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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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Autores principales: Weche, McWayne, DeSantis, Anthony J., McGee, Michelle Y., Enten, Garrett A., Gao, Xianlong, Majetschak, Matthias
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10112773/
https://www.ncbi.nlm.nih.gov/pubmed/37071651
http://dx.doi.org/10.1371/journal.pone.0284472
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author Weche, McWayne
DeSantis, Anthony J.
McGee, Michelle Y.
Enten, Garrett A.
Gao, Xianlong
Majetschak, Matthias
author_facet Weche, McWayne
DeSantis, Anthony J.
McGee, Michelle Y.
Enten, Garrett A.
Gao, Xianlong
Majetschak, Matthias
author_sort Weche, McWayne
collection PubMed
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.
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spelling pubmed-101127732023-04-19 Effects of chemokine (C-C motif) receptor 2 and 3 antagonists in rat models of hemorrhagic shock Weche, McWayne DeSantis, Anthony J. McGee, Michelle Y. Enten, Garrett A. Gao, Xianlong Majetschak, Matthias PLoS One Research Article 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. Public Library of Science 2023-04-18 /pmc/articles/PMC10112773/ /pubmed/37071651 http://dx.doi.org/10.1371/journal.pone.0284472 Text en © 2023 Weche et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Weche, McWayne
DeSantis, Anthony J.
McGee, Michelle Y.
Enten, Garrett A.
Gao, Xianlong
Majetschak, Matthias
Effects of chemokine (C-C motif) receptor 2 and 3 antagonists in rat models of hemorrhagic shock
title Effects of chemokine (C-C motif) receptor 2 and 3 antagonists in rat models of hemorrhagic shock
title_full Effects of chemokine (C-C motif) receptor 2 and 3 antagonists in rat models of hemorrhagic shock
title_fullStr Effects of chemokine (C-C motif) receptor 2 and 3 antagonists in rat models of hemorrhagic shock
title_full_unstemmed Effects of chemokine (C-C motif) receptor 2 and 3 antagonists in rat models of hemorrhagic shock
title_short Effects of chemokine (C-C motif) receptor 2 and 3 antagonists in rat models of hemorrhagic shock
title_sort effects of chemokine (c-c motif) receptor 2 and 3 antagonists in rat models of hemorrhagic shock
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10112773/
https://www.ncbi.nlm.nih.gov/pubmed/37071651
http://dx.doi.org/10.1371/journal.pone.0284472
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