Leukocyte and endothelial cell adhesion molecules as targets for therapeutic interventions in inflammatory disease

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Abstract

Inflammation is a fundamental response to tissue injury and invasion of pathogens, but it is detrimental in clinically important inflammatory disorders. Leukocytes are key players in the inflammatory response because of their antimicrobial, secretory and phagocytic activities. They are recruited to the inflamed tissue by sequential adhesive interactions between leukocytes and the endothelium that are mediated by cell-adhesion molecules (CAMs) on the surface of the interacting cells. The effects of many anti-inflammatory drugs can be ascribed, in part, to inhibition of the expression of CAMs. However, in the search for more selective and potent drugs for clinically important diseases such as multiple sclerosis, asthma, rheumatoid arthritis, inflammatory bowel disease, allergies and atherosclerosis, direct inhibition of the function of CAMs has attracted increasing interest. In recent years, the development of synthetic antagonists has provided better opportunities for drug targeting. Future advances in this field hold new prospects for therapeutic intervention in human inflammatory disorders.

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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