Trends in Pharmacological Sciences
Leukocyte and endothelial cell adhesion molecules as targets for therapeutic interventions in inflammatory disease
Section snippets
Leukocyte recruitment
The recruitment of leukocytes from circulating blood is crucial in the inflammatory reaction. It occurs through a multistep process in which leukocytes interact with the endothelium in postcapillary venules. This process involves sequential capture on, rolling along and firm adhesion to the microvascular endothelium, followed by transmigration through the vessel wall and further migration in extravascular tissue (Figure 1) [3]. All the steps in the recruitment cascade are orchestrated by
Selectins and selectin ligands
The selectin family of CAMs consists of three members which all mediate rolling of leukocytes along the endothelium (Figure 1) 6, 7. P-selectin is stored in granules in endothelial cells and platelets and translocates rapidly to the cell surface in response to several inflammatory stimuli. E-selectin is present exclusively in endothelial cells and its expression is regulated by increased transcription after stimulation by inflammatory cytokines such as tumor necrosis factor α (TNF-α and
Therapeutic targeting of CAMs
The function of inflammatory CAMs can be modulated by several mechanisms, including competitive blockade, altered expression on the cell surface and, for integrins, interference with receptor activation. The ultimate therapeutic goal of each is to break the path of the multistep recruitment cascade. There are several groups of pharmaceutical agents in use clinically that interfere with the function of CAMs either directly or indirectly. For example, inhibiting either IL-1β or TNF-α using
Clinical inhibition of CAMs – failure or success
Blocking CAMs that mediate the accumulation of leukocytes in inflammation is thought to be an effective treatment strategy in clinical inflammatory disorders. However, despite promising preclinical results, the outcome of clinical trials has been inconsistent. With the exception of some positive effects in psoriasis and asthma, preventing activity of either the selectins or the common β2 integrin CD18 has had limited effects, especially in the treatment of ischemia–reperfusion injuries [41].
Concluding remarks
Leukocyte adhesion to the endothelial lining and recruitment to extravascular tissue is a fundamental event in the host defense against foreign and noxious stimuli. It is also pivotal in the pathogenesis of inflammatory diseases and, thus, is a focus for therapeutic intervention. The CAMs involved in leukocyte trafficking constitute excellent targets for pharmacological modulation of the cellular response in inflammation. Given the strong data in animal models, CAM inhibition is expected to
Acknowledgements
Our work is supported by the Swedish Research Council, the Swedish Heart-Lung Foundation, the Vardal Foundation, the AFA Health Fund and the Swedish Society of Medicine. H.U. is recipient of a post-doctoral fellowship from Deutsche Forschungsgemeinschaft (UL-199/1).
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