Asthma is a chronic inflammatory disease of the airways. Using a murine model which replicates many characteristic features of human asthma, this study evaluated the effects of treatment with anti-inflammatory drugs on the lesions of chronic asthma, and investigated potential underlying molecular mechanisms. Treatment with dexamethasone, a glucocorticoid, was compared with roflumilast, a novel phosphodiesterase-4 (PDE4) inhibitor. BALB/c mice sensitised to ovalbumin were challenged with a low mass concentration of aerosolised antigen for 30 min/day, 3 days/week for 6 weeks. In weeks 5 and 6, groups of animals were treated with either dexamethasone or roflumilast. Assessment included changes in acute-on-chronic inflammation, structural remodelling of the airways and airway hyper-responsiveness to a bronchoconstrictor stimulus. These were correlated with the expression of pro-inflammatory cytokines and growth factors. Compared to vehicle-treated control animals, dexamethasone- and roflumilast-treated mice exhibited reduced accumulation of intra-epithelial eosinophils and chronic inflammatory cells, including CD3+ T-lymphocytes in the airways. Similarly, both drugs inhibited subepithelial fibrosis and airway epithelial thickening, although only dexamethasone inhibited goblet cell hyperplasia/metaplasia. Airway hyper-reactivity was not diminished by either drug. Both treatments suppressed production of Th2 cytokines by ovalbumin-restimulated peribronchial lymph node cells. In selectively dissected airway tissue from vehicletreated animals, increased expression of mRNA for several pro-inflammatory cytokines (TNF-α, GM-CSF, IL-6) and cytokines characteristic of Th1 (IFN-γ), Th2 (IL-5, IL-13)and Th17 (IL-17A) cells was demonstrated using real-time PCR. Enhanced expression of growth factors (TGF-β1 and FGF-2) was also demonstrated in airway epithelium isolated by laser capture microdissection. Interestingly, whereas treatment with dexamethasone significantly inhibited expression of mRNA for all of the inflammationrelated cytokines examined, roflumilast inhibited only IL-17A, TNF-α, GM-CSF and IL-6. Both drugs inhibited mRNA expression of growth factors by epithelial cells. Because roflumilast was as effective as dexamethasone in suppressing inflammation and most changes of remodelling, the selective suppression of IL-17A, TNF-α, GM-CSF and IL-6 suggests that these mediators, or the cells that produce them, may have critical roles in pathogenesis. Furthermore, they may be particularly appropriate therapeutic targets in chronic asthma.

Copy of author's previously published article. / Bibliography: leaves 189-219. / ix, 219, [69] leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Explores pathways by which therapeutic agents may affect the inflammatory reaction in rheumatoid arthritis and confirms and expands observation on anti-rheumatic agents that are capable of regulating the activity as well as the expression and production of a variety of inflammatory mediators related to tissue destruction in the inflamed joint. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1997

Copies of author's previously published articles in back-cover pocket. / Bibliography: leaves 180-205. / x, 205 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Examines aspects of the potential enantioselective pharmacokinetics and pharmacodynamics of ketoprofen in humans, and develops methods for quantifying total (bound plus unbound) and unbound ketoprofen enantiomers in plasma. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1993?

Thesis (Ph. D.)--University of Adelaide, Dept. of Pathology, 1986. / Includes bibliographical references (leaves 211-260).

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine and Royal Adelaide Hospital, Rheumatology Unit, 2004. / Includes list of publications arising from this thesis. Erratum attached to inside back cover. "25/03/2004." Includes bibliographical references (leaves 185-257).

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Thesis (M.Sc.). / Written for the Dept. of Epidemiology, Biostatistics and Occupational Health. Title from title page of PDF (viewed 2008/07/30). Includes bibliographical references.

Thesis (M. Phil.)--University of Hong Kong, 2008. / Includes bibliographical references (leaf 76-77) Also available in print.