Class of 2007 Abstract / Objectives: Study objective: This study assessed the impact of an Open Airways for Schools Program for children with asthma that is delivered in their school by trained asthma volunteers sponsored by the local American Lung Association. Methods: Design: Retrospective. Setting: Eight elementary schools located throughout Tucson, Arizona. Participants: A total of 77 pre and post questionnaires for children in grades 3 to 5 with asthma, 30 pre and post questionnaires for parents, and 6 demographic questionnaires for school nurses. Measurements and results: Data collection involved obtaining pre and post questionnaires from the sponsoring agency measuring outcomes in knowledge of when and how much medication to take, triggers of asthma, steps to take upon wheezing, and social aspects such as the ability to talk with an adult or teacher when having problems. The dependent variables for the pre and post parent questionnaires include unscheduled visits to providers, and whether the child knows how much medication to take. Paired t test was used to determine whether differences existed between pre and post child and parent questionnaires. Nurse questionnaires were analyzed and reported to see the change in nurse visits. The results are reported as the mean post/pre ± SD. The child questionnaire data for outcomes in knowledge include: when to take medicine (0.14+/-0.35 vs 0.34+/-0.61;p=0.015), how much medicine to take upon wheeze/cough (0.38+/- 0.71 vs 0.67+/-0.80;p=0.003), identifying home triggers (0.36+/-0.68 vs 0.58+/-0.80;p=0.051), identifying school triggers (0.53+/-0.75 vs 0.70+/-0.80;p=0.228), and steps to take upon wheezing (0.21+/-0.48 vs 0.46+/-0.74;p=0.018). Social aspects data include: ability to talk to adult about asthma (0.17+/-0.45 vs 0.29+/-0.58;p=0.159), talk to teacher about asthma (0.28+/-0.57 vs 0.30+/-0.67;p=0.858), and talk to teacher about taking things out of classroom that make them wheeze (0.43+/-0.17 vs 0.77+-0.85;p=0.19). The parent questionnaire data include: unscheduled provider visits (2.83+/- 4.01 vs 3.61+/-7.15;p=0.508) and quantity of medicine to take with incomplete data. The nurse questionnaire showed a mean number of visits at 92.5+/-64.09. Results: See above Conclusions: Conclusion: Providing an asthma education program to children in school can significantly increase outcomes in knowledge of when and how much medicine to take upon wheezing, and the steps to follow when wheezing occurs. Additionally, areas to focus on in the program include identification of triggers at home and school, as well as the ability to talk with an adult or teacher regarding asthma.

The Measurement and Characterisation of Aerosol in the Urban Atmosphere (PM 10) and an Evaluation of the Sources of these Particles by Number Andrew Lindsay Dye Abstract The link between human health and the mass of fine particulate matter below 10 tm (PM10) in air is well documented. Current research suggests that the number, size and shape of particles may be of most concern and that in the urban atmosphere combustion sources of PM10, especially diesel engine sources, dominate the fine (< 1µm) and ultra-fine (<0.1 µm) particles. Despite this, the number, size and shape of particles in urban air has not been reported to any great extent or detail, and the percentage contribution to the numbers of particles from different sources is largely unknown. The objectives of this research were to characterise fine particles with respect to their morphology and thus apportion the sources of particles by number. Urban aerosol above 1 µm was initially examined to study the fluctuations in PM10 number and make retrospective analysis of periods of elevated PM10 for source identification in Plymouth, UK. Aerosol was collected via a Burkard spore trap and examined using light microscopy with image analysis between 16 March 1995 and 31 August 1996, at a background site in Plymouth, UK. Two periods, 19 Januamy-4 February and 10-25 March 1996, identified as UK wide PM 10 episodes, were retrospectively studied and compared with PM10 mass measurements. The mean number count for the whole period was 10.5 x 104 ± 7.9 x 104 particles m-3 . The two PM10 episodes had elevated average number concentrations of 13.5 x 104 ± 7.6 x 104 particles m-3 for 19 January - 4 February 1996, and 13.0 x 104 ± 9.7 x 104 particles n13 for 10-25 March 1996. During the periods of elevated PM10 the tapered element oscillating microbalance (TEOM) mass of particles had a low correlation with the particles less than 5 µm and an increased correlation to the particles greater than 5 µm in size. Outside of these peak periods the PM10 TEOM mass was most closely correlated with the number of particles less than 5 µm in size. This work shows the difference in urban aerosol during periods of air quality guideline exceedence. These findings agree with literature that an aged continental aerosol source has a key role in the generation of UK wide PM10 mass exceedances. Further analysis of the fine urban aerosol (< 1 µm) was made using direct sampling of urban aerosol on to porous carbon films (PCF) developed in this research. The efficiency of collection was low (ca 5%) but the samples were representative and enabled transmission electron microscopy (TEM) for sub-micron particle analysis. Measurement was made of the fractal dimensions and diameter of particles. This was used to identif' any ageing and ultimately the sources of aerosol. PCF were used in the simultaneous collection of urban roadside and background aerosol, on seven dates between December 1996 and August 1997 in Plymouth, UK. The average perimeter fractal dimension (PFD) of aerosol was consistently significantly greater at the roadside than the background (+ 0.02), indicative of a smoother, aged aerosol at the background site. The sampling of a variety of combustion engines was made for source identification purposes. The particle morphology produced from the diesel engines showed great uniformity of particle morphology with varying speed and load; no consistent significant differences were found. The morphology results were comparable to other density fractal dimensions and penmneter fractal dimension values found in other studies for diesel. A natural log relationship between the median particle size and the median PFD was found for the diesel engine sources but not in petrol samples. This natural log trend was considered as a tentative 'fingerprint' of diesel engine combustion and was in harmony with literature values of PFD for diesel engine particles. Using the fractal measures, size and particle classification the bulk of aerosol was identified as from hydrocarbon combustion sources; ca. 88-92% of the roadside and ca. 77-86% of background. A component of carbon ceno-spheres were identified contributing ca. 6-12% of both the roadside and background aerosol. Non-combustion particles increased from ca. 1-4% of the roadside to ca. 7-9% of the background, as did the proportion of aged combustion particles, from 0-1% of roadside to 2-3% of the background aerosol. A strong correlation for the median size vs. PFD morphology curve between, the roadside and diesel sources (0.93 - 0.95) and the background and petrol sources was found (0.95). The roadside aerosol was significantly different to the petrol source in the 120-220nm size range (p=O.007) and there was a low correlation of the petrol and the roadside size vs. morphology curve (0.66). This suggests the domination of roadside aerosol by diesel engine particles. The background aerosol was similar to both diesel and petrol engine sources, especially from a dilution tunnel, thus indicative of a mixture of sources and an aged combustion aerosol. Roadside sources thus dominate the fine and ultra fine urban aerosol by number as compared to most other studies which have only apportioned the sources of particles in the air by mass.

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfdment of the requirements for the degree of Doctor of Philosophy / Asthma is a complex syndrome which has a significant inflammatory basis which results from the complex interactions between heterogenous genetic and environmental factors. Although the environmental allergens are fairly well known, little information concerning the genetic differences between atopic and non-atopic individuals is available. Alpha-1 antitrypsin is the archetypal member of the serine proteinase inhibitor or serpin superfamily and the most important proteinase inhibitor in the lung with specificity to neutrophil elastase. Genetic deficiency of the protein is classically associated with early onset emphysema, bronchiecstasis, panniculitis, rheumatoid arthritis and glomerulonephritis. The S(E264V), Z(E342K), Ml (213 Ala) and M2 (R101H) variants of alpha-1 antitrypsin have been implicated in the pathogenesis of asthma. A novel finding was the identification of 2 new variants, the M1E(JOhannesburg) and the M IN(johannesburg) associated with asthma in individuals from South Africa / IT2018

A alta prevalência de broncoespasmo induzido pelo exercício (BIE) tem sido observada em atletas que praticam modalidades de longa duração. Até o presente momento, nenhum estudo foi realizado no Brasil. Por essa razão, o objetivo deste estudo foi verificar a prevalência de BIE em corredores de longa distância. Para isto, 22 atletas do gênero masculino foram submetidos à prova de função pulmonar, teste de esforço ergoespirométrico e teste de broncoprovocação induzida por hiperpnéia (BIH). Os atletas responderam um questionário sobre sintomas de asma e forneceram informações relacionadas aos seus treinamentos. Após realizarem o teste de BIH, os atletas foram classificados de acordo com a variação do volume expiratório forçado no primeiro segundo (VEF1) em comparação ao valor basal. Aqueles que apresentaram queda do VEF1 igual ou superior a 10% foram denominados Grupo BIE+; os demais foram designados Grupo BIE-. Os resultados demonstraram a presença de BIE em 25% dos atletas. Não foram evidenciadas diferenças estatisticamente significantes em relação às características antropométricas, aos valores basais de função pulmonar, assim como aos parâmetros analisados durante o teste ergoespirométrico. Um aspecto interessante xi observado foi que, os atletas do Grupo BIE+ percorrem, nos seus treinamentos, uma distância inferior quando comparados aos atletas do Grupo BIE- (p&#8804;0,05). Estes resultados sugerem que a presença de BIE pode limitar o rendimento esportivo / The high prevalence of exercise-induced bronchospasm (EIB) has been observed in endurance athletes. Until today, no such study had been conducted in Brazil. The aim of this study was to look for prevalence of EIB among long-distance runners. Twenty-two male athletes were subjected to pulmonary function tests, maximal exercise tests and hyperpnea-induced broncoprovocation (HIB). The athletes also answered questions about asthma symptoms and provided information about their training programs. After the HIB test, they were ranked by the variation in the FEV1 (Forced Expiratory Volume in the first second). Those with a decrease of 10% or more were labeled EIB+ group; all the others were labeled EIB - group. Results show the presence of exercise-induced bronchospasm in 25% of the athletes. Among them, there were no significant statistical differences related to anthropometric characteristics, basal pulmonary function values or other parameters analyzed during the ergospirometric test. One interesting aspect observed was that, in their training sessions, the EIB+ Group athletes ran a shorter distance when compared to those in the EIB- Group (p&#8804;0.05). These results suggest that EIB presence may be a limitting factor in sports performance

A asma é uma doença crônica das vias aéreas responsável por significativa morbidade e mortalidade mundial. Medicamentos anti-inflamatórios, tais como os corticosteróides, são algumas das opções de tratamento mais importantes, no entanto, elas podem causar efeitos secundários indesejáveis. Historicamente, as plantas foram uma fonte principal de moléculas com atividade biológica. O objetivo deste estudo foi avaliar o efeito do MC, um extrato vegetal brasileira com propriedades anti-inflamatórias, no tratamento da asma em um modelo animal. Métodos: Camundongos machos Balb/C, com idade de 5 a 6 semanas, foram sensibilizados com ovalbumina (OVA) por via intraperitoneal (IP) por duas vezes, com uma semana de intervalo, e desafiados diariamente com OVA intranasal durante três dias. Os animais foram tratados diariamente com a MCA (aquoso) MCHA (hidroalcóolico) na dose 500 mg/kg ip por três dias, durante os desafios. Os camundongos do grupo controle receberam solução salina nos mesmos dias. Cinco a oito animais por grupo foram utilizados. Vinte e quatro horas após o último desafio, os ratinhos foram ventilados com um respirador animal pequeno (FlexiVent®), e foram realizadas medições in vivo da hiperreactividade brônquica com concentrações crescentes de metacolina em aerossol (6,25, 12,5, 25 e 50 mg / ml). Os parâmetros avaliados e comparados foram: a resistência total (RRS), elastância total (ERS), resistência do tecido (G) e elastância tecidual (H). Após ventilação, foi colhido lavado broncoalveolar (LBA) para análise da contagem de células totais e diferenciais. Interleucinas inflamatórias (IL-4, IL-5, IL-10, IL- 13, IFN-?) foram analisadas no homogenato pulmonar além da dosagem sérica de IgE antiOVA. Os pulmões dos animais foram coletados para análise histológica (H&E). Resultados: O tratamento com extrato MCHA reduziu significativamente a hiperresponsividade brônquica através da mensuração das medidas RRS (p<0,001), ERS (p<0,05), G (p<0,05) and H (p<0,001), quando comparado com o grupo de animas asmáticos não tratados. Extratos de MCA e MCHA reduziram tambem significativamente células totais (p<0,05) e contagem de eosinófilos (p<0,05). MCHA reduziu a concentração de IFN-? (p<0,01) quando comparado aos animais asmáticos não tratados. MCA (p<0,001) mostrou uma significativa redução do número de células inflamatórias por área quando comparado ao grupo asmático não tratado. Conclusão: Os dois extratos (aquoso e hidroetanólico) das folhas da espécie Momordica charantia L., na dose de 500 mg/kg, foi eficaz no tratamento da asma em modelo animal induzido por ovalbumina tanto em medidas da mecânica pulmonar quando em marcadores inflamatórios e estudo histológico, sendo o extrato hidroetanólico potencialmente mais eficaz na dose estudada. / Asthma is a chronic disease of the airways responsible for significant morbidity and mortality worldwide. Anti-inflammatory medications, such as corticosteroids, are some of the most important treatment options, however they can cause undesirable side effects. Historically, plants have been a major source of molecules with biological activity. The objective of this study was to evaluate the effect of MC, a Brazilian herbal extract with anti-inflammatory properties, on asthma treatment in an animal model. Methods: Male Balb/c mice, 5 to 6 weeks, were sensitized twice with ovalbumin (OVA) intraperitoneally (ip), one week apart, and challenged daily with OVA intranasally for three days. Mice were treated daily with MCA (aqueous) MCHA (hydroethanolic) extract (500 mg/kg) ip for three days, during challenges. Control mice received saline on the same days. Five to eight mice were utilized per group. Twenty-four hours after the last challenge, mice were ventilated with a small-animal ventilator (FlexiVent®), and in vivo measurements of bronchial hyperresponsiveness were performed with increasing concentrations of methacholine aerosol (6.25, 12.5, 25 and 50 mg/ml). The following parameters were evaluated and compared: total resistance (RRS), total elastance (ERS),, tissue resistance (G) and tissue elastance (H). After ventilation, was collected bronchoalveolar lavage (BAL) for analysis of total and differential count inflammatory cells. Interleukins (IL-4, IL-5, IL-10, IL-13, IFN-?) were analyzed in lung homogenate. Morover serum anti-OVA IgE were dosage. The lungs of the animals were collected for histological analysis (H & E) Results: Treatment with MCHA extract significantly decreased airway hyperresponsiveness, measured by RRS (p<0,001), ERS (p<0,05), G (p<0,05) and H (p<0,001), when compared to OVA-challenged mice. MCA e MCHA extract also significantly reduced BAL total cell (p<0,05) and eosinophil counts (p<0,05). MCHA reduced IFN-? concentration (p<0,01) as compared to the untreated group asthmatic. MCA (p<0,001) showed a significant reduction in the number of inflammatory cells per unit area in the air compared to the asthmatic untreated group. Conclusion: The administration of MCA and MCHA from the leaves of Momordica charantia L. species, at a dose of 500 mg / kg was effective in the treatment of asthma in animal models induced by ovalbumin in both pulmonary mechanics measurements as inflammatory markers, and histological study, and potentially more effective MCHA extract the studied dose.

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

A asma é uma doença crônica das vias aéreas responsável por significativa morbidade e mortalidade mundial. Medicamentos anti-inflamatórios, tais como os corticosteróides, são algumas das opções de tratamento mais importantes, no entanto, elas podem causar efeitos secundários indesejáveis. Historicamente, as plantas foram uma fonte principal de moléculas com atividade biológica. O objetivo deste estudo foi avaliar o efeito do MC, um extrato vegetal brasileira com propriedades anti-inflamatórias, no tratamento da asma em um modelo animal. Métodos: Camundongos machos Balb/C, com idade de 5 a 6 semanas, foram sensibilizados com ovalbumina (OVA) por via intraperitoneal (IP) por duas vezes, com uma semana de intervalo, e desafiados diariamente com OVA intranasal durante três dias. Os animais foram tratados diariamente com a MCA (aquoso) MCHA (hidroalcóolico) na dose 500 mg/kg ip por três dias, durante os desafios. Os camundongos do grupo controle receberam solução salina nos mesmos dias. Cinco a oito animais por grupo foram utilizados. Vinte e quatro horas após o último desafio, os ratinhos foram ventilados com um respirador animal pequeno (FlexiVent®), e foram realizadas medições in vivo da hiperreactividade brônquica com concentrações crescentes de metacolina em aerossol (6,25, 12,5, 25 e 50 mg / ml). Os parâmetros avaliados e comparados foram: a resistência total (RRS), elastância total (ERS), resistência do tecido (G) e elastância tecidual (H). Após ventilação, foi colhido lavado broncoalveolar (LBA) para análise da contagem de células totais e diferenciais. Interleucinas inflamatórias (IL-4, IL-5, IL-10, IL- 13, IFN-?) foram analisadas no homogenato pulmonar além da dosagem sérica de IgE antiOVA. Os pulmões dos animais foram coletados para análise histológica (H&E). Resultados: O tratamento com extrato MCHA reduziu significativamente a hiperresponsividade brônquica através da mensuração das medidas RRS (p<0,001), ERS (p<0,05), G (p<0,05) and H (p<0,001), quando comparado com o grupo de animas asmáticos não tratados. Extratos de MCA e MCHA reduziram tambem significativamente células totais (p<0,05) e contagem de eosinófilos (p<0,05). MCHA reduziu a concentração de IFN-? (p<0,01) quando comparado aos animais asmáticos não tratados. MCA (p<0,001) mostrou uma significativa redução do número de células inflamatórias por área quando comparado ao grupo asmático não tratado. Conclusão: Os dois extratos (aquoso e hidroetanólico) das folhas da espécie Momordica charantia L., na dose de 500 mg/kg, foi eficaz no tratamento da asma em modelo animal induzido por ovalbumina tanto em medidas da mecânica pulmonar quando em marcadores inflamatórios e estudo histológico, sendo o extrato hidroetanólico potencialmente mais eficaz na dose estudada. / Asthma is a chronic disease of the airways responsible for significant morbidity and mortality worldwide. Anti-inflammatory medications, such as corticosteroids, are some of the most important treatment options, however they can cause undesirable side effects. Historically, plants have been a major source of molecules with biological activity. The objective of this study was to evaluate the effect of MC, a Brazilian herbal extract with anti-inflammatory properties, on asthma treatment in an animal model. Methods: Male Balb/c mice, 5 to 6 weeks, were sensitized twice with ovalbumin (OVA) intraperitoneally (ip), one week apart, and challenged daily with OVA intranasally for three days. Mice were treated daily with MCA (aqueous) MCHA (hydroethanolic) extract (500 mg/kg) ip for three days, during challenges. Control mice received saline on the same days. Five to eight mice were utilized per group. Twenty-four hours after the last challenge, mice were ventilated with a small-animal ventilator (FlexiVent®), and in vivo measurements of bronchial hyperresponsiveness were performed with increasing concentrations of methacholine aerosol (6.25, 12.5, 25 and 50 mg/ml). The following parameters were evaluated and compared: total resistance (RRS), total elastance (ERS),, tissue resistance (G) and tissue elastance (H). After ventilation, was collected bronchoalveolar lavage (BAL) for analysis of total and differential count inflammatory cells. Interleukins (IL-4, IL-5, IL-10, IL-13, IFN-?) were analyzed in lung homogenate. Morover serum anti-OVA IgE were dosage. The lungs of the animals were collected for histological analysis (H & E) Results: Treatment with MCHA extract significantly decreased airway hyperresponsiveness, measured by RRS (p<0,001), ERS (p<0,05), G (p<0,05) and H (p<0,001), when compared to OVA-challenged mice. MCA e MCHA extract also significantly reduced BAL total cell (p<0,05) and eosinophil counts (p<0,05). MCHA reduced IFN-? concentration (p<0,01) as compared to the untreated group asthmatic. MCA (p<0,001) showed a significant reduction in the number of inflammatory cells per unit area in the air compared to the asthmatic untreated group. Conclusion: The administration of MCA and MCHA from the leaves of Momordica charantia L. species, at a dose of 500 mg / kg was effective in the treatment of asthma in animal models induced by ovalbumin in both pulmonary mechanics measurements as inflammatory markers, and histological study, and potentially more effective MCHA extract the studied dose.

Introduction: Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases with a wide range of clinical manifestations not adequately described within the current diagnostic criteria. Exhaled breath analysis may provide a novel method for diagnosing and phenotyping these diseases. Our aim was to ascertain patterns of breath volatile organic compounds (VOCs) and nuclear magnetic resonance (NMR) spectral regions identifying diseased patients and subgroups determined by treatment requirement, asthma control, exacerbation frequency and inflammatory phenotypes. The validity and reproducibility of the methodology and the outcome were also investigated. Methods: Three separate clinical studies (two involving exhaled gas and one involving breath condensate) were conducted, as well as validation studies. In exhaled gas analysis, the adaptive breath sampler developed by Basanta et al was modified; efficiency of air supply and air filter and the reproducibility and stability of VOCs in storage were determined by comparing breath chromatograms. Concentrated late-expiratory breath samples were collected from asthmatics, COPD subjects and healthy controls. In the asthmatic group, sputum induction with hypertonic saline, fraction exhaled nitric oxide (FeNO) measurement and asthma control questionnaire (ACQ) were performed. In COPD subjects, sputum induction and exacerbation frequency were collected. In the exhaled breath condensate (EBC) study, similar data were collected in asthmatics and healthy controls. Breath samples were analysed using gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) while EBC was analysed using NMR spectroscopy. Discriminatory compounds or NMR spectral regions were identified by univariate logistic regression, followed by multivariate analysis: 1. principal component analysis (PCA); 2. multivariate logistic regression; 3. receiver operating characteristic (ROC) analysis. The reproducibility was assessed using intraclass correlation coefficient (ICC).Results: In the COPD exhaled breath study, 11 VOCs significantly discriminated the COPD and healthy controls with AUROC of 0.74. The AUROC for phenotype discrimination was 0.83, 0.90, 0.94, 0.96 and 0.97 for inhaled corticosteroid (ICS) use, sputum eosinophilia (1% and 2% cut-off), neutrophilia (median cut-off) and exacerbation frequency respectively. In the asthma study, 15 VOCs significantly discriminated the two groups with AUROC of 0.93. The AUROC for phenotype discrimination was 0.96, 0.98, 0.90 and 0.97 for ICS use, eosinophils (2% cut-off), neutrophils (40% cut-off) and asthma control respectively. In EBC analysis, AUROC for asthmatics vs controls comparison was 0.96. Phenotyping results in this study were less good: only ICS use and sputum neutrophilia (65% cut-off) were clearly classified with AUROC of 0.89 and 0.88 while eosinophilia (3% cut-off) and asthma control had poor discrimination; 0.69 and 0.62 respectively. Breath VOC reproducibility varied greatly depending on the class of compounds studied, while for the EBC analysis, reproducibility was moderate to very good (ICCs in the range of 0.42-0.99).Conclusions: We have demonstrated the ability of breath analysis in discriminating asthmatics and COPD subjects from controls. Exhaled breath analysis was also able to phenotype these patients based on steroid treatment, sputum inflammatory cells, exacerbation frequency and asthma control. This metabolomic approach could provide a novel, non-invasive method of diagnosing and phenotyping obstructive lung diseases in the future.

Asthma is a common chronic inflammatory condition which affects over 300 million people worldwide. Thickening of the subepithelial layer is a key feature of asthmatic airways and the extent of thickening has been correlated with severity of asthma and increased exacerbations. Recent epidemiological studies have shown a link between fungal sensitisation primarily with Aspergillus fumigatus (A. fumigatus) and exacerbations of asthma leading to increased morbidity and mortality. The airway epithelium acts as an initial defence barrier to inhaled allergens such as A. fumigatus and emerging evidence suggests that as well as orchestrating an allergic immune response, it initiates aspects of airway wall remodelling including subepithelial thickening. However, induction of a profibrogenic response by the airway epithelium following exposure to inhaled fungi associated with severe asthma has not been well documented. The epithelial expression and production of the profibrotic growth factors, TGF-β1, TGF-β2, IL-6, endothelin-1 and periostin, selected as implicated in the aetiology of asthma and their profibrotic activity, were investigated in response to both A. fumigatus spores and culture filtrate in vitro. Furthermore, in vivo chronic inhalation models using either live spores or culture filtrate from two different strains of A. fumigatus (AF293 and CEA10) were used to determine the ability of the fungi to induce murine airway wall remodelling. In vitro, spores from both strains were able to induce the expression and production of IL-6 and endothelin-1 from human bronchial epithelial cells but none of the other profibrotic growth factors. In vivo, despite spores from both strains inducing expression and production of IL-6 and endothelin-1, only CEA10 spores caused significant subepithelial collagen deposition however, both strains induced α-SMA, a myofibroblast and smooth muscle marker around the airways. As a secreted factor was suspected of driving airway wall remodelling, subsequent studies used culture filtrate produced by the two strains, AF293, a low and CEA10, a high protease producer in basal medium. Only AF293 culture filtrate induced IL-6 and endothelin-1 from human bronchial epithelial cells in vitro. However, in vivo, culture filtrate from both strains was able to induce IL-6 and endothelin-1 expression, with AF293 causing a more profound subepithelial collagen deposition and significantly increased α-SMA abundance. It was hypothesised that epithelial-derived endothelin-1 drives airway wall remodelling and hence Endothelin receptor A was inhibited in the in vivo culture filtrate inhalation model. A significant reduction in subepithelial collagen deposition and α-SMA localisation around the airways was demonstrated in mice receiving an Endothelin receptor A antagonist compared with culture filtrate alone. This thesis indicates that A. fumigatus exposure can drive features of airway wall remodelling such as subepithelial fibrosis possibly through the epithelial production of profibrotic growth factor, endothelin-1.

Asthma has long been considered as one of the most common health problems in the world. In Hong Kong, the prevalence of childhood asthma has increased from 4.8% in 1989, to 10.2% in 2002. In spite of the popularity of using Chinese herbs to treat asthma in Hong Kong, evidence on the effectiveness of herbal treatments is lacking. The Chinese herbal formula CUF2 is an innovative formula developed in the Institute of Chinese Medicine, The Chinese University of Hong Kong and it is composed of 5 commonly used Chinese herbs: Radix astragali, Cordyceps sinesis, Radix Scutellaria, Bulbus fritillariae cirrhosae and Radix stemonae. These herbs are chosen because of their well-known effects on either reducing coughing and sputum production, or anti-inflammatory and immunomodulatory activities. Based on the theoretical benefits of CUF2, we conducted a series of animal, in vitro and clinical studies to explore the efficacy, safety and mechanism of action of CUF2. / Following the establishment of the animal model, we have investigated the effect of CUF2 using this model of asthma. We found that 28 days pretreatment with CUF2 could reduce total cell number and eosinophilia in bronchoalveolar lavage fluid (BALF), prevent the eosinophil infiltration of airways, decrease pulmonary inflammatory cells, and reduce mucus and goblet cell hyperplasia. Especially in the reduction of goblet cell hyperplasia, we demonstrated that there was no significant difference between the effects of high dose CUF2 and dexamethasone (DEX). The eosinophilic immune-inflammatory responses in the airways in OA-sensitized/challenged rats were completely blocked by DEX returning to almost the same as those in normal rats, but the loss of thymus index and body weight were also observed. In contrast to the overall immunosuppressive effects of DEX, decreased production of inflammatory cytokines and chemokines [interleukin (IL)-4, tumor necrosis factor (TNF)-alpha, macrophage inflammatory protein (MIP)-2 and monocyte chemotactic protein-1 (MCP-1)], increased production of IL-10 and interferon-gamma (IFN-gamma) in BALF and no suppression of body weight and thymus index were demonstrated in the CUF2-treated groups. There was a dose-response relationship with more prominent effects seen with higher doses of CUF2. These findings indicate that the CUF2 has anti-airway inflammatory activity and exhibits immunomodulatory effect on Th1/Th2 responses in ovalbumin sensitized rats after allergen challenge, and this may imply its potential application to patients with allergic asthma. / In order to evaluate the clinical efficacy and safety, we conducted a multicenter, randomized, double blind, parallel and placebo controlled clinical trial. The same Chinese herbal formula was used in this clinical trial in 85 children aged 7-15 years with mild to moderate perennial asthma as an adjuvant therapy for 6 months. The primary outcome measure was the steroid dosage reduction. Other outcome measures included changes in disease severity score (DSS), lung function, serum concentrations of total IgE and the levels of some key allergy and inflammatory markers in peripheral blood, fractional exhaled nitric oxide (FENO), frequency of asthma attacks and quality of life (QOL). To assess safety, we did urinalysis, complete blood count, liver function and renal function at baseline and the end of the study. Drug compliance and adverse effects were also checked at each monthly visit. All patients were maintained on inhaled corticosteroid at their usual dose and dosing interval, and continued to receive short-acting, inhaled beta2-agonists as needed. There were no serious adverse events reported in the 6-month study period by any of the subjects. Hematological (except eosinophils count) and biochemical profiles (including renal function and liver function) remained within normal limits in the CUF2 group and placebo group at the end of the study. CUF2 was well tolerated in asthmatic children. Both CUF2 group and placebo group showed an improvement in most of clinical parameters. The dosage of inhaled corticosteroid was successfully reduced in both groups. Both groups had similar decrease in DSS, improved QOL and improved lung function parameter PEFR (L/min). Although these parameters showed no statistically significant difference between two groups, the percentage of eosinophils and lymphocytes were significantly decreased in CUF2 group as compared with the placebo group. The CUF2 group also showed improved diary symptom score, reduced expression of TNF-alpha and slight increase in anti-inflammation cytokine IL-18 in the blood. A trend of greater improvement in frequency of upper respiratory infection (URI) in CUF2 group was noted, but no statistical significance was attained. The changes in lung function parameter FEV1%, FENO, frequency of asthma attacks and serum concentrations of total IgE, IgE HDM, IgE cat, cockroach, TARC, LTB4 and LTC4D4E4 showed no statistically significant difference CUF2 group and placebo group. Overall, our data demonstrated that CUF2 treatment had some immunomodulatory effect in childhood asthma. Our findings should support further investigations of Chinese herbal medicine in the area of asthma without steroid therapy. / In the animal study, firstly we attempted to establish a novel murine model of asthma. We adopted a modified sensitization procedure using 10-point subcutaneous and intraperitoneal injections of Ovalbumin (OA) with freshly prepared Al(OH)3 and successfully induced severe airway allergic reactions in young Sprague Dawley (SD) rats. In this SD rat model, allergen exposure triggered accumulation of inflammation cells and eosinophils in the airway submucosa and goblet cells hyperplasia in mucosa, lung function test revealed obstructive lung function changes that included increase of lung resistance (RL) and decrease of dynamic lung compliance (Cdyn). Cytokine and chemokine assays showed that there was a change of the TH1/Th2 balance as illustrated by the high Th2 (interleukin-4)/Th1 (interferon-gamma) ratio. These results demonstrated the feasibility and validity of the SD rat model for studying allergic asthma. This SD model is much cheaper and readily available than the Brown Norway rat model and may facilitate further drug trial in asthma. / In the in vitro study, we investigated the effect of CUF2 on the release of cytokines and/or gene expression using human mast cell line HMC-1, human bronchial epithelial cell line BEAS-2B, peripheral blood mononuclear cells (PBMCs) from healthy subjects and airway cells present in induced sputum from asthmatic patients. We have shown (1) the CUF2 had no cytotoxic effects in final working concentration; (2) CUF2 had inhibitory effects on IL-6, TNF-alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion from HMC-1 in a dose-dependent manner. However, no reduction of IL-8 production in HMC-1 was demonstrated. (3) In addition, study of the effect of CUF2 on the expression of cytokine gene from HMC-1 showed that IL-4, IL-6 and GM-CSF mRNA expressions were down regulated at 24 hours, 24 hours, 16 hours and 24 hours of time points, respectively. No effects on IL-8 and TNF-alpha mRNA expression was observed. (4) Furthermore, CUF2 also significantly inhibited in vitro IL-6 and GM-CSF secretion in TNF-alpha stimulated BEAS-2B cell and reduced GM-CSF production in airway cells present in induced sputum from asthmatic children. (5) We observed that CUF2 enhanced TNF-alpha and IL-6 production but did not alter the levels of GM-CSF and IL-8 in mitogen-stimulated PBMCs from health subject. These findings suggest that pharmacological activities of the CUF2 may be mediated by regulating the production of cytokines in human mast cell, bronchial epithelial cell, airway cell and PBMCs. / In this study, a novel animal asthma model has been established. This model has extensively characterized and exhibited several inflammatory, immunological features that resemble those of human asthma and may facilitate further drug trial in asthma. CUF2 showed its efficacy treating the animal model of allergic asthma. In vitro study also provided evidence of its beneficial dichotomous effects on cytokine and chemokine production in HMC-1, PBMCs and airway cells. A multi-center, randomized, double blind, placebo controlled clinical trial showed that CUF2 had a certain degree of clinical efficacy. Furthermore, the use of CUF2, with the study dose and treatment period, was safe. The efficacy of individual ingredient and the mechanism of CUF2 have not been clarified and further investigations are warranted. In conclusion, our results provided evidence of the potential beneficial effect of CUF2 on immune system functions and supported the potential use of TCM as therapeutic drugs for allergic inflammatory diseases. / by Wong Yeuk Oi. / "September 2005." / Advisers: Yn Tz Sung; Kowk Pui Fung. / Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6296. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 330-349). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.