Christine Douglass. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1992. / Includes bibliographical references (leaves 76-86). / Bibliography --- p.5 / Summary --- p.6 / Chapter 1. --- Introduction --- p.8 / Chapter 1.1 --- The problem --- p.8 / Chapter 1.2 --- The purpose of the study --- p.10 / Chapter 1.3 --- Study Design --- p.11 / Chapter 2. --- Literature Review --- p.12 / Chapter 2.1 --- Bronchial hyperresponsiveness --- p.12 / Chapter 2.12 --- "Asthma, bronchial hyperresponsiveness and respiratory symptoms suggestive of asthma" --- p.13 / Chapter 2.2 --- Atopy --- p.17 / Chapter 2.3 --- Genetics and the environment --- p.21 / Chapter 2.4 --- Environmental influences --- p.24 / Chapter 2.41 --- Smoking --- p.24 / Chapter 2.42 --- Passive smoking --- p.25 / Chapter 2.43 --- Pollution --- p.28 / Chapter 2.44 --- Upper respiratory tract infection --- p.31 / Chapter 3 --- Hong Kong --- p.34 / Chapter 4. --- Ethical approval --- p.35 / Chapter 5 --- Methods --- p.36 / Chapter 5.1 --- Subjects and study period --- p.36 / Chapter 5.2 --- Questionnaires --- p.36 / Chapter 5.3 --- Bronchial provocation --- p.38 / Chapter 5.31 --- Agents for provocation --- p.38 / Chapter 5.311 --- Histamine --- p.39 / Chapter 5.312 --- Guidelines for the storage and preparation of histamine --- p.39 / Chapter 5.32 --- Route of administration --- p.39 / Chapter 5.321 --- Inhalation provocation tests --- p.40 / Chapter 5.33 --- Parameters used to measure response and expression of results --- p.41 / Chapter 5.34 --- Preconditions for bronchial provocation testing- nontechnical factors --- p.43 / Chapter 5.35 --- A rapid method for measurement of bronchial responsiveness --- p.43 / Chapter 5.351 --- Nebulizer output --- p.43 / Chapter 5.352 --- Histamine solution preparation --- p.44 / Chapter 5.353 --- Lung function measurement --- p.44 / Chapter 5.354 --- Challenge procedure --- p.44 / Chapter 5.4 --- Measurement of atopic status --- p.46 / Chapter 6 --- Expression and analysis of data --- p.48 / Chapter 7 --- Results --- p.51 / Chapter 7.1 --- Repeatability of questionnaires --- p.51 / Chapter 7.2 --- Results from questionnaires --- p.51 / Chapter 7.21 --- Lifetime symptoms --- p.51 / Chapter 7.22 --- Symptoms within the past year --- p.52 / Chapter 7.23 --- Classification of groups for random selection --- p.54 / Chapter 7.3 --- Nebulizer output --- p.54 / Chapter 7.4 --- Computer generated random selection --- p.55 / Chapter 7.5 --- "Recording of ""yes"" when unsure of answers" --- p.55 / Chapter 7.6 --- Univariate statistical analysis --- p.56 / Chapter 7.61 --- Bronchial hyperresponsiveness of asthma --- p.56 / Chapter 7.66 --- "Respiratory symptoms suggestive of asthma, bronchial hyperresponsiveness and doctors diagnosis of asthma" --- p.58 / Chapter 7.67 --- Air quality and passive smoking --- p.58 / Chapter 7.68 --- Place of birth --- p.58 / Chapter 8. --- Discussion --- p.60 / Chapter 9. --- Conclusion and Recommendations --- p.73 / Acknowledgements --- p.75 / References --- p.76 / Tables --- p.87 / Figures --- p.113 / Appendix --- p.119

Diss. (sammanfattning) Linköping : Univ., 2003. / Härtill 4 uppsatser.

Diss. Linköping : Univ., 2003.

Thesis (Ph.D.)--University of Alabama at Birmingham, 2008. / Title from PDF title page (viewed on Feb. 4, 2010). Includes bibliographical references.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 5 uppsatser.

Thesis (Ph.D. in Immunology) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 124-138). Free to UCD Anschutz Medical Campus. Online version available via ProQuest Digital Dissertations;

INTRODUÇÃO: A indução de tolerância oral atenua a resposta inflamatória e a produção de anticorpos anafiláticos secundários presentes em quadros alérgicos pulmonares tanto em humanos quanto em modelos experimentais. Nestas situações, a modulação do remodelamento brônquico e o papel do óxido nítrico não foram previamente estudados. OBJETIVOS: 1. Desenvolver dois modelos de tolerância oral em cobaias com inflamação crônica pulmonar caracterizando: mecânica pulmonar, hiper-responsividade a metacolina, óxido nítrico exalado (NOex), anticorpos IgG1, inflamação brônquica e eosinofilopoiese. 2. Avaliar o remodelamento brônquico e a expressão da enzima óxido nítrico sintase neuronal (nNOS) no epitélio brônquico nestes animais. MÉTODOS: As cobaias receberam inalações de ovoalbumina ou soro fisiológico durante 15 minutos ou até que apresentassem desconforto respiratório (este tempo foi denominado tempo de inalação). O protocolo foi repetido duas vezes por semana durante quatro semanas. Para a indução da tolerância foi administrada ovoalbumina a 2% por via oral e oferecida ad libitum, sendo formados os grupos: 1. TO1 (recebeu ovoalbumina oral a 2% a partir da primeira inalação com ovoalbumina); 2. TO2 (recebeu ovoalbumina oral a 2% a partir da quarta inalação com ovoalbumina); 3. SAL (recebeu água ad libitum e inalações com soro fisiológico); 4. OVA (recebeu água ad libitum e inalações com solução de ovoalbumina). Após os animais serem anestesiados e ventilados, foram avaliados: 1. mecânica pulmonar basal e após inalação com ovoalbumina (30mg/ml) ou soro fisiológico, 2. hiper-responsividade brônquica à metacolina, 3. coletado o NOex. Ao final do experimento, os fragmentos pulmonares foram retirados e corados com hematoxilina e eosina, com a técnica histoquímica cianeto resistente para peroxidase eosinofílica (células EPO+), com a técnica imunoistoquímica para a detecção da óxido nítrico sintase neuronal (nNOS) e com resorcina-fucsina, resorcina-fucsina oxidada e picro-sírius. A medula óssea foi retirada e corada com hematoxilina e eosina. O índice de edema peribrônquico, as células EPO+, os mononucleares e os polimorfonucleares brônquicos e os eosinófilos da medula óssea foram avaliados por morfometria. As células epiteliais brônquicas nNOS+ e as fibras elásticas e colágenas foram avaliadas por densitometria óptica. Os anticorpos IgG1 foram detectados por anafilaxia cutânea passiva. A análise estatística foi feita com o programa SigmaStat e considerado significante um P<0,05. RESULTADOS: Nos grupos TO1 e TO2 houve aumento no tempo de inalação, diminuição na resposta máxima de elastância do sistema respiratório após desafio antigênico e com metacolina, diminuição do edema peribrônquico, dos eosinófilos, dos polimorfonucleares, das fibras elásticas e colágenas, da eosinofilopoiese e dos títulos de IgG1 (P < 0,05). Os mononucleares, a resposta máxima de resistência do sistema respiratório depois do desafio antigênico, e a metacolina diminuíram em TO2 (P < 0,05). O NOex e a percentagem de células epiteliais nNOS+ não foram alterados nos grupos tolerizados. CONCLUSÕES: A indução de tolerância oral concomitante ao início da sensibilização ou depois de estabelecida a resposta alérgica foi capaz de atenuar a inflamação eosinofílica, os títulos de IgG1 e o remodelamento brônquico presentes neste modelo de inflamação crônica pulmonar. A redução dos linfomononucleares e da hiper-responsividade brônquica foi mais efetiva quando a indução de tolerância foi feita em animais previamente sensibilizados. A dissociação entre o controle da inflamação eosinofílica e a avaliação do NOex e da expressão da nNOS no epitélio brônquico sugere um mecanismo novo ativado pela indução de tolerância oral / INTRODUCTION: The oral tolerance induction attenuates the inflammatory response and the production of secondary anaphylactic antibodies present in pulmonary allergy pictures in humans as well as in experimental models. In these situations, the bronchial remodeling modulation and the role of nitric oxide have not been previously studied. OBJECTIVES: 1. To develop two models of oral tolerance in guinea pigs with chronic pulmonary inflammation, characterizing: pulmonary mechanics, hyperreponsiveness to methacholine, exhaled nitric oxide (NOex), IgG1 antibodies, bronchial inflammation and eosinophylopoiesis. 2. To evaluate the bronchial remodeling and the expression of the neuronal nitric oxide synthase enzyme (nNOS) in bronchial epithelium of these animals. METHODS: The guinea pigs were submitted to ovalbumin or saline solution inhalation for 15 minutes or until they presented respiratory stress (this time period was called inhalation time). The protocol was repeated twice a week for 4 weeks. Oral tolerance induction was carried out by the administration of 2% oral ovalbumin, offered ad libitum, and the following groups were formed: 1. OT1 (received 2% oral ovalbumin from the first ovalbumin inhalation; 2. OT2 (received 2% oral ovalbumin from the fourth ovalbumin inhalation; 3. SAL (received water ad libitum and saline solution inhalations; and 4. OVA (received water ad libitum and ovalbumin solution inhalations). After being anesthetized, the animals were ventilated and evaluated regarding: 1. basal pulmonary mechanics and after ovalbumin (30mg/ml) or saline solution inhalation; 2. bronchial hyperresponsiveness to methacholine; and 3. NOex was collected. At the end of the experiment, the pulmonary fragments were removed and stained with hematoxylin-eosin, with the cyanide-resistant eosinophilic peroxidase histochemical technique (EPO+ cells), with the immunohistochemical technique for the detection of neuronal nitric oxide synthase (nNOS) and with Resorcin-fuchsin, Resorcin-fuchsin with oxidation and Picrosirius. The bone marrow was removed and stained with hematoxylin-eosin. The index of peribronchial edema, the EPO+ cells, the bronchial mononuclear and polymorphonuclear cells and the eosinophils from the bone marrow were evaluated by morphometry. The epithelial bronchial nNOS+ cells and the elastic and collagen fibers were evaluated by optical densitometry. IgG1 antibodies were detected by Passive Skin Anaphylaxis. Statistical analysis was performed with the SigmaStat software program and a P value < 0.05 was considered significant. RESULTS: The OT1 and OT2 groups showed increased inhalation time, decrease in the maximum elastance response of the respiratory system after the antigenic challenge and with methacholine, decrease of peribronchial edema, eosinophils, polymorphonuclear, elastic and collagen fibers, eosinophylopoiesis, and IgG1 titers (P < 0.05). The mononuclear cells, the maximum resistance response of the respiratory system after the antigenic challenge and methacholine decreased in OT2 (P < 0.05). NOex and the percentage of nNOS+ epithelial cells were not altered in the tolerized groups. CONCLUSIONS: The oral tolerance induction concomitant to the start of sensitization or after the allergic response has been established, was capable of attenuating the eosinophilic inflammation, IgG1 titers and the bronchial remodeling present in this model of chronic pulmonary inflammation. The decrease in lymphomononuclear cells and bronchial hyperresponsiveness was more effective when the tolerance induction was carried out in animals that had been previously sensitized. The dissociation between the eosinophilic inflammation and NOex evaluation and the expression of nNOS in the bronchial epithelium suggests a new mechanism activated by the oral tolerance induction

O treinamento físico (TF) melhora a resposta imune de indivíduos saudáveis e traz benefícios para o paciente asmático, mas seu papel na resposta alérgica é desconhecido. Objetivo: Avaliar o papel do TF de moderada intensidade na inflamação pulmonar alérgica crônica. Métodos: 54 cobaias, divididas em 4 grupos: grupo controle (C) (não sensibilizados e não treinados), grupo OVA (sensibilizados à ovalbumina (OVA) e não treinados), grupo treinamento físico (TF) (não sensibilizados e submetidos a um TF), e grupo OVA+TF (sensibilizados à OVA e submetidos a um TF). A sensibilização à OVA teve duração de 8 semanas e o programa de TF de 6 semanas iniciando 15 dias após o início da sensibilização. Cada grupo foi dividido em 2 subgrupos. No primeiro foi avaliada a inflamação pulmonar e os níveis de óxido nítrico exalado (NOex) e no segundo, a hiperresponsividade brônquica à metacolina (Mch). Resultados: A sensibilização à OVA induziu a um aumento da densidade de eosinófilos e linfócitos, expressão de IL(interleucina)-4 e IL-13 e na espessura do músculo liso na via aerea assim como espessura do epitélio comparado aos animais não-sensibilizados (p<0,05). Os animais do grupo OVA+TF apresentaram uma redução da densidade de eosinófilos, linfócitos, IL-4 e IL-13 comparado com o grupo OVA (p<0,05). Nem a sensibilização crônica a OVA ou TF influenciaram a expressão das citocinas Th1 (IL-2 e IFN-) ou a expressão das citocinas regulatórias (IL-10 e IL-1-ra) e nos níveis de NOex. Os grupos que realizaram TF tiveram aumento na espessura do epitélio quando comparados com grupos não-treinados embora não há diferença entre os grupos na avaliação da hiperresponsividade brônquica. Conclusão: Nossos resultados sugerem que o TF reduz a inflamação alérgica sem modificar a hiperresponsividade brônquica e o remodelamento das vias aéreas / Background: Aerobic training (TF) has a positive effects on health subjects and bring benefits on the immune system of asthmatic patients. However, its role on allergic immune response remains poorly understood. Objective: To evaluate the effects of TF in chronic allergic inflammation. Methods: Fiftyfour animals, divided in 4 groups: non-trained and non-sensitized (C), nonsensitized and aerobic exercise (TF), ovalbumin sensitized and non-trained (OVA), and sensitized and aerobic exercise (OVA+TF). OVA or saline sensitization was performed during 8 weeks. TF was performed in a treadmill during 6 weeks beginning in the 3rd week of sensitization. Each group were divided in two groups. In the first one, it was evaluated airway inflammation and levels of exhaleted oxide nitric (NOex), on the second, airway hyperresponsiveness to a methacholine (Mch). Results: OVA sensitization induced an increase in the eosinophils and lymphocytes counting, expression of IL-4 and IL-13 and the amount of airway smooth muscle and epithelium thickness compared to non-sensitized animals (p<0.05). Sensitized animals submitted to TF presented a reduction in the eosinophil and lymphocyte counting, expression of IL-4 and IL-13 compared with OVA group (p<0.05) but not OVA-induced changes in airway remodeling (p>0.05). Neither OVA nor TF induced any difference in the expression of Th1 (IL-2 and IFN-) and regulatory cytokine (IL-10 and IL1-ra) and the levels of NOex. Trained groups presented an increase in epithelium thickness as compared to the nontrained groups however we did not find difference between groups on hyperresponsiveness avaliation. Conclusion: Our results suggest that TF reduces allergic airway inflammation without changes in bronchial hyperresponsiveness and airway remodeling