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 |
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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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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.</description><identifier>ISSN: 1087-0571</identifier><identifier>ISSN: 2472-5552</identifier><identifier>EISSN: 1552-454X</identifier><identifier>DOI: 10.1177/1087057113500073</identifier><identifier>PMID: 23983232</identifier><language>eng</language><publisher>Los Angeles, CA: SAGE Publications</publisher><subject>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</subject><ispartof>Journal of biomolecular screening, 2013-12, Vol.18 (10), p.1223-1233</ispartof><rights>2013 Society for Laboratory Automation and Screening</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-b6edfb125974c46fb65d9bd9659d91876a162d7f982b6a07f8a5991631d42b563</citedby><cites>FETCH-LOGICAL-c412t-b6edfb125974c46fb65d9bd9659d91876a162d7f982b6a07f8a5991631d42b563</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23983232$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kaur, Rejbinder</creatorcontrib><creatorcontrib>Sloan, Lisa A.</creatorcontrib><creatorcontrib>Blanchard, Andy D.</creatorcontrib><creatorcontrib>Smith, Janet L.</creatorcontrib><creatorcontrib>Churcher, Ian</creatorcontrib><creatorcontrib>Wayne, Gareth J.</creatorcontrib><creatorcontrib>Ludbrook, Steven B.</creatorcontrib><title>A Phenotypic Screening Approach in Cord Blood–Derived Mast Cells to Identify Anti-Inflammatory Compounds</title><title>Journal of biomolecular screening</title><addtitle>J Biomol Screen</addtitle><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.</description><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>Biological Assay</subject><subject>Cell Degranulation - drug effects</subject><subject>Cells, Cultured</subject><subject>Drug Evaluation, Preclinical - methods</subject><subject>Fetal Blood - cytology</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Mast Cells - drug effects</subject><subject>Mast Cells - metabolism</subject><subject>Phenotype</subject><subject>Prostaglandin D2 - metabolism</subject><subject>Small Molecule Libraries</subject><issn>1087-0571</issn><issn>2472-5552</issn><issn>1552-454X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1O3TAQhS1ExV-776rykk2ox7_x8nJp4UpUrQSVuouc2IFcJXawE6S74x14wz5JjS5lgYTEakaa7xzNnEHoM5ATAKW-AikVEQqACUKIYjvoAISgBRf8z27u87h4mu-jw5TWhACThO-hfcp0ySijB2i9wL9unQ_TZuwafNVE53znb_BiHGMwzS3uPF6GaPFpH4L9-_B45mJ37yz-YdKEl67vE54CXlnnp67d4EUuxcq3vRkGM4W4yephDLO36SP60Jo-uU_P9Qj9_v7tenlRXP48Xy0Xl0XDgU5FLZ1ta6BCK95w2dZSWF1bLYW2GkolDUhqVatLWktDVFsaoTVIBpbTWkh2hI63vvmCu9mlqRq61ORNjXdhThVwyQUpGSPvQEUpiCqBZpRs0SaGlKJrqzF2g4mbCkj19Izq9TOy5Muz-1wPzr4I_qefgWILJHPjqnWYo8_BvG34D3g-kQs</recordid><startdate>201312</startdate><enddate>201312</enddate><creator>Kaur, Rejbinder</creator><creator>Sloan, Lisa A.</creator><creator>Blanchard, Andy D.</creator><creator>Smith, Janet L.</creator><creator>Churcher, Ian</creator><creator>Wayne, Gareth J.</creator><creator>Ludbrook, Steven B.</creator><general>SAGE Publications</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7QO</scope><scope>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope></search><sort><creationdate>201312</creationdate><title>A Phenotypic Screening Approach in Cord Blood–Derived Mast Cells to Identify Anti-Inflammatory Compounds</title><author>Kaur, Rejbinder ; Sloan, Lisa A. ; Blanchard, Andy D. ; Smith, Janet L. ; Churcher, Ian ; Wayne, Gareth J. ; Ludbrook, Steven B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-b6edfb125974c46fb65d9bd9659d91876a162d7f982b6a07f8a5991631d42b563</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Anti-Inflammatory Agents - pharmacology</topic><topic>Biological Assay</topic><topic>Cell Degranulation - drug effects</topic><topic>Cells, Cultured</topic><topic>Drug Evaluation, Preclinical - methods</topic><topic>Fetal Blood - cytology</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>Mast Cells - drug effects</topic><topic>Mast Cells - metabolism</topic><topic>Phenotype</topic><topic>Prostaglandin D2 - metabolism</topic><topic>Small Molecule Libraries</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kaur, Rejbinder</creatorcontrib><creatorcontrib>Sloan, Lisa A.</creatorcontrib><creatorcontrib>Blanchard, Andy D.</creatorcontrib><creatorcontrib>Smith, Janet L.</creatorcontrib><creatorcontrib>Churcher, Ian</creatorcontrib><creatorcontrib>Wayne, Gareth J.</creatorcontrib><creatorcontrib>Ludbrook, Steven B.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Journal of biomolecular screening</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kaur, Rejbinder</au><au>Sloan, Lisa A.</au><au>Blanchard, Andy D.</au><au>Smith, Janet L.</au><au>Churcher, Ian</au><au>Wayne, Gareth J.</au><au>Ludbrook, Steven B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Phenotypic Screening Approach in Cord Blood–Derived Mast Cells to Identify Anti-Inflammatory Compounds</atitle><jtitle>Journal of biomolecular screening</jtitle><addtitle>J Biomol Screen</addtitle><date>2013-12</date><risdate>2013</risdate><volume>18</volume><issue>10</issue><spage>1223</spage><epage>1233</epage><pages>1223-1233</pages><issn>1087-0571</issn><issn>2472-5552</issn><eissn>1552-454X</eissn><abstract>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. 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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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