Corticosteroid insensitivity in airways disease

Abstract

Corticosteroids (CS) are the most widely used and effective anti-inflammatory agents. In severe asthma, despite high doses of CS, patients remain symptomatic, whereas in COPD, CS fail to halt progression of the disease, highlighting the need for alternative anti-inflammatory agents. The hypothesis investigated in this thesis was that inflammation in severe asthma and COPD was less responsive to inhibition by corticosteroids. In COPD, cells of the monocyte-macrophage lineage did not demonstrate corticosteroid insensitivity compared to smoking and non-smoking controls in response to LPS. In response to IFNγ stimulation, CXCL9 release from peripheral blood mononuclear cells (PBMC) from COPD patients was significantly higher than from controls. JAK-STAT inhibitors significantly reduced the secretion of CXCR3 chemokines compared to dexamethasone. PBMC from subjects with severe asthma not on regular prednisolone exhibited corticosteroid insensitivity compared to non-severe asthmatics and severe asthmatics on regular prednisolone in terms of suppression of IL-6 release. There was a very variable response to a 2-week course of prednisolone amongst patients with severe asthma. 5 p38 MAPK inhibitors were tested in alveolar macrophages, monocyte-derived macrophages and PBMC, and they suppressed release of inflammatory cytokines from COPD, severe asthma and controls. Examination of bronchial biopsies revealed that severe asthmatic patients had significantly increased basement membrane thickness and smooth muscle area compared to non-severe asthma. There was a significant negative correlation between airways hyper-responsiveness and the SBM thickness, suggesting that the extracellular matrix may influence airway contractility. Inhibition of the p38 and JAK-STAT pathways had a greater ability to suppress induced cytokine release than dexamethasone in inflammatory cells from COPD and asthma. A 2-week course of prednisolone improved asthma control and quality of life scores in patients with severe asthma. CS use does not prevent airway wall remodelling in severe asthma. Together, these data highlight the need for alternative anti-inflammatory agents.