Background
Human polymorphic granulocytes can be divided into three distinct types : neutrophils, eosinophils and basophils. While all three play a role in mediating allergic inflammatory activity, neutrophils and eosinophils are phagocytic cells that also play a critical role in host defense against microbial organisms. At the site of infection, the granulocyte participates in the inflammatory reaction by (a) phagocytosis and intracellular killing of bacteria, and (b) production of inflammatory mediators such as chemotactic factors and vasoactive lipid metabolites, as well as release of pre-formed cytotoxic enzymes and proteins. An unfortunate consequence of activation is the ability to cause tissue damage during acute inflammation and thus the activity of granulcoytes must be tightly controlled.
Granulocyte function can be rapidly amplified by environmental factors through a mechanism termed 'PRIMING', which is independent of protein synthesis. For example, traces of bacterial lipopolysaccharide, which itself does not cause activation of the respiratory burst, induces an enhanced superoxide formation upon subsequent stimulation with chemotactic factors such as fMLP. Activation thus refers to processes that lead to a measurable alteration in cells, for example degranulation while priming refers to a process whereby the response of the cells to a subsequent (activating) stimulus is amplified if these cells were previously exposed to a (priming) stimulus. Thus it is the activation 'state' rather than the mere presence of granulocytes in tissues that is important, and dissection of the mechanisms of priming enables elucidation of the pathogenesis of granulocyte mediated tissue injury.
Work in the Dept. of Pulmonary Diseases is based on the premise that antagonism of activation or priming and production of granulocytes will decrease allergic inflammatory symptoms of affected individuals. In particular work is focused on the development of antagonists for cytokine induced eosinophil priming. The recruitment of eosinophils into the airways and their subsequent activation plays an important role in the pathogenesis of allergic asthma. Work in the lab can be subdivided into the following projects :
Characterization
of COPD based on the peripheral neutrophil proteome
Proteomics
analysis of alveolar macrophages in sarcoidosis patients
Mechanisms and
function of granulocyte signal transduction
Inflammation:
The role of the lung and neutrophil margination
Inside-out signalling
of integrins on granulocytes
Mechanisms of granulocyte adhesion
and chemotaxis
