Effects of chemokine (C-C motif) receptor 2 and 3 antagonists in rat models of hemorrhagic shock
Systemic concentrations of chemokine CCL2, an agonist at chemokine receptors CCR2/3/5, have been associated with hemodynamic instability after traumatic-hemorrhagic shock. We reported previously that the CCR2 antagonist INCB3284 prevents cardiovascular collapse and reduces fluid requirements after 3...
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| description | Systemic concentrations of chemokine CCL2, an agonist at chemokine receptors CCR2/3/5, have been associated with hemodynamic instability after traumatic-hemorrhagic shock. We reported previously that the CCR2 antagonist INCB3284 prevents cardiovascular collapse and reduces fluid requirements after 30min of hemorrhagic shock (HS), whereas the CCR5 antagonist Maraviroc was ineffective. The effects of CCR3 blockade after HS are unknown and information on the therapeutic potential of INCB3284 after longer periods of HS and in HS models in the absence of fluid resuscitation (FR) is lacking. The aims of the present study were to assess the effects of CCR3 blockade with SB328437 and to further define the therapeutic efficacy of INCB3284. In series 1-3, Sprague-Dawley rats were hemorrhaged to a mean arterial blood pressure (MAP) of 30mmHg, followed by FR to MAP of 60mmHg or systolic blood pressure of 90mmHg. Series 1: 30min HS and FR until t = 90min. SB328437 at t = 30min dose-dependently reduced fluid requirements by >60%. Series 2: 60min HS and FR until t = 300min. INCB3284 and SB328437 at t = 60min reduced fluid requirements by more than 65% (p0.05 vs. vehicle), respectively, until t = 220min. Thereafter, all animals developed a steep increase in fluid requirements. Median survival time was 290min with SB328437 and >300min after vehicle and INCB3284 treatment (p |
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We reported previously that the CCR2 antagonist INCB3284 prevents cardiovascular collapse and reduces fluid requirements after 30min of hemorrhagic shock (HS), whereas the CCR5 antagonist Maraviroc was ineffective. The effects of CCR3 blockade after HS are unknown and information on the therapeutic potential of INCB3284 after longer periods of HS and in HS models in the absence of fluid resuscitation (FR) is lacking. The aims of the present study were to assess the effects of CCR3 blockade with SB328437 and to further define the therapeutic efficacy of INCB3284. In series 1-3, Sprague-Dawley rats were hemorrhaged to a mean arterial blood pressure (MAP) of 30mmHg, followed by FR to MAP of 60mmHg or systolic blood pressure of 90mmHg. Series 1: 30min HS and FR until t = 90min. SB328437 at t = 30min dose-dependently reduced fluid requirements by >60%. Series 2: 60min HS and FR until t = 300min. INCB3284 and SB328437 at t = 60min reduced fluid requirements by more than 65% (p<0.05 vs. vehicle) and 25% (p>0.05 vs. vehicle), respectively, until t = 220min. Thereafter, all animals developed a steep increase in fluid requirements. Median survival time was 290min with SB328437 and >300min after vehicle and INCB3284 treatment (p<0.05). Series 3: HS/FR as in series 2. INCB3284 at t = 60min and t = 200min reduced fluid requirements by 75% until t = 300min (p<0.05 vs. vehicle). Mortality was 70% with vehicle and zero with INCB3284 treatment (p<0.05). Series 4: INCB3284 and SB328437 did not affect survival time in a lethal HS model without FR. Our findings further support the assumption that blockade of the major CCL2 receptor CCR2 is a promising approach to improve FR after HS and document that the dosing of INCB3284 can be optimized.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0284472</identifier><identifier>PMID: 37071651</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animal models ; Animals ; Benzamides ; Biology and Life Sciences ; Blood pressure ; Care and treatment ; Catheters ; CC chemokine receptors ; CCR2 protein ; CCR5 protein ; Chemokine receptors ; Chemokines ; Disease Models, Animal ; Dosage ; Drug dosages ; Experiments ; Gases ; Health aspects ; Hemodynamics ; Hemorrhage ; Hemorrhage - complications ; Hemorrhagic shock ; Laboratory animals ; Medicine and Health Sciences ; Monocyte chemoattractant protein 1 ; Patient outcomes ; Pneumothorax ; Rats ; Rats, Sprague-Dawley ; Receptors, CCR ; Resuscitation ; Shock, Hemorrhagic ; Survival ; Variance analysis</subject><ispartof>PloS one, 2023-04, Vol.18 (4), p.e0284472-e0284472</ispartof><rights>Copyright: © 2023 Weche et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>COPYRIGHT 2023 Public Library of Science</rights><rights>2023 Weche et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2023 Weche et al 2023 Weche et al</rights><rights>2023 Weche et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c543t-daaca376048b6593a3ba593f572f8d762cd3238704e561828efe3f6e1c6ab31b3</cites><orcidid>0000-0002-9012-0246 ; 0000-0002-4086-0887</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10112773/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10112773/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23847,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37071651$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Raju, Raghavan</contributor><creatorcontrib>Weche, McWayne</creatorcontrib><creatorcontrib>DeSantis, Anthony J</creatorcontrib><creatorcontrib>McGee, Michelle Y</creatorcontrib><creatorcontrib>Enten, Garrett A</creatorcontrib><creatorcontrib>Gao, Xianlong</creatorcontrib><creatorcontrib>Majetschak, Matthias</creatorcontrib><title>Effects of chemokine (C-C motif) receptor 2 and 3 antagonists in rat models of hemorrhagic shock</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Systemic concentrations of chemokine CCL2, an agonist at chemokine receptors CCR2/3/5, have been associated with hemodynamic instability after traumatic-hemorrhagic shock. We reported previously that the CCR2 antagonist INCB3284 prevents cardiovascular collapse and reduces fluid requirements after 30min of hemorrhagic shock (HS), whereas the CCR5 antagonist Maraviroc was ineffective. The effects of CCR3 blockade after HS are unknown and information on the therapeutic potential of INCB3284 after longer periods of HS and in HS models in the absence of fluid resuscitation (FR) is lacking. The aims of the present study were to assess the effects of CCR3 blockade with SB328437 and to further define the therapeutic efficacy of INCB3284. In series 1-3, Sprague-Dawley rats were hemorrhaged to a mean arterial blood pressure (MAP) of 30mmHg, followed by FR to MAP of 60mmHg or systolic blood pressure of 90mmHg. Series 1: 30min HS and FR until t = 90min. SB328437 at t = 30min dose-dependently reduced fluid requirements by >60%. Series 2: 60min HS and FR until t = 300min. INCB3284 and SB328437 at t = 60min reduced fluid requirements by more than 65% (p<0.05 vs. vehicle) and 25% (p>0.05 vs. vehicle), respectively, until t = 220min. Thereafter, all animals developed a steep increase in fluid requirements. Median survival time was 290min with SB328437 and >300min after vehicle and INCB3284 treatment (p<0.05). Series 3: HS/FR as in series 2. INCB3284 at t = 60min and t = 200min reduced fluid requirements by 75% until t = 300min (p<0.05 vs. vehicle). Mortality was 70% with vehicle and zero with INCB3284 treatment (p<0.05). Series 4: INCB3284 and SB328437 did not affect survival time in a lethal HS model without FR. Our findings further support the assumption that blockade of the major CCL2 receptor CCR2 is a promising approach to improve FR after HS and document that the dosing of INCB3284 can be optimized.</description><subject>Animal models</subject><subject>Animals</subject><subject>Benzamides</subject><subject>Biology and Life Sciences</subject><subject>Blood pressure</subject><subject>Care and treatment</subject><subject>Catheters</subject><subject>CC chemokine receptors</subject><subject>CCR2 protein</subject><subject>CCR5 protein</subject><subject>Chemokine receptors</subject><subject>Chemokines</subject><subject>Disease Models, Animal</subject><subject>Dosage</subject><subject>Drug dosages</subject><subject>Experiments</subject><subject>Gases</subject><subject>Health aspects</subject><subject>Hemodynamics</subject><subject>Hemorrhage</subject><subject>Hemorrhage - complications</subject><subject>Hemorrhagic shock</subject><subject>Laboratory animals</subject><subject>Medicine and Health 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of chemokine (C-C motif) receptor 2 and 3 antagonists in rat models of hemorrhagic shock</title><author>Weche, McWayne ; DeSantis, Anthony J ; McGee, Michelle Y ; Enten, Garrett A ; Gao, Xianlong ; Majetschak, Matthias</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c543t-daaca376048b6593a3ba593f572f8d762cd3238704e561828efe3f6e1c6ab31b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Benzamides</topic><topic>Biology and Life Sciences</topic><topic>Blood pressure</topic><topic>Care and treatment</topic><topic>Catheters</topic><topic>CC chemokine receptors</topic><topic>CCR2 protein</topic><topic>CCR5 protein</topic><topic>Chemokine receptors</topic><topic>Chemokines</topic><topic>Disease Models, Animal</topic><topic>Dosage</topic><topic>Drug dosages</topic><topic>Experiments</topic><topic>Gases</topic><topic>Health 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One</addtitle><date>2023-04-18</date><risdate>2023</risdate><volume>18</volume><issue>4</issue><spage>e0284472</spage><epage>e0284472</epage><pages>e0284472-e0284472</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Systemic concentrations of chemokine CCL2, an agonist at chemokine receptors CCR2/3/5, have been associated with hemodynamic instability after traumatic-hemorrhagic shock. We reported previously that the CCR2 antagonist INCB3284 prevents cardiovascular collapse and reduces fluid requirements after 30min of hemorrhagic shock (HS), whereas the CCR5 antagonist Maraviroc was ineffective. The effects of CCR3 blockade after HS are unknown and information on the therapeutic potential of INCB3284 after longer periods of HS and in HS models in the absence of fluid resuscitation (FR) is lacking. The aims of the present study were to assess the effects of CCR3 blockade with SB328437 and to further define the therapeutic efficacy of INCB3284. In series 1-3, Sprague-Dawley rats were hemorrhaged to a mean arterial blood pressure (MAP) of 30mmHg, followed by FR to MAP of 60mmHg or systolic blood pressure of 90mmHg. Series 1: 30min HS and FR until t = 90min. SB328437 at t = 30min dose-dependently reduced fluid requirements by >60%. Series 2: 60min HS and FR until t = 300min. INCB3284 and SB328437 at t = 60min reduced fluid requirements by more than 65% (p<0.05 vs. vehicle) and 25% (p>0.05 vs. vehicle), respectively, until t = 220min. Thereafter, all animals developed a steep increase in fluid requirements. Median survival time was 290min with SB328437 and >300min after vehicle and INCB3284 treatment (p<0.05). Series 3: HS/FR as in series 2. INCB3284 at t = 60min and t = 200min reduced fluid requirements by 75% until t = 300min (p<0.05 vs. vehicle). Mortality was 70% with vehicle and zero with INCB3284 treatment (p<0.05). Series 4: INCB3284 and SB328437 did not affect survival time in a lethal HS model without FR. Our findings further support the assumption that blockade of the major CCL2 receptor CCR2 is a promising approach to improve FR after HS and document that the dosing of INCB3284 can be optimized.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>37071651</pmid><doi>10.1371/journal.pone.0284472</doi><orcidid>https://orcid.org/0000-0002-9012-0246</orcidid><orcidid>https://orcid.org/0000-0002-4086-0887</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2023-04, Vol.18 (4), p.e0284472-e0284472 |
| issn | 1932-6203 1932-6203 |
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| subjects | Animal models Animals Benzamides Biology and Life Sciences Blood pressure Care and treatment Catheters CC chemokine receptors CCR2 protein CCR5 protein Chemokine receptors Chemokines Disease Models, Animal Dosage Drug dosages Experiments Gases Health aspects Hemodynamics Hemorrhage Hemorrhage - complications Hemorrhagic shock Laboratory animals Medicine and Health Sciences Monocyte chemoattractant protein 1 Patient outcomes Pneumothorax Rats Rats, Sprague-Dawley Receptors, CCR Resuscitation Shock, Hemorrhagic Survival Variance analysis |
| title | Effects of chemokine (C-C motif) receptor 2 and 3 antagonists in rat models of hemorrhagic shock |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T05%3A07%3A06IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Effects%20of%20chemokine%20(C-C%20motif)%20receptor%202%20and%203%20antagonists%20in%20rat%20models%20of%20hemorrhagic%20shock&rft.jtitle=PloS%20one&rft.au=Weche,%20McWayne&rft.date=2023-04-18&rft.volume=18&rft.issue=4&rft.spage=e0284472&rft.epage=e0284472&rft.pages=e0284472-e0284472&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0284472&rft_dat=%3Cgale_plos_%3EA746079757%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2802842672&rft_id=info:pmid/37071651&rft_galeid=A746079757&rft_doaj_id=oai_doaj_org_article_07d89c8c650f447ba74b500f85856555&rfr_iscdi=true |