Adenosine A 2A receptor agonists may be important regulators of inflammation. Such conclusions have come from studies demonstrating that, (i) adenosine A 2A agonists exhibit anti-inflammatory properties in vitro and in vivo, (ii) selective A 2A antagonists enhance inflammation in vivo and, (iii) knock outs of this receptor aggravate inflammation in a wide variety of in vivo models. Inflammation is a hallmark of asthma and COPD and adenosine has long been suggested to be involved in disease pathology. Two recent publications, however, suggested that an inhaled adenosine A 2A receptor agonist (GW328267X) did not affect either the early and late asthmatic response or symptoms associated with allergic rhinitis suggesting that the rationale for treating inflammation with an adenosine A 2A receptor agonist may be incorrect. A barrier to fully investigating the role of adenosine A 2A receptor agonists as anti-inflammatory agents in the lung is the side effect profile due to systemic exposure, even with inhalation. Unless strategies can be evolved to limit the systemic exposure of inhaled adenosine A 2A receptor agonists, the promise of treating lung inflammation with such agents may never be fully explored. Using strategies similar to that devised to improve the therapeutic index of inhaled corticosteroids, UK371,104 was identified as a selective agonist of the adenosine A 2A receptor that has a lung focus of pharmacological activity following delivery to the lung in a pre clinical in vivo model of lung function. Lung-focussed agents such as UK371,104 may be suitable for assessing the anti-inflammatory potential of inhaled adenosine A 2A receptor agonists.
Image-based screening, a new and flexible tool in the drug discovery cascade, is amenable to many different targets. This article describes a particular use of the Cellomics ArrayScan in developing a functional screen for histamine H 4 receptor (H 4 R) antagonists that have potential utility in inflammatory diseases of the airways such as asthma, with H 4 R being expressed on a wide variety of immune cells including eosinophils. Exposure to histamine causes eosinophils to migrate from the bloodstream into the tissue where they contribute to inflammation. Migration is manifested through rearrangements of the actin cytoskeleton and phalloidin, a biological peptide, selectively binds F-actin over G-actin and can be used to detect these cytoskeletal changes mediating inflammatory function. A fluorescent conjugate of phalloidin was used to visualize histamine-induced actin polymerization in human eosinophils on the Cellomics ArrayScan. Inhibition of this phenomenon by commercially available histamine receptor antagonists was measured. The selective H 4 R antagonist JNJ7777120 inhibited histamine-induced actin polymerization in eosinophils most potently. This assay illustrates that this phenomenon is mediated through the H 4 R and that the image-based format has enhanced screening utility for identifying selective H 4 R antagonists over traditional flow cytometry methods. ' 2007 International Society for Analytical Cytology
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