The long term pulmonary consequences of prematurity are of increasing importance as more neonates with chronic lung disease, in particular those who developed bronchopulmonary dysplasia (BPD) survive to adulthood (Eber and Zach, 2001). There is growing concern that lung injury in early life may be associated with the premature development of chronic obstructive pulmonary disease (COPD). The nature and extent of lung impairment in adults surviving BPD has not been well studied. The aim of this thesis was to test the hypothesis that adult survivors of BPD have evidence of greater lung function impairment, reduced exercise capacity, evidence of structural lung abnormalities and persisting airways inflammation compared to two age/gender matched reference groups, one to control for premature birth and the other comprising individuals born healthy at term. Subjects underwent full lung function testing, high resolution chest HRCT scans and performed symptom limited cardiopulmonary stress tests (CPEST). BPD subjects reported significantly more respiratory symptoms when compared to term controls. BPD subjects had significant lung function impairment (lower FEV1, FEV1/ FVC ratio and FEF25-75% predicted), compared with both control groups. In the majority (87%) of BPD subjects with airflow obstruction the impairment was fixed. Lung volume measurements were more impaired in BPD subjects consistent with air trapping. BPD subjects had evidence of significantly lower diffusing capacity than both control groups. LCI scores were significantly more impaired in BPD subjects compared to term controls. All BPD subjects had evidence of significant radiological abnormalities on HRCT scans. The severity of radiological abnormality was strongly and significantly correlated with lung function impairment but not exercise capacity. Exercise capacity was significantly lower in BPD subjects compared with term controls, when corrected for general activity levels. Gestational age and birthweight were significant predictors of lung function impairment and radiological abnormalities in adult life. The studies detailed in this thesis confirm that lung function impairment in survivors of BPD persists into adult life. A large proportion of survivors have lung function in the abnormally low range with fixed airflow obstruction. These findings combined with the presence of structural lung abnormalities with evidence of reduced exercise capacity, suggest clinically important impairment in respiratory health persists in adult survivors of BPD

<I>AIM OF STUDY: </I>To assess the relationships between age, respiratory symptoms, airways calibre and nonspecific bronchial responsiveness in a population sample including large numbers of elderly adults. <I>RESULTS: </I>783 questionnaires were sent to eligible subjects. 395 subjects were invited to attend; 247 did so, of whom 246 performed spirometry and 208 completed bronchial challenge. Prevalence of smoking was high (29.2% current smokers, 37.3% ex-smokers). Asthma was reported by 7.3%, bronchitis by 15.4%; a further 7.3% reported both diagnoses. 53.8% of subjects reported one or more respiratory symptoms. Chronic airflow obstruction (defined as FEV<SUB>1</SUB>/FVC<60% for age <65 years; for age ≥65 lower limit of FEV<SUB>1</SUB>/FVC was calculated from reference ranges [Enright PD et al, Am Rev Respir Dis 1993; 147: 125-331]) was present in 26.4% of the population; bronchial hyper-responsiveness (PD<SUB>20</SUB><100μg) was found in 26.0%. Comparison with values calculated from reference ranges suggested that FEV<SUB>1</SUB> in non-smoking Manchester adults was lower than predicted. Only 55.4% of those with chronic airflow obstruction reported a diagnosis of asthma or bronchitis, and only 35.4% were using appropriate inhaled medications. There was no difference in the prevalence of reported symptoms, diagnoses, or chronic airflow obstruction between adults aged <65 or ≥65 years. Multiple regression analysis with bronchial responsiveness (log dose-response slope) as the dependent variable showed an independent negative relationship with FEV<SUB>1</SUB>, and positive relationships with age and total IgE level. <I>CONCLUSIONS: </I>Respiratory morbidity is common in this middle-aged and elderly inner-city population, but is frequently undiagnosed and untreated. There is a positive relationship between bronchial responsiveness and age. Atopy is associated with bronchial responsiveness even in older adults.

No description available.

This thesis describes an investigation of the respiratory drive to breathe in a rabbit model of pulmonary emphysema. I propose that an altered respiratory drive in emphysematous rabbits may model the origin of the sensation of dyspnoea experienced by many human patients with emphysema. Pulmonary emphysema was induced in Dutch rabbits by endotracheal administration of type IV porcine pancreatic elastase. In rats it was induced by endotracheal administration of papain. Respiratory drive was measured as phrenic activity (phrenic slope, G and phrenic height, H). since emphysema changes the mechanical properties of the lungs and ventilation will be changed for a given respiratory drive. Rats' and rabbits' conscious pattern of breathing (expiratory time, tE; inspiratory time, tl and tital volume. VT) was measured barometrically to investigate the role of sensation in changed conscious pattern of breathing. To elucidate the role of pulmonary receptors in changing the pattern of breathing and respiratory drive, the respiratory variables were measured during 3 stages: 1) preSO<SUB>2</SUB>: when all pulmonary receptors were intact 2) post SO<SUB>2</SUB>: when pulmonary stretch receptors (SARs) were blocked by inhaled sulphur dioxide 3) postvagotomy: when all pulmonary receptors input was removed by bilateral vagotomy. Emphysema increased static lung compliance in rabbits (normal (N): 4.12± .49 ml/cmH<SUB>2</SUB>O, n=25 vs. emphysematous (E): 4.61±0.31. n=35) and rats (N: 0.61±0.02 ml/cmH<SUB>2</SUB>O, n=10 vs. E: 0.82±0.03, n=10). It also increased mean linear intercept in rabbits (N: 79.71±8.42μm, n=25 vs. E: 99.62±2.32n, n=35) and rats (N: 80.5±2.9, n=10 vs. 108.4±3.2, n=10). Breathing accelerated by 6% CO<SUB>2</SUB> inhalation in all three stages (calculated as Δ %) showed that emphysematous rabbits have a stronger respiratory drive indicating the relative importance of vagal and extravagal inputs (preSO<SUB>2</SUB>, G (N): 30.9±3 vs. E: 37.6±1.8; postSO<SUB>2</SUB>, G(N): 24.4±2.3 vs. E: 33.92±1.5; postvagotomy, GN(N): 27.95±3.2 vs. E: 45.61±2.08). It is concluded from this study that it is this stronger respiratory drive in eupnoea and in response to CO<SUB>2</SUB>, that patients with pulmonary emphysema perceive as dyspnoea.

The objectives of the study were: (1) to determine if there is a similar pattern of enhanced binding of <I>Neisseria meningitidis</I>, <I>Haemophilus influenzae </I>type b, <I>Staphylococcus aureus, </I>and <I>Bordetella pertussis</I> to RSV subgroup B infected cells as observed with RSV subgroup A infection; (2) to determine if there is increased binding of other species of bacteria associated with meningitis and those associated with secondary respiratory infections or exacerbation of chronic bronchitis to RSV infected cells; (3) to determine if there was similar pattern of increased bacterial binding to influenza virus infected cells; (4) to determine if as with RSV infected cells there was an increase in expression of native cell surface antigens which can act as receptors for bacteria; (5) to determine if there is enhanced binding of bacteria associated with meningitis or respiratory disease to cells of smokers; (6) to assess cells of smokers and non-smokers for differences in levels of antigens proposed to act as bacterial receptors. With the exception of an antibiotic-sensitive strain of <I>Moraxella catarrhalis</I> (MC2) infection of an epithelial cell line (HEp-2) with RSV (subgroups A or B) enhanced binding of all bacterial strains tested. Compared with the antibiotic resistant strain, MC2 and other antibiotic-sensitive isolates of <I>M. catarrhalis</I> were found to express differences in outer membrane proteins, sensitivity to complement-mediated killing, phagocytosis and intracellular survival. Cells infected with human influenza A virus showed increased adherence of each of the species tested, including the antibiotic-sensitive isolates of <I>M. catarrhalis</I>. Compared with uninfected cells, influenza virus infected HEp-2 cells showed significantly increased binding of monoclonal antibodies for the cell surface antigens CD14 and CD18 that can act as receptors for some bacteria. Pre-treatment of HEp-2 cells with neuraminidase showed increased bacterial binding compared with untreated HEp-2 cells, but the increase was less than that observed for influenza infected cells. The results suggest that while smoking is a predisposing factor for viral infection, it can enhance bacterial binding of strains associated with meningitis or respiratory infection on its own.

The physiology of venous flow in the proximal deep veins of the leg was studied. A pulsed Doppler ultrasound study of flow phasicity showed respiratory phasicity to be present in 95% of subjects. In the supine position during pregnancy and the puerperium, venous flow velocity was maximal on inspiration but on standing upright it was maximal during expiration indicating that intra-abdominal pressure may influence venous return. The effect of posture was further considered in a longitudinal study of gestational changes in vessel diameter, flow velocity and respiratory fluctuation in flow. In the supine position, vessel diameter increased and flow velocity decreased with advancing gestation. These changes were most marked in the common femoral vein. No significant gestational changes in respiratory flow fluctuation were observed. Flow velocity was significantly slower in the left compared to the right common femoral and popliteal veins, in keeping with the observed increased incidence of left ileofemoral DVT in pregnancy. Adoption of the left lateral position increased flow velocity in both legs throughout pregnancy and postnatally. These novel findings re-evaluate the role of the gravid uterus in determining venous return from the lower limbs. The deep venous system of the leg was studied with duplex Doppler ultrasound in the early and late puerperium. Flow velocity was reduced in the left leg and changes in vessel diameter and flow velocity were observed between the 4<SUP>th</SUP> and 42nd postnatal day. Although flow velocity was significantly lower in the common femoral vein after caesarean section compared to vaginal delivery, no other differences were observed. Duplex Doppler ultrasound was used to study the effects of three types of stocking on venous diameter, flow velocity and respiratory fluctuation in the supine, left lateral and upright positions in non-pregnant women. Graduated stockings reduced vessel diameter at the popliteal vein, but no other effects were observed.

In patients undergoing resuscitation from shock three groups were defined on the basis of the responses of arterial blood lactate (ABL) concentrations. The first group had hyperlactataemia which corrected following therapy which achieved significant increases in mean arterial blood pressure (MAP: p<0.01) and DO<SUB>2</SUB> (p<0.005). Group two had similar lactate levels, but vigorous therapy, which increased MAP significantly (p<0.05) did not increase DO<SUB>2</SUB>. ABL concentrations remained elevated, and mortality was high. These differences emphasise the importance of simultaneous reversal of hypotension and attainment of adequate DO<SUB>2</SUB>. In the third group, despite severe cardio-respiratory abnormalities hyperlactataemia was not seen. Shock may occur with normal ABL concentrations. In patients with shock and adult respiratory distress syndrome (ARDS) an elevated ABL has been proposed as a marker of delivery dependent VO<SUB>2</SUB>, a potential indicator of tissue hypoxia. Septic shock and ARDS patients were classified on the basis of normal or elevated ABL concentrations. The level of ABL had no value in predicting the response of VO<SUB>2</SUB> to changing DO<SUB>2</SUB> in either the grouped data, or in individual patients. The absence of hyperlactataemia in ARDS does not preclude the presence of delivery dependent VO<SUB>2</SUB>, and by implication tissue hypoxia. The anaesthetic induction agent propofol has been used for sedation in adult critically ill patients. In a group of ventilated, invasively monitored patients its effects on cardiorespiratory function were documented. Heart rate and MAP fell significantly (p<0.05) but DO<SUB>2</SUB> and VO<SUB>2</SUB> were unchanged despite a significant increase in the sedation score (p<0.01), suggesting there was no improvement in overall oxygen supply/demand balance.

Introduction: Many asthmatics smoke, and this has a detrimental effect on the course and control of the disease. The pathophysiological mechanisms through which smoking exerts these effects remain ill defined. The main aims of the studies described in this thesis are to investigate the effects of cigarette smoke on airways structural cells, in particular how it influences the expression of pro-inflammatory and pro-remodelling cytokines, and thereby to understand the role that structural cells may play in the development of Th17/IL-17A mediated neutrophilic inflammation in asthmatics who smoke. A further aim is to show that there is increased vascular remodelling in the airways of asthmatic smokers. Methods: The neutrophilic and angiogenesis hypotheses were addressed by investigating the effects of cigarette smoke extract (CSE) and IL-17A on human tracheal epithelial cells (HTEpC) and primary bronchial fibroblasts cells in vitro, and also by measuring the expression of these mediators and remodelling changes in bronchial mucosal biopsies from smoking and non-smoking asthmatics in vivo. Results: There was elevated expression of IL-17A in the bronchial mucosa of asthmatic smokers compared to non-smokers. This was accompanied by elevated expression of IL-6 and IL-8 as well as elevated numbers of neutrophils. In the smoking asthmatics, the expression of IL-17A correlated both with that of IL-8 and with the numbers of neutrophils. Interestingly, the numbers of bronchial mucosal eosinophils also correlated with the expression of IL-8, IL-17A and the numbers of neutrophils. In these mild asthmatic patients there was no difference in the extent of vascular remodelling or numbers of mucosal eosinophils in smokers compared to nonsmokers. Exposure of HTEpC cells to both CSE and IL-17A resulted in increased expression of IL-6 and IL-8 synergistically. The data further suggested that the synergistic interaction between CSE and IL-17A in HTEpC cells may be mediated by reactive oxygen species (ROS). Co-stimulation of HTEpC cells with CSE, IL-17A and allergens lacking intrinsic protease activity (cat dander and Timothy grass pollen) also increased IL-6 and IL-8 production synergistically. Stimulation of primary human airways fibroblasts with both CSE and IL-17A also resulted in increased expression of IL-6 and VEGF, again with a suggestion of synergy in the effects. CSE exposure induced HTEpC cells to express VEGF in a concentration-dependent manner. This induction was dependent on MAPK signalling (p38 MAPK, Erk and JNK) and, upstream from this, PI3 kinase-dependent Akt phosphorylation. CSE also induced expression of IL-6, TGF-β1 and VEGF in primary bronchial fibroblasts in a concentration-dependent manner. The induction of IL-6 and VEGF by CSE was found to be dependent on p38 MAPK and ERK signalling, while the induction of TGF-β1 was dependent on ERK and JNK signalling. When primary bronchial fibroblasts were co-stimulated with either Poly I:C or LTA and CSE, there was a synergistic increase in the expression of VEGF. When HTEpC cells were stimulated with Poly I:C the expression of TSLP was inhibited by CSE, while there was no effect on the expression of IL-6. Conclusion: Asthmatic smokers have IL-17A mediated neutrophilic inflammation of the airways, which is supported by the effects of CSE interacting with other environmental stimuli (allergens, viruses) on airways epithelial cells and fibroblasts. This evidence supports the categorisation of asthmatic smokers as a specific endotype of asthma.

Respiratory failure, due to infection and concomitant inflammation is the major cause of morbidity and mortality in people suffering from the genetic disorder, cystic fibrosis (CF). Consequently, the CF Foundation currently estimates that patients with CF have a median predicted life expectancy of only 41.1 years. Understanding the relationship between the complex and diverse bacterial community present within the lower respiratory tract and patient outcomes has therefore become a top priority. Through the use of next generation sequencing technologies (Roche 454 and Illumina MiSeq) and ecological statistics and modelling, the complex relationships between the bacterial community within the CF lung and host related clinical factors were investigated. By first establishing guideline methodologies for the reduction of bias in the collection, storage and treatment of respiratory samples, this thesis aimed to use large scale spatial and longitudinal studies to investigate key relationships between the bacterial community and clinical factors. It has been well established that a complex and diverse bacterial community exists within the CF lung. Spatial sampling revealed key relationships between the bacterial community and other diagnostic parameters including, FEV1, gender, and clinic location. Longitudinal sampling aimed principally to investigate CF pulmonary exacerbations (CFPE), implicated in the progressive loss of lung function associated with CF lung disease. Over the course of a CFPE the common bacterial taxa show resistance to perturbations while the rare taxa show resilience. Through this investigation, Veillonella parvula was identified as a potential bioindicator of CFPE, introducing the potential for a rapidly testable parameter for clinicians to identify a CFPE. This finding could provide one of the most important recent developments in CF therapy.

Almitrine Bismesylate (ABM) is a highly lipophillic compound of molecular weight 669.7, under development as a peripheral chemoreceptor stimulant in the treatment of chronic bronchitis and emphysema. Its pharmacokinetics and metabolism were investigated in animals and man. Following oral administration of [14C]-ABM, absorption of radioactivity is rapid and variable in man, rat, rabbit and dog. Plasma levels of radioactivity decline rapidly after both oral and intravenous administration, suggesting rapid uptake into tissues. A high affinity of almitrine for the carotid body of the urethane-anaesthetised rat confirms a prolonged and specific action of the compound. Elimination of radioactivity is slow and mainly faecal and independent of administration route or species. Recovery of the adminstered radioactivity is incomplete in all other species except rat and in man, only 86 to 94% of the administered dose was recovered in 140 days. This slow elimination may be due to repeated gut secretion and reabsorption of almitrine. Almitrine is metabolised by oxidation and N-dealkylation of the allyl side chain to form, respectively, the di- and tetrahydroxy almitrine and mono and di-deallyl almitrine with the corresponding dihydroxy monodeallyl almitrine. The major faecal metabolite in all species is tetrahydroxy almitrine (not found in plasma) and all species had qualitatively similar metabolic patterns to man both in-vivo and in-vitro from liver microsomes. The pharmacokinetics of unchanged almitrine in man shows a rapid absorption from both solution and tablet formulations. Absorption is increased (48%) in the presence of food and bioavailability is high (74%). A large volume of distribution (3100 litres) and low clearance (64ml.min-1) are consistent with a long half-life (614 to 1164h). Plasma protein binding is high (99%) in all species and is not affected by drugs likely to be coadministered with almitrine. Clinically, there is a relationship between almitrine plasma concentration and changes in Pa02 from baseline during repeated administration. Some patients with high plasma levels of almitrine (>300ng.ml-1) experienced peripheral paresthesia which is reversible. Using simulations, dosage adjustments have shown that it is possible to maintain therapeutic levels of almitrine without side effects.