Uncontrolled oxygen is often administered to breathless patients regardless of whether hypoxaemia is present. In acute exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) this may result in carbon dioxide (CO2) retention and worsening respiratory failure in some patients. In AECOPD the main mechanism is the release of hypoxic pulmonary vasoconstriction and an increase in the physiological dead space to tidal volume ratio (VD/VT). Acute asthma and pneumonia have features in common with AECOPD, namely significant ventilation – perfusion mismatch; and there is the potential for CO2 retention to occur if uncontrolled high concentration oxygen is given. There have been no randomised controlled trials of oxygen therapy in pneumonia and only one in asthma. The potential mechanisms of any change in arterial CO2 that may occur with oxygen therapy in respiratory disorders other than COPD remain uncertain. This thesis presents work from three clinical studies. In two randomised controlled trials, high concentration oxygen was compared to titrated oxygen therapy in patients with either acute severe asthma and suspected community acquired pneumonia. Oxygen was administered for one hour in conjunction with standard medical treatment. Transcutaneous CO2 (PtCO2) was continuously monitored and the number of patients with pre-specified increases in PtCO2 were calculated. The proportion of patients with a rise in PtCO2 4 mmHg was significantly higher in the high concentration oxygen groups of both studies. In the pneumonia study 36/72 (50.0%) vs 11/75 (14.7%) met this endpoint, with a relative risk of 3.4 (95% CI 1.9 to 6.2; P <0.001), and in the asthma study 22/50 (44%) vs 10/53 (18.9%) met this endpoint, with a relative risk of 2.3 (95% CI 1.2 to 4.3; P=0.009). Similarly, a rise in PtCO2 8 mmHg was more common with high concentration oxygen. In the pneumonia study 11/72 (15.3%) vs 2/75 (2.7%) of patients met this endpoint, with a relative risk of 5.7 (95% CI 1.3 to 25.0; P=0.007), and 10/50 (20%) vs 3/53 (5.7%) of asthma patients met this endpoint, with a relative risk of 3.6 (95% CI 1.1 to 12.3; P=0.03). A third study measured the physiological response to 20 minutes of 100% oxygen in chronic severe asthma, with comparison to a group of negative controls (normal subjects) and positive controls (COPD patients). There was a significant rise in PtCO2 of similar magnitude in the asthma and COPD groups compared with the normal controls. The mechanism of the PtCO2 rise was similar in asthma and COPD, with an increase in VD/VT but no change in minute ventilation. These studies demonstrate than uncontrolled high concentration oxygen has the potential to cause CO2 retention in respiratory diseases other than COPD, and that in asthma the mechanism of hypercapnia is similar to that in AECOPD. In acute asthma and community-acquired pneumonia oxygen should be administered only to those patients with evidence of arterial hypoxaemia in a dose that relieves hypoxaemia without causing hyperoxia, thereby achieving the benefits of oxygen therapy while reducing the potential for harm.

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TLRs play a key role in initiating innate immunity and in regulating the nature of the adaptive immune response. We hypothesized that functional responsiveness to TLR stimulation differs in clinically; environmentally; ethnically distinct pediatric populations. PBMC obtained from 272 children were stimulated with a panel of TLR ligands. Levels of pro- and anti-inflammatory, Th1-, Th2-associated cytokines were quantified by ELISA. We demonstrate that use of threshold concentrations of TLR4 and TLR2 ligands reveal striking differences in cytokine responses between asthmatic and non-atopic children. Specifically, non-atopic controls produce higher levels of pro-inflammatory cytokines, whereas asthmatics exhibit increased anti-inflammatory IL-10 responses. Asthmatic children exposed to environmental tobacco smoke (ETS) demonstrated elevated levels of chemokines relative to non-ETS exposed asthmatics and controls. First Nation children favor anti-inflammatory IL-10 responses, whereas Caucasian population respond to TLR activation by production of more robust pro-inflammatory and Th1 biased cytokine and chemokine responses.

The study was conducted with a total of 13980 children of the 1995 birth cohort, who were living in Manitoba by the end of December, 2006. Higher frequency of RSV-associated LRTI before 2 years was associated with higher risks of asthma diagnosis at 7 and 11 years and also with risks of transient wheeze and early persistent asthma. Higher risk of asthma diagnosis was associated with more severe episode(s) of RSV-associated LRTI within the first 2 years of life. First clinically significant RSV-LRTI between 6 and 12 months was associated with the highest risks of asthma diagnosis at 7 and at 11 years. But first RSV-associated LRTI within the first 6 months of life was associated with the highest risk of asthma/transient wheezing before the age of 3 years and early persistent asthma and transient wheeze. These associations were diminishing with increasing age of the children of the study cohort.

Objective: To estimate national prevalence and direct incremental expenditures in Chronic Obstructive Pulmonary Disease (COPD) and asthma using 2007 Medical Expenditure Panel Survey (MEPS) data. &lt;br&gt;Methods: COPD and asthma were identified using ICD-9 codes and were the main independent variables. Covariates included age, gender, race, income, region, insurance and marital status. Dependent variables were total health care, office-based, outpatient, inpatient, emergency room and prescription expenditures. Descriptive statistics and regression analysis were used to fulfill the study objectives. &lt;br&gt;Results: Prevalence of COPD and asthma was 1.3 million and 28.3 million, respectively. Total direct incremental health care expenditures per person for COPD and asthma were $1,739.27 and $2,133.83, respectively. High cost categories among COPD and asthma included office-based, inpatient and prescription expenditures. Age, gender, region, insurance and marital status were significant predictors for health care expenditures. &lt;br&gt;Conclusion: Results highlight socio-demographic disparities and high health care expenditures due to COPD and asthma in the United States. &lt;br&gt;Keywords: Asthma, COPD, Medical Expenditures Panel Survey (MEPS), incremental health care expenditures, retrospective analysis / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences / Pharmacy Administration / MS / Thesis

Although exposed to similar environmental stimuli, not all humans develop asthma. Similarly, mouse strains vary in the degree of pathophysiology seen following induction of experimental asthma. A model involving immunization and aerosol challenge with ovalbumin (OVA) was used to investigate factors that may confer strain-dependent resistance or susceptibility to pathology. BALB/c and C57BL/6 mice developed many features of human asthma including inflammation, mucus production and airway obstruction. In contrast, CBA/Ca mice were relatively resistant to development of disease. This was despite the presence of a robust systemic allergic response, as indicated by high levels of OVA-specific and total immunoglobulin and increases in circulating eosinophils comparable to those in BALB/c and C57BL/6 mice. In interleukin (IL)-5 transgenic (Tg) mice the strain specific susceptibility to lung mucus production and airway obstruction was maintained and pathology was greatly accentuated in C57BL/6 and BALB/c but not in CBA/Ca mice. Eosinophils recovered by bronchoalveolar lavage (BAL) from wt and IL-5 Tg CBA/Ca mice lost viability faster than BAL eosinophils from the other two strains and this phenomenon was lung-specific. This may result in less eosinophil accumulation in the lungs of CBA/Ca mice and resistance to asthma-like pathology. Fl hybrids of CBA/Ca mice crossed with either BALB/c or C57BL/6 mice had BAL leukocyte, eosinophil lifespan and cell-free protein profiles similar to those of the respective disease-susceptible parental strains. It is likely that eosinophil apoptosis was not mediated through the extrinsic or receptor mediated pathway. Bcl-2 and Bcl-xL, which both inhibit the intrinsic pathway of apoptosis were highest in BAL eosinophils from the BALB/c strain and this correlated with relatively high IL-5 levels in the lungs. Survivin inhibits apoptosis and expression was significantly higher in BALB/c and C57BL/6 BAL eosinophils than in cells from CBA/Ca mice. This suggests a possible mechanism whereby eosinophils from the asthma-susceptible C57BL/6 and BALB/c mice are more resistant to apoptosis and may account, in part, for the more extensive pathology in these strains. Using global gene expression analysis we identified groups of genes that were differentially regulated in the lungs of mice that are susceptible or resistant to development of asthma-like pathology. 242, 145 and 42 genes were differentially regulated in the lungs of the C57BL/6, BALB/C and CBA/Ca strains respectively. In C57BL/6 mice, transcripts were significantly enriched for adhesion molecules and we postulate that heightened expression of L-selectin, CD 18, PGSL-1 and LPAM-l on lung eosinophils is responsible for robust recruitment and therefore accumulation of these cells in C57BL/6 mice. 64 genes were differentially regulated only in the asthma-susceptible strains, several of which have not previously been associated witb asthma. The late expression of Chi313, Retnla and Mmp12 correlated with increased expression of IL-10 in the lungs and we hypothesise that this cytokine may be produced by alternatively activated macrophages as part of the resolution of disease. This study identifies several novel genes and mechanisms associated with the modulation of airway inflammation and pathology. The identification of factors that control allergic inflammation may provide novel therapeutic targets for disease intervention. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1366239 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2009

Although exposed to similar environmental stimuli, not all humans develop asthma. Similarly, mouse strains vary in the degree of pathophysiology seen following induction of experimental asthma. A model involving immunization and aerosol challenge with ovalbumin (OVA) was used to investigate factors that may confer strain-dependent resistance or susceptibility to pathology. BALB/c and C57BL/6 mice developed many features of human asthma including inflammation, mucus production and airway obstruction. In contrast, CBA/Ca mice were relatively resistant to development of disease. This was despite the presence of a robust systemic allergic response, as indicated by high levels of OVA-specific and total immunoglobulin and increases in circulating eosinophils comparable to those in BALB/c and C57BL/6 mice. In interleukin (IL)-5 transgenic (Tg) mice the strain specific susceptibility to lung mucus production and airway obstruction was maintained and pathology was greatly accentuated in C57BL/6 and BALB/c but not in CBA/Ca mice. Eosinophils recovered by bronchoalveolar lavage (BAL) from wt and IL-5 Tg CBA/Ca mice lost viability faster than BAL eosinophils from the other two strains and this phenomenon was lung-specific. This may result in less eosinophil accumulation in the lungs of CBA/Ca mice and resistance to asthma-like pathology. Fl hybrids of CBA/Ca mice crossed with either BALB/c or C57BL/6 mice had BAL leukocyte, eosinophil lifespan and cell-free protein profiles similar to those of the respective disease-susceptible parental strains. It is likely that eosinophil apoptosis was not mediated through the extrinsic or receptor mediated pathway. Bcl-2 and Bcl-xL, which both inhibit the intrinsic pathway of apoptosis were highest in BAL eosinophils from the BALB/c strain and this correlated with relatively high IL-5 levels in the lungs. Survivin inhibits apoptosis and expression was significantly higher in BALB/c and C57BL/6 BAL eosinophils than in cells from CBA/Ca mice. This suggests a possible mechanism whereby eosinophils from the asthma-susceptible C57BL/6 and BALB/c mice are more resistant to apoptosis and may account, in part, for the more extensive pathology in these strains. Using global gene expression analysis we identified groups of genes that were differentially regulated in the lungs of mice that are susceptible or resistant to development of asthma-like pathology. 242, 145 and 42 genes were differentially regulated in the lungs of the C57BL/6, BALB/C and CBA/Ca strains respectively. In C57BL/6 mice, transcripts were significantly enriched for adhesion molecules and we postulate that heightened expression of L-selectin, CD 18, PGSL-1 and LPAM-l on lung eosinophils is responsible for robust recruitment and therefore accumulation of these cells in C57BL/6 mice. 64 genes were differentially regulated only in the asthma-susceptible strains, several of which have not previously been associated witb asthma. The late expression of Chi313, Retnla and Mmp12 correlated with increased expression of IL-10 in the lungs and we hypothesise that this cytokine may be produced by alternatively activated macrophages as part of the resolution of disease. This study identifies several novel genes and mechanisms associated with the modulation of airway inflammation and pathology. The identification of factors that control allergic inflammation may provide novel therapeutic targets for disease intervention. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1366239 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2009

This research focuses on investigating the vibration characteristics of branched circular cylindrical shells with applications to airway passages. Analytical modelling is carried out based on Donnell-Mushtari equations of thin elastic membrane type of shells while numerical validation is conducted using the Finite Element Method (COSMOS/Works). Further validation of the results is performed using experimental investigation of tracheobronchial tissues dissected from pigs. The analytical, numerical and experimental results are in acceptable agreement. Further investigation of the vibration characteristics of the airways for cases which cannot be dealt with analytically is carried out using COSMOS/Works. Results show a strong trend relationship which suggests that the natural frequency of the trachea and the primary tracheobronchi is approximately 10 Hz. Radial resonances of lower bronchi are predictable through trends found in this work that the resonant frequency is a linear function in certain region of generations.