A Phenotypic Screening Approach in Cord Blood–Derived Mast Cells to Identify Anti-Inflammatory Compounds

Mast cells are unique hematopoietic cells that are richly distributed in the skin and mucosal surfaces of the respiratory and gastrointestinal tract. They play a key role in allergic inflammation by releasing a cocktail of granular constituents, including histamine, serine proteases, and various eic...

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Veröffentlicht in:Journal of biomolecular screening 2013-12, Vol.18 (10), p.1223-1233
Hauptverfasser: Kaur, Rejbinder, Sloan, Lisa A., Blanchard, Andy D., Smith, Janet L., Churcher, Ian, Wayne, Gareth J., Ludbrook, Steven B.
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container_end_page 1233
container_issue 10
container_start_page 1223
container_title Journal of biomolecular screening
container_volume 18
creator Kaur, Rejbinder
Sloan, Lisa A.
Blanchard, Andy D.
Smith, Janet L.
Churcher, Ian
Wayne, Gareth J.
Ludbrook, Steven B.
description Mast cells are unique hematopoietic cells that are richly distributed in the skin and mucosal surfaces of the respiratory and gastrointestinal tract. They play a key role in allergic inflammation by releasing a cocktail of granular constituents, including histamine, serine proteases, and various eicosanoids and cytokines. As such, a number of drugs target either inhibition of mast cell degranulation or the products of degranulation. To identify potential novel drugs and mechanisms in mast cell biology, assays were developed to identify inhibitors of mast cell degranulation and activation in a phenotypic screen. Due to the challenges associated with obtaining primary mast cells, cord blood–derived mononuclear cells were reproducibly differentiated to mast cells and assays developed to monitor tryptase release and prostaglandin D2 generation. The tryptase assay was particularly sensitive, requiring only 500 cells per data point, which permitted a set of approximately 12,000 compounds to be screened robustly and cost-effectively. Active compounds were tested for concomitant inhibition of prostaglandin D2 generation. This study demonstrates the robustness and effectiveness of this approach in the identification of potential novel compounds and mechanisms targeting mast cell–driven inflammation, to enable innovative drug discovery efforts to be prosecuted.
doi_str_mv 10.1177/1087057113500073
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subjects Anti-Inflammatory Agents - pharmacology
Biological Assay
Cell Degranulation - drug effects
Cells, Cultured
Drug Evaluation, Preclinical - methods
Fetal Blood - cytology
Humans
Inhibitory Concentration 50
Mast Cells - drug effects
Mast Cells - metabolism
Phenotype
Prostaglandin D2 - metabolism
Small Molecule Libraries
title A Phenotypic Screening Approach in Cord Blood–Derived Mast Cells to Identify Anti-Inflammatory Compounds
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