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Since the 1970s research on how people take, or "adhere" to prophylactic medications, has been dominated by individualistic approaches emphasising the role of attitudes in explaining adherence, with limited predictive success. Such limitations may be related to a restricted conceptualisation of talk about medicine taking as an accurate representation of individuals' attitudes. Using asthma as a case example, this thesis explored whether we can more productively view such talk as social action reflecting the interactional and social conditions in which it is produced. This enables us to examine interactional issues with specific influence on everyday decisions about medicine taking. Key amongst these issues are likely to be moral discourses of illness management. Using ideas and tools associated with Discursive Psychology and Linguistic Ethnography, the author examined a range of data sources for how moral discourses of asthma management structured talk of people with asthma in face-to-face interview and focus group settings. Participants could be seen to deploy a range of rhetorical devices to justify medicine taking, positioning versions of their asthma management, views and themselves within a range of moral discourses that can be seen to circulate different social spaces. Building on Goffman's term "performance," these findings indicated that people's talk about medicine taking can be seen as transference of linguistic resources across contexts, manifested in different interactions. The "meaning" of performances is therefore a result of how different criteria, set up within interactions about illness management, match available resources deployed by individuals with chronic illness. These findings suggest that rather than seeing lay-professional discussions of medicine taking as being about persuading people to adopt particular attitudes, this approach allows us to see how mutually-agreed treatment decisions may, instead, require us to identify appropriate linguistic resources for facilitating discussion of patients' everyday concerns about illness management, within that interaction.

A quantitative study of collagen and elastin content in human lung tissue has been made in relation to a morphometric measure of airspace size. The subjects included non-smokers, smokers with and without macroscopic emphysema and three subjects with alpha 1-protease inhibitor (α1-Pi) deficiency. Airspace size was determined morphometrically as Alveolar Wall surface area per Unit Volume of lung (AWUV). The results were as follows: 1. There were no significant differences in AWUV, collagen content or elastin content between the upper and lower lobes with a single lung from both a non-smoker and a smoker without macroscopic emphysema. 2. Analysis of 102 samples from 9 smokers' lungs with no signs of macroscopic emphysema showed significant negative correlations between AWUV and collagen content and between AWUV and elastin content such that as the surface area of alveolar wall per unit volume decreased there was an increase in both the collagen and elastin content of the remaining alveolar tissue. 3. In tissue samples from 14 non-smokers there was no significant correlation between age and collagen content or between AWUV and collagen content. 4. Samples taken from smokers' lungs where either macroscopic centriacinar emphysema or panacinar emphysema or a mixture of centriacinar and panacinar emphysema were present were found to have a significantly higher collagen content than samples from non-smokers. 5. Tissue samples from the lungs of three α1-Pi deficient subjects had a significantly higher collagen content than samples from a non-smoker. In view of these findings the definition of emphysema, which states that no obvious fibrosis is present, may have to be revised.

Exposure to the fibrous silicate mineral, asbestos, is associated with pulmonary fibrosis and lung cancer as well as different types of pleural pathology. The aim of the present study was to assess the pleural leukocyte response to asbestos fibre deposition in the bronchoalveolar space using a rat intratracheal instillation model. Intratracheal heat-killed <i>C.parvum</i> organism was also used to produce pleural inflammation. Normal pleural leukocytes were comprised of macrophages, mast cells, eosinophils and lymphocytes. This population produced urokinase-type plasminogen activator inhibitor (PAI) in culture and contained plasminogen activator intracellularly. Normal pleural leukocytes also released tumor necrosis factor (TNF) and interleukin-1 (IL-1) in culture and the release was enhanced further with LPS stimulation. After intratracheal instillation (I/T) of crocidolite asbestos, pleural leukocyte components were changed with a significant recruitment of macrophages and eosinophils. These populations were found to release increased PAI activity and decreased TNF activity. In contrast, I/T asbestos coupled with other compact mineral dusts considerably increased TNF production by pleural leukocytes. The elaboration of IL-1 by the leukocytes showed an enhanced response to asbestos exposure. In comparison, after I/T asbestos, bronchoalveolar leukocytes produced increased TNF and IL-1 activity in culture. <i>C.parvum</i> induced-pleural inflammation, characterised by substantial recruitment of neutrophils, produced increased PAI activity but decreased TNF and IL-1. During the later stages of the inflammation, the pleural leukocytes released even less TNF and IL-1, but normal levels of PAI.

Cystic Fibrosis (CF) is an autosomal recessive disorder in which the genetic defect is the ΔF 508 deletion in 70% of patients (Tsui and Collins et al, 1989). The ΔF 508 deletion gene predicts encodement of the cystic fibrosis transmembrane conductance regulator (CFTR), (Riordan, 1989). The mechanisms by which this abnormal regulatory protein leads to chronic airway infection, respiratory failure and death in CF are not clear. This thesis examines one basic problem seen in patients with F, namely the incrased viscosity of their sputum. The increased viscosity leads to decreased mucociliary clearance and may be one of the factors leading to delayed bacterial clearance, chronic respiratory infection and respiratory failure. The problem of increased mucus viscosity is examined by looking at two molecules which contribute to the increased viscosity of sputum: mucins and DNA. The fundamental physicochemistry of mucin rheology is explored, and the theoretical model of mucin expansion is developed further in an experimental intervention in patients with CF using an experimetal new drug, aerosolized recombinant human DNase which fragments DNA and decreases sputum viscosity. The models used to examine the questions of mucus rheology were the giant secretory granule of the slug, <i>Ariolimax columbianus</i>, and the goblet cell of the trachea of the New Zealand white rabbit. Normal subjects and patients with CF were used for the human studies. Mucus is a polymer hydrogel that functions as a protective coat on the skin and mucosa of many species ranging from simple animals such as <i>coelenterates</i> to mammals. The polymer matrix of mucus is made out of long-chain glycoproteins called mucins that are tangled together to form a randomly woven, polyionic network. The swelling kinetics of both slug granules and the mucin granules of the goblet cell of the rabbit are similar to those of artificial polyacrylamide gels. Mucins are condensed within granules and expand by hydration during or after exocytosis. The polyionic charges of mucins would prevent condensation unless they were shielded by a balancing cation. The experiments using the slug granule demonstrate the presence of shielding cations in the granule and the role of these cations at the time of secretion.

The purpose of this study was to try to explain, using a rat model, the symptoms of bronchitis reported by some members of the workforce in wool textile mills in the north of England and in grain handlers. Inflammation was evident in rats following intratracheal instillation of dust collected from the air of wool mills and grain dusts. The inflammation could arise from at least four possible pathways and so we investigated each of these. 1) Direct toxicity towards airspace epithelial cells or alveolar macrophages. We demonstrated that there was no significant toxicity of wool or grain dust toward either cells of a human alveolar epithelial cell line (A549), or rat alveolar macrophages. 2) Activation of adhesion molecules on leukocytes. A constant finding in the lungs from wool and grain-treated animals was aggregates of mononuclear cells which were almost entirely macrophages. We hypothesised that prolonged up-regulation of adhesion molecules could account for aggregate formation, which may be mediated through the action of bacterial endotoxin present on the dusts, and which could enhance inflammation. We demonstrated that macrophage aggregation could be produced in vitro after stimulation, and that antagonists of adhesion molecule activation pathways abolished the formation of aggregates. 3) Secretion of pro-inflammatory cytokines by dust-exposed alveolar macrophages. Tumor Necrosis Factor (TNF) was secreted by alveolar macrophages after treatment with wool and grain dusts in vitro. Additionally, bacterial endotoxin which we detected on the dusts and which was present in leachates of dust, was shown to play an important role. Depletion of endotoxin in dust leachates resulted in substantially less TNF being released. 4) Immune responses to organic and antigens in the wool dust.

Emphysema is defined as the increase beyond normal in the size of airspaces distal to the terminal bronchiole. Such increases in airspace size are associated with a reduction in alveolar wall surface area <i>per</i> unit volume of lung tissue (AWUV). This study involved the development and assessment of the fast interval processor (FIP) as a new automated technique for measuring AWUV on histological sections of lung tissue. A minimum of 726 individual field AWUV measurements were made from each lung specimen, and frequency distributions of these AWUV values were compiled for each of the 165 specimens in the study. Various aspects of the frequency distributions were then used to establish the normal range of AWUV values with advancing age in non-smokers, and to assess the effects of age, sex and cigarette smoking on the amount and distribution of microscopic emphysema within the lung. Mean AWUV was found to decrease with advancing age in adult non-smokers, and this decrease was considered to be normal. A range of normal mean AWUV values was established for subjects between the ages of 21 and 93 years. No evidence was found to suggest that senile emphysema exists in non-smokers. Microscopically assessed emphysema (MAE) was defined as the condition where the mean AWUV measurement of a lung was below the lower limit of the normal range. Only 26% of the smokers studied had MAE as defined in this way, suggesting the existence of a suceptible sub-group of smokers. Neither the susceptibility to, nor the severity of, MAE were dose-related to tobacco consumption in the cigarette smokers studied. There were no sex differences in the incidence of MAE. MAE was found to be related to macroscopic panacinar emphysema, but was not related to macroscopic centriacinar emphysema. The 5th and 10th percentile values of the AWUV frequency distribution were found to be related to the presence of centriacinar emphysema. These results indicate that the early (microscopic) lesions in centriacinar emphysema are also focal in their distribution, and do not develop on a background of generalised MAE.

The predisposing factors leading to the development of sleep apnoea/hypopnoea syndrome (SAHS) in many cases are unclear. Snoring, a prerequisite for SAHS, runs in families. There have been reports of familial SAHS in several families but this may have resulted from an association with obesity. I have therefore investigated whether SAHS is familial. In a pilot study breathing and oxygen desaturation data during sleep in 40 first degree relatives of 20 non obese SAHS patients has been compared with that in retrospective controls. Ten out of 40 relatives had >15 apnoeas+hypopnoeas/hr of sleep and 8 had >5 4% desaturations/hr. These frequencies of irregular breathing (p<0.005) and desaturation (p<0.0001) are significantly higher than in the British population. A case control study has therefore been performed examining sleep symptoms, sleep studies, upper airway calibre by acoustic reflectance and facial structure by cephalometry in first degree relatives of non obese (BMI<30 kg/m<SUP>2</SUP>) patients with SAHS and matched controls drawn from a general practitioner's register. In a pilot study to determine whether there might be any association between SAHS and Sudden Infant Death Syndrome, it was found that 8 unexpected sudden infant deaths were reported in 28 SAHS families compared to none in 35 control families (p<0.01). This preliminary observation requires independent verification. Thus SAHS is familial and this family tendency is associated with anatomical changes which predispose to upper airway narrowing.

The inherited intensity of the hypoxic ventilatory response may be important in determining the severity of hypoxaemia in chronic obstructive pulmonary disease (COPD). However, existing methodology does not allow adequate quantification of peripheral chemoreceptor sensitivity in conscious humans. The aim of this project was to validate a new mathematical model and apply this model to investigate the hypoxic ventilatory response of healthy offspring of patients with COPD. The mathematical model (consisting of two linear differential equations in parallel, each with either a fast or slow time constant component, both using the fall in SaO<SUB>2</SUB> as the stimulus and with the equation outputs summed to give the rise in ventilation above the normoxic baseline value) was used to analyse the ventilatory response to transient and step change hypoxic stimuli in normal conscious human volunteers. Ten repeated measurements of the hypoxic ventilatory response in four subjects showed that the model parameter estimation was reproducible within a subject, and capable of distinguishing between subjects. Studies at rest and increasing levels of exercise showed that the hypoxic ventilatory response expressed both as the V<SUB>E</SUB>inst/SaO<SUB>2</SUB> relationship and as the model gain parameters increased with increasing exercise level. No significant effect could be demonstrated upon the ventilatory response of varying the rate of onset of the hypoxic stimulus to give a time course for the fall in SaO2 from 17 to 50 seconds. The central adenosine blocker theophylline given as a slow-release oral preparation did not consistently affect the hypoxic ventilatory response expressed either as the V<SUB>E</SUB>inst/SaO<SUB>2</SUB> relationship or as the model gain parameters of six normal subjects. Thus, the mathematical model appears to quantitate the hypoxic ventilatory response in normal subjects and is capable of reflecting true physiological changes. It may also provide further information regarding the components of the response than conventional methods of analysis. Studies in 35 offspring of patients with COPD showed a significant relationship between the PaO<SUB>2</SUB> of a group of patients with COPD and the hypoxic ventilatory response of their offspring in response to step change hypoxia. However the PaO<SUB>2</SUB> of the patients was best predicted by a combination of the model gain parameters of their offspring (where gain 1 may represent the peripheral chemoreceptor response, and gain 2, the central or combined hypoxic response). Hence the PaO<SUB>2</SUB> of the patients may be determined by hereditary characteristics of the peripheral chemoreceptor and central components of the hypoxic ventilatory response. The hypoxic ventilatory response of the offspring group was no different from that of a group of 26 age and sex-matched control subjects whose parents did not have COPD, suggesting that the offspring group were within the wide range of the normal hypoxic ventilatory response. The studies in the offspring of patients with COPD suggest that the PaO<SUB>2</SUB> in COPD seems to depend on a genetically determined normal variation of both peripheral stimulation and central depression of ventilation by hypoxia.

The relationship between ventilation and oxygen saturation during hypoxia is usually assumed to be approximately linear, but when the ventilatory response to hypoxia, expressed as ventilation/oxygen saturation, was measured for 10 subjects, in 8 of the subjects it was found to be greater when measured using step change hypoxia than when using transient hypoxia. Using Fourier techniques, the ventilation/saturation relationship was shown not to be linear. Use of a detailed physiological model failed to reveal a cause for the difference between the response to step and transient hypoxia, and rate of fall of oxygen saturation was shown experimentally and theoretically not to be an important factor in the difference. In the absence of a clear quantitative explanation for the discrepancy, a mathematical model was developed to describe the dynamic ventilatory response. The model was built by adding terms of increasing complexity to a simple linear differential equation. The simplest model which adequately described the responses of all the subjects consisted of two linear differential equations (1 and 2) in parallel, the input of both being the fall in oxygen saturation, the sum of the outputs giving the rise in ventilation. Equation 1 had a fast time constant (&60 3 sec), and Equation 2, a slow time constant. Non-linear terms included were a 'saturating effect', similar to that described by the Michaelis-Menten formulation, which reduced gain 2 as oxygen saturation fell; and 'inhibition' or 'potentiation' of gain 1 as the output of Equation 2 increased. This model produced statistically better fits to the data than any of the simpler models tried. As well as providing a more precise description of the hypoxic ventilatory response, the model suggested further experiments that might elucidate the physiological mechanisms occurring during hypoxia. Using a further model, an appendix discusses flaws in the widely-used technique of attempting to control arterial carbon dioxide tension by using end-tidal carbon dioxide pressure as a controlled variable.