Tools for anti-inflammatory drug design: in vitro models of leukocyte migration.

ABSTRACT

Inhibiting leukocyte recruitment is now a major focus in the design of novel anti-inflammatory drugs. Following the identification of lead compounds from conventional high-throughput screens using appropriate receptors or enzymes, it is important to validate the action of the compounds in a suitable in vitro model of leukocyte migration. Here, we review a range of different experimental approaches to modelling leukocyte migration, and identify the multi-well filter migration assay as the best compromise between the amount of resources required to screen multiple compounds and the amount of information gained about the effects of the compounds on cell movement behavior. However, there are pitfalls in the interpretation of data obtained using the multi-well filter migration assay, which arise from the imperfect correlation between the number of cells undergoing migration and the inhibitory activity of the test substances. We examine a number of such pitfalls and provide practical approaches to mitigate these problems as far as possible. We recommend a general strategy for screening inhibitors of cell migration using in vitro functional assays. While being more resource intensive than surrogate measures such as calcium flux, functional approaches nevertheless provide superior correlations with anti-inflammatory activity in vivo.