Systemic inflammatory responses in asthma

Abstract

In asthma, inflammatory cells undergo a process referred to as priming. During priming responses, cells are not directly activated by inflammatory stimuli, but acquire increased responsiveness towards heterologous stimuli. The focus of the studies presented in the thesis of Willem ten Hove was directed towards the regulation and outcome of priming of leukocytes: granulocytes and monocytes in several phenotypes of asthmatics. As treatment of inflammatory processes in asthmatics is predominantly based on inhibition by corticosteroids, the effects of steroids were studied on several effector functions of granulocytes. To understand the regulation of priming and activation in granulocytes, components of intracellular signalling pathways were studied. In this thesis in vivo priming was measured by determination of cellular expression profiles of priming associated epitopes on leukocytes or via gene expression analysis. Using priming of leukocytes in vivo as readout for inflammatory processes in pulmonary tissue, it was confirmed that (mild) asthmatics with well-controlled disease patterns were characterized by a phenotype with clear systemic inflammatory responses that involved primed eosinophils, subtle primed neutrophils and unprimed monocytes in peripheral blood. Poorly-controlled asthmatics, which were relatively difficult-to-treat, were characterized by primed neutrophils and monocytes. From these patient-data it was concluded that determination of priming of leukocytes is a biomarker, which has a high potential in the characterization of asthma phenotypes. To further characterize the cellular mechanisms and effects that are responsive to the inflammation induced priming of granulocytes the granulocyte responses to anti-inflammatory corticosteroids were evaluated. The focus was directed to processes involved in eosinophil recruitment to inflammatory sites, which include eosinophil adhesion and migration. Interestingly, steroids inhibited both responses of eosinophils, provided that the experiments were performed in the presence of priming cytokines. These data are consistent with a model that eosinophils in vivo are only inhibited by steroids after priming by inflammatory mediators. Potential rapid (non-genomic) effects of steroids on several functional responses of eosinophils were also investigated. Incubation of eosinophils with steroid dexamethasone (Dex) for 15 min resulted in a clear functional upregulation of the immunoglobulin (Ig)A receptor (FcαR). It seems likely that this Dex-induced selective priming of FcαR has an important impact on the control of eosinophils in asthma, because both eosinophils and IgA are abundantly present at mucosal surfaces and IgA is an important secretagogue of these immune cells. After the identification of steroid-induced priming of FcαR, the underlying 'inside-out' signals have been investigated. These investigations showed that steroid-induced FcαR activation was regulated via the glucocorticoid receptor. Further characterisation of this 'inside-out' signalling showed a central role for kinase P38 MAPK in the signal transduction towards the functionality of FcαR. Studies performed in this thesis have provided evidence for distinct systemic responses of leukocytes in different phenotypes of asthma and gave more insight in the regulation of leukocyte priming and the effects of steroids on leukocyte functions. The characterization of asthma phenotypes and their underlying priming responses might help the development of useful and more tailor-made pharmacotherapy for the different asthma phenotypes