por TGF-<font face=\"Symbol\">b e este processo é regulado por moléculas anti-fibróticas. Nosso objetivo foi elucidar mecanismos envolvidos na fibrose das vias aéreas em um modelo de asma. Na primeira parte, investigamos o eixo síntese/resposta da PGE2. A PGE2 e seu análogo forskolina inibiram síntese de colágeno I e proliferação de fibroblastos. Estas células apresentaram perda tempo-dependente na capacidade de sintetizar PGE2 sob estímulo com IL-1<font face=\"Symbol\">b, e menor expressão de COX-2 e mPGEs-1. Na segunda parte, estudamos a relação TGF-<font face=\"Symbol\">b1/BMP-7 na fibrose das vias aéreas. Há predomínio da molécula pró-fibrótica TGF-<font face=\"Symbol\">b1 sobre a molécula anti-fibrótica BMP-7 nos pulmões de animais asmáticos. Em fibroblastos, a BMP-7 inibe a síntese de colágeno tipo I induzida pelo TGF-<font face=\"Symbol\">b1 e as vias de SMAD-2, SMAD-3 e p38. O tratamento dos animais com BMP-7 causou diminuição significativa da fibrose. Os resultados implicam estes mecanismos na fibrose das vias aéreas na asma. / Allergic asthma is a chronic inflammatory disease of the airways that involves activation of lung fibroblasts. This activation is induced by TGF-<font face=\"Symbol\">b and this process is regulated by anti-fibrotic molecules. Our goal was to elucidate mechanisms involved in airway fibrosis in an animal model of asthma. In the first part, we investigated the PGE2 synthesis/response axis. PGE2 and its analog forskolin inhibited collagen I synthesis and proliferation of fibroblasts. These cells showed a time-dependent loss in the ability to synthesize PGE2 under IL-1<font face=\"Symbol\">b stimulation, and downregulated COX-2 and mPGEs-1. In the second part, we studied the ratio TGF-<font face=\"Symbol\">b1/BMP-7 in airway fibrosis. There is predominance of the pro-fibrotic TGF-<font face=\"Symbol\">b1 over the anti-fibrotic BMP-7 in the lungs of asthmatic animals. In fibroblasts, BMP-7 inhibits TGF-<font face=\"Symbol\">b1-induced type I collagen synthesis and the SMAD-2, SMAD-3 and p38 pathways. Treatment of the animals with BMP-7 caused significant decrease in fibrosis. The results implicate these mechanisms in airway fibrosis in asthma.
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"Relação da poluição atmosférica com a citologia nasal em pacientes com rinite alérgica, residentes na cidade de São Paulo, nas diferentes estações do ano" / Relationship between environmental pollution and nasal cytology in patients with allergic rhinitis, living in São Paulo city, during the different seasons of the yearFabiana Maia Nobre Rocha 18 November 2005 (has links)
Diferentes estudos têm demonstrado uma maior prevalência de rinite alérgica nas áreas urbanas, sugerindo um efeito decorrente da exposição à poluentes. Por esta razão, resolvemos estudar a relação da poluição atmosférica com os achados do citológico nasal em 11 pacientes com rinite alérgica nas quatro estações do ano e compará-los a 12 indivíduos normais. No verão, observamos um aumento significante de eosinófilos no grupo alérgico (p = 0,007) e um predomínio de células ciliadas no grupo controle (p = 0,021). No outono, houve um predomínio de neutrófilos no grupo controle (p = 0,027). No inverno, ocorreu um aumento de neutrófilos (p = 0,015) no grupo controle. Houve um aumento das células caliciformes (p = 0,019) no grupo alérgico. Na primavera, ocorreu um aumento dos neutrófilos (p = 0,025) no grupo controle / Different studies have demonstrated an increase in the prevalence of allergic rhinitis in urban areas, suggesting an effect resulting from exposure to pollutants. Therefore, we studied the relationship between atmospheric pollution and nasal cytological findings in 11 patients with allergic rhinitis during the four seasons of the year compared to 12 normal individuals. In summer, a significant increase in eosinophils was observed in the allergic group (p = 0.007) and there was a predominance of ciliated cells in the control group (p = 0.021). In autumn, neutrophils predominated in the control group (p = 0.027), and an increase in neutrophils (p = 0.015) was observed in winter. An increase in goblet cells (p = 0.019) was observed in the allergic group. In spring, there was an increase of neutrophils (p = 0.025) in the control group
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O estresse físico modula a mecânica de tecido pulmonar periférico, a expressão de citocinas e o estresse oxidativo em cobaias com inflamação alérgica crônica / Physical stress modulates lung tissue mechanics, cytokines and oxidative stress activation in guinea pigs with chronic allergic inflammationReis, Fabiana Gomes dos 23 September 2009 (has links)
Existem evidências de que o estresse exerce papel importante na piora dos sintomas da asma, mas os exatos mecanismos que os interligam ainda não estão elucidados, principalmente no parênquima distal. Recentemente tem sido enfatizada a importância do parênquima pulmonar na modulação das alterações funcionais, inflamatórias e de remodelamento que caracterizam os quadros asmáticos. Cabe ressaltar, que tais alterações tem sido observadas tanto em humanos quanto em modelos de inflamação pulmonar alérgica crônica. Objetivos: Nossos objetivos foram avaliar se a mecânica de tecido pulmonar periférico, a ativação de vias de estresse oxidativo, a expressão celular de citocinas, o recrutamento eosinofílico e o processo de remodelamento da matriz extracelular podem ser modulados pelo estresse físico repetido, induzido pela natação forçada, em cobaias com inflamação alérgica crônica pulmonar. Métodos: Os animais foram expostos a sete inalações com doses crescentes de ovoalbumina (1~5mg/ml) ou soro fisiológico por quatro semanas (grupos OVA e SAL). Após 24 horas da quarta inalação os animais foram submetidos ao protocolo de natação forçada, considerado um modelo de indução de estresse gerado por esforço pela sobrevivência com dificuldade de escapar (grupos SAL-E e OVA-E). Os animais foram expostos ao protocolo de estresse por dois períodos de cinco dias, intercalados por dois dias após os cinco primeiros dias. Após 72 horas da sétima inalação os animais foram anestesiados, exsanguinados e fatias de tecido pulmonar periférico foram retiradas e submetidas à avaliação de mecânica oscilatória. Foram avaliadas a resistência (Rt), a elastância (Et) e a histerisividade (h) em condições basais e após desafio com ovoalbumina e acetilcolina. Os resultados de Rt e Et foram expressos em % de aumento em relação aos valores basais. As fatias de tecido pulmonar periférico foram então submetidas à avaliação histopatológica e imunohistoquímica para quantificação do número de eosinófilos, do conteúdo de colágeno, actina e de 8-iso-PGF2a e do número de células positivas para IL-2, IL-4, IL-5, IL-13, IFN-g e iNOS. As duas glândulas adrenais foram retiradas, pesadas e seu peso foi corrigido pelo peso total do animal. Os níveis séricos de catecolaminas (adrenalina, noradrenalina e dopamina) e do cortisol também foram obtidos. Resultados: Houve aumento na %Rt, %Et tanto após o desafio antigênico bem como após o contato com o agonista constritor, no número de eosinófilos, no conteúdo de 8-iso-PGF2a, de fibras colágenas e de actina, no número de células positivas para IL-4, IL-5, IL-13 e iNOS no septo alveolar dos animais expostos à ovoalbumina (grupos OVA e OVA-E) quando comparados aos animais expostos ao soro fisiológico (grupos SAL, p<0,05 para todas as comparações). As cobaias sensibilizadas e submetidas ao protocolo de estresse (grupo OVA-E) apresentaram aumento na %Rt e %Et após o desafio antigênico quando comparadas ao grupo OVA (p<0,05). Em relação à avaliação de mecânica pulmonar periférica após o desafio com acetilcolina, observamos aumento apenas na %Et no grupo OVA-E comparativamente ao grupo OVA (p<0,05). Houve aumento no numero de células IL-4 positivas, no conteúdo de 8-iso-PGF2a e de actina nos animais OVA-E comparativamente aos animais do grupo OVA (p<0,05). Considerando o grupo SAL-E houve aumento da %Rt e %Et após desafio com o agonista constritor, no número de células positivas para iNOS, IFN-g, IL-2, IL-5 e IL-13, bem como no conteúdo de 8-iso-PGF2a comparativamente ao grupo SAL (p<0,05). Finalmente, o peso relativo das adrenais e os níveis de cortisol sérico foram maiores nos grupos submetidos ao estresse físico (grupos SAL-E e OVA-E) quando comparados aos grupos não estressados (grupos SAL e OVA, p<0,004). Não houve diferença nos níveis séricos das catecolaminas entre os quatro grupos experimentais. Conclusões: A natação forçada repetida como modelo de estresse foi capaz de causar alterações funcionais como a constrição do parênquima pulmonar bem como aumento da expressão de citocinas e da produção de 8-iso-PGF2a, marcador da ativação de vias do estresse oxidativo. Além disso, neste modelo de inflamação crônica pulmonar, a exposição repetida à natação forçada foi capaz de potencializar a constrição do parênquima pulmonar. Esta alteração funcional associou-se ao aumento do conteúdo de actina e de 8-iso-PGF2a e do número de células IL-4 positivas no septo alveolar. Estes resultados sugerem que tanto a ativação inflamatória quanto o estresse oxidativo estão envolvidos na modulação da resposta inflamatória crônica pulmonar pelo estresse físico repetido. / There are evidences showing that stress can worsen asthma symptoms, but the exact mechanisms that link them are not clarified, especially in the distal lung parenchyma. Recently, the importance of the lung parenchyma has been emphasized in the modulations of the functional alterations, inflammatory and remodeling that characterizes asthma. These alterations have been observed in humans as well as experimental models of chronic allergic pulmonary inflammation. Objectives: Our goals were to evaluate if lung tissue mechanics, activation of oxidative stress pathways, cytokines cellular expressions, eosinophil recruitment and the remodeling process of the extracellular matrix can be modulated by repeated physical stress, induced by forced swimming, in guinea pigs with chronic allergic pulmonary inflammation. Methods: Animals were exposed to seven inhalations with ovalbumin increased doses (1~5mg/ml) or saline solution during four weeks (OVA and SAL groups). Twenty-four hours after the fourth inhalation animals were submitted to forced swimming protocol, that is a type of an unavoidable stress that induces an effort for survival with an escape deficit (SAL-E and OVA-E groups). Animals were exposed to the stress protocol for two periods of five days, intercalated by two days. Seventy-two hours after the seventh inhalation animals were anesthetized, lung strips were removed and submitted to oscillatory mechanic evaluation. Resistance (Rt), elastance (Et) and hysteresivity were evaluated at base line and after OVA and acetylcholine challenge in bath. Rt and Et results were expressed as a % of baseline values. The pulmonary tissue strips were then submitted to histological and Immunohistochemistry analysis, to quantify the number of eosinophils, collagen, actin, 8-iso-PGF2a content and the number of positive cells for IL-2, IL-4, IL-5, IL-13, IFN-g and iNOS. Both adrenal glands were removed and weighted. The weight of the adrenal glands was corrected by the animals total weight. The serum levels of catecholamine (epinephrine, norepinephrine and dopamine) and cortisol were also obtained. Results: There was an increase in Rt%, Et% after the antigenic challenge as well as after the acetylcholine challenge, in the number of eosinophils, 8-iso-PGF2a content, collagen and actin fibers and in the number of IL-4, IL-5, IL-13 and iNOS positive cells in the alveolar septum of the animals exposed to ovalbumin (OVA and OVA-E groups) when compared to the animals exposed to saline solution (SAL, p<0.05 for all comparisons). The sensitized guinea pigs submitted to the stress protocol (OVA-E group) presented an increase in Rt% and Et% after the OVA challenge when compared to the OVA group (p<0.05). Due to the acetylcholine challenge, we observed an increase only in the Et% in OVA-E group compared the OVA group (p<0.05). There was an increase in the IL-4 positive cells, in the 8-iso-PGF2a and actin content in OVA-E animals compared to OVA group (p<0.05). Considering the SAL-E group there was an increase in Rt% and Et% after acetylcholine challenge, in the number of iNOS, IFN-g, IL-2, IL-5, and IL-13 positive cells, as well as in the 8-iso-PGF2a content compared to SAL group (p<0.05). Finally, the relative adrenal weight and the serum cortisol levels were greater in the groups submitted to physical stress (SAL-E e OVA-E groups) when compared to the non-stressed groups (SAL and OVA groups, p<0.05). There was no difference in the catecholamine serum levels among the four experimental groups. Conclusion: The repeated forced swimming, as a stress model was capable of causing functional alterations like lung tissue constriction and increase in cytokines expression and 8-iso-PGF2a production. Besides that, in this chronic pulmonary inflammation, the repeated exposure to forced swimming was capable of empowering lung tissue constriction. This functional alteration was associated with an augmentation in actin and 8-iso-PGF2a content and in the number of IL-4 positive cells in the alveolar septum. These results suggest that activation of inflammatory and oxidative stress pathways were involved in the modulation of stress responses in this animal model of chronic lung inflammation.
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