3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Aspects of inflammation in asthma(2017) Kalla, Ismail SikanderAsthma is the most prevalent chronic respiratory disease worldwide, with South Africa having the fourth highest asthma mortality rate in the world (1.5 per 100,000 people) and the fifth highest asthma mortality among five to thirty-five year old asthmatics (18.5 per 100,000 asthmatics). Current guidelines recommend that the achievement of ‘asthma control’ may still be plagued with persistent airway inflammation despite normalisation of spirometric parameters and control of asthmatic symptoms. This may result in structural damage with airway remodelling, fibrosis and progressive loss of lung capacity over time. Assessment of inflammation,‘Inflammometry’ is now increasingly used to titrate therapeutic interventions and achieve better asthma control. The current study aims to identify simple, objective, non invasive and reproducible biomarkers for airway inflammation; that would allow documentation of the presence or absence of airway inflammation in individual asthmatic patients. The availability of such tests may allow titration of therapeutic interventions to an outcome parameter that is a true reflection of the state of inflammation of the airways. This was a prospective, single centre, cross-sectional study of patients with confirmed asthma attending a dedicated specialist asthma clinic at the Charlotte Maxeke Johannesburg Academic Hospital Asthma Clinic. Patients attending the clinic were identified from patient records and those who met the inclusion and exclusion criteria, were selected for the study. The level of asthma control of each patient was determined using the Asthma Control Questionnaire (ACQ). Patients undertook the Asthma Control Test (ACT), had an independent assessment of their asthma control as well as performed lung function tests in a dedicated lung function laboratory. Blood and exhaled breath samples from patients were analysed for inflammatory biomarkers. Optimisation experiments were performed to establish a protocol for the measurement of serum leukotrienes in the asthmatic patient. For the statistical analyses, patients were characterised into asthma control groups as defined by the ACQ. The current study found that the ACQ and the ACT, as well as the ACQ and an independent physician’s assessment of the level of asthma control were in synchrony. Baseline FEF 25-75 levels, expressed as percentage of predicted, were low in the totally controlled, well-controlled and uncontrolled groups of asthmatic patients with medians of 35.7%, 27.3% and 17.3% respectively. The FEF 25-75 values in the three groups demonstrated an absolute post bronchodilator reversibility of 32%, 27% and 31% respectively. These findings confirmed the presence of bronchial airway hyper-reactivity (BAH), and suggest probable remodelling in the small airways. Impulse oscillometry (IOS) had a greater value in differentiating small airway resistance in the controlled when compared to the uncontrolled adult asthmatic patient. Biomarker assessments found that CRP, IL-2 and RANTES were significantly higher in the uncontrolled group when compared with the controlled group of asthmatic patients (p = 0.03, p = 0.02 and p = 0.03 respectively). Of the three serum leukotrienes measured (i.e. LTB4, LTC4 and LTE4), LTE4 levels were significantly higher in the totally controlled group compared to the uncontrolled and well-controlled groups (p = 0.007 and p = 0.006 respectively). Therefore, an elevated LTE4 coupled to a suppressed level of RANTES in the same patient may identify a different asthma phenotype. This could provide opportunities for identifying asthma phenotypes and using biomarkers in assessing asthma control. The study also found that TGFβ1 and TGFβ2 levels were significantly higher in patients using high-dose inhaled corticosteroids (ICS) (dose category as defined by the Global Initiative for Asthma (GINA)), compared to those patients not using high-dose ICS (p = 0.01 and p = 0.001 respectively). By comparison, TGFβ1 and TGFβ2 levels were significantly lower in the patients using moderate-dose ICS (dose category as defined by GINA), compared to those not using moderate-doses of ICS (p = 0.02 and p = 0.001 respectively). These findings suggest that airway inflammation is modulated by the upregulation of Treg cells as TGFβ is produced by Treg cells. It is also possible that Treg cells under the influence of elevated IL-2 levels inhibited the expression of the other Th1 as well as Th2 cytokines measured. Therefore, an elevated TGFβ level coupled with an elevated IL-2 level in the same patient may also identify a different asthma phenotype. Collectively, biomarker assessments may prove useful in assessing asthma control. Such assessments may require individualisation for different asthma endotypes and phenotypes, possibly even using biomarker profiling using multiple biomarkers for future patient care considering the heterogeneity of inflammation in asthma.Item Aspects of iron metabolism in infection, inflammation and neoplasia. Vol. 2(1987) Baynes, Roy, DennisThis thesis evaluates several aspects of iron metabolism in the setting of infection, inflammation and neoplasia. The work is divided into three major sections. The first investigate the changes in iron metabolism that occur as part of the acute phase response to infection, inflammation and neoplasia. The second section evaluates the normal and pathological biology of the iron-binding glycoprotein lactoferrin. IN the third section the iron transport protein transferrin is investigated in relation to its interaction with the macrophage, a cultured malignant hepatoma cell and a cultured malignant ovarian cell.Item Cardiac effects of infective and obesity-induced inflammation(2012-07-13) Van Rensburg, Nicol JanseThe cause of cardiac pathology in a significant number of patients with heart failure is unclear. Although chronic inflammatory changes may contribute toward progressive heart failure, whether low-grade chronic systemic inflammation, produced by infective processes or obesity accounts in-part for the development of cardiac dysfunction and heart failure requires further study. In this regard, although lipopolysaccharide (LPS) administration, an inflammatory mediator derived from the walls of gram negative organisms has been shown to produce an increased cardiomyocyte apoptosis, the lowest dose of LPS previously employed is commensurate with doses that produce vascular shock. Hence this does not reflect the impact of inflammatory changes produced by low-grade systemic infections. Moreover, although inflammatory substances have been shown to be released from adipose tissue and obesity is a cause of cardiac dysfunction and heart failure, it is uncertain to what extent inflammatory changes mediate obesity-induced myocardial dysfunction. To clarify the role of LPS and obesity-induced inflammation as potential causes of cardiac damage and dysfunction, in the present dissertation I therefore evaluated the influence of pyrogenic, but non-septic doses of LPS on cardiomyocyte apoptosis and cardiac systolic function in rats and the contribution of inflammation as indexed by circulating high sensitivity C-reactive protein concentrations (hs- CRP) to the relationship between obesity and myocardial systolic function in humans. In normal rats, core body temperature (surgically implanted [in the peritoneal cavity], temperature-sensitive radiotransmitters), cardiomyocyte apoptosis (Terminal Deoxynucleotidyl Transferase Mediated dUTP Nick End Labeling [TUNEL]) staining) and left ventricular (LV) systolic function (two-dimensional directed M-mode echocardiography) were evaluated following two doses of LPS (250 μg/kg), derived from Eschericia coli, delivered 24 hours apart. Cardiac assessments were performed 6 hours after the second LPS dose to ensure that cardiac measurements were obtained at the time of a febrile response, whilst the first LPS dose was employed to ensure that a sufficiently long period had occurred for apoptotic cell death to be iii detected using a TUNEL system. In this study LPS was able to induce a febrile response (p<0.05, n=26, compared to normal circadian rhythm), yet failed to produce an increased cardiomyocyte apoptosis or decreased LV systolic chamber (LV endocardial fractional shortening-FSend) or myocardial (LV midwall fractional shortening-FSmid) function. In 292 randomly selected participants from an urban, developing community not receiving antihypertensive therapy, I also assessed the independent relationship between indices of obesity or hs-CRP and LV FSend and FSmid. In this study indices of adiposity including waist circumference (partial r=0.35, p<0.0001) were independently related to log hs- CRP. Furthermore, waist circumference was independently and inversely associated with FSmid (standardized β-coefficient= -0.19±0.07, p<0.01), but not with FSend. Although log hs- CRP was associated with FSmid on bivariate analysis, no independent relationship between these variables was noted (p=0.21). Furthermore, with the inclusion of both waist circumference and log hs-CRP in the same regression model, waist circumference remained independently associated with FSmid (standardized β-coefficient= -0.18±0.08, p<0.05). In conclusion, the results of the present dissertation do not support a role for pyrogenic, but non-septic doses of LPS in mediating cardiomyocyte apoptosis or dysfunction or a role for low grade inflammation, as indexed by hs-CRP concentrations in mediating obesity-induced myocardial systolic dysfunction.