Doctoral Degrees (Clinical Pharmacology)

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Browsing Doctoral Degrees (Clinical Pharmacology) by Subject "Alveolar Macrophages"

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    Immunoactive, Antibacterial and Drug-Carrying properties of selective surfactants
    (Stellenbosch : Stellenbosch University, 2018-03) Van Rensburg, Lyne; Van Zyl, Johann Martin; Smith, Johan; Van Zyl, Johann Martin; Smith, Johan; Stellenbosch University. Faculty of medicine of Health Sciences. Dept. Medicine: Clinical Pharmacology.
    ENGLISH ABSTRACT: Surfactant replacement therapy is used the treatment of neonatal respiratory distress syndrome as surfactant’s biophysical behaviour helps to maintain proper lung function and reduces the work associated with breathing. Secondly, surfactant associated proteins are important role players in the innate immune response within the pulmonary environment and therefore assist in pulmonary host defence. However, natural and synthetic exogenous surfactants have gained much interest in other areas of therapy such as possibly aiding in dual-drug delivery systems for infectious or inflammatory pulmonary conditions. Both types have been studied extensively in animal models and in clinical trials and have elicited positive and negative effects on lung function. This thesis aims to determine whether a synthetic peptide containing surfactant, Synsurf®, may have potential immunomodulatory effects compared to the naturally derived surfactants, Curosurf® and Liposurf®. Two formulations of Synsurf®, combined with the antibiotic linezolid were tested for its efficacy as a respirable compound in a pressurised metered dose inhaler. The outcome of these experiments revealed the prospect of Synsurf®’s adaptability as a pulmonary drug carrier. Furthermore, the tuberculosis isolates H37Rv and MDR-X51 displayed enhanced susceptibility to surfactant-drug micro-particle combinations. The main findings of this study show that the natural surfactants Curosurf® and Liposurf® as well as Synsurf® inhibit secretion of pro-inflammatory cytokines and influence the production of reactive oxygen species in NR8383 alveolar macrophages and therefore influence cell viability. The inhibitory effects on cytokine secretion was displayed in a dose-dependent manner as well as a threshold effect that was seen for all three surfactants. This may result from unique mechanisms of decreasing cell signalling or up-regulating anti-inflammatory activity that was further elucidated by the employment of proteomics. The findings in this thesis on the comparison of the two natural and one synthetic surfactant led to the following main conclusions: a) Different surfactant compositions modulate the anti-inflammatory activity in lipopolysaccharide stimulated alveolar macrophages via the possible involvement of different signalling pathways. The initial hypothesis regarding the protective nature that is linked to the protein content in natural surfactants is challenged and may be deemed as “not fully supported” as these new findings suggest non-specific lipid or synthetic peptide protection with alveolar macrophages as seen with Synsurf®. b) Different surfactant compositions effect cell viability and morphology in a time and dose-dependent manner revealing that the treatment of neonatal respiratory distress syndrome may depend upon the specific preparation or dose used. c) All three surfactants displayed an impact on the antibiotic activity of linezolid that holds positive ramifications for drug loaded surfactants. d) The data shows that linezolid in combination with Synsurf® can be aerosolised in desired particle ranges for optimal lung deposition for a possible non-invasive, site-specific, delivery model via pressurised metered dose inhaler.