The Chemokine (C-C Motif) Receptor 2 Antagonist INCB3284 Reduces Fluid Requirements and Protects From Hemodynamic Decompensation During Resuscitation From Hemorrhagic Shock
OBJECTIVES:. Clinical correlations suggest that systemic chemokine (C-C motif) ligand (CCL) 2 release may contribute to blood pressure regulation and the development of hemodynamic instability during the early inflammatory response to traumatic-hemorrhagic shock. Thus, we investigated whether blocka...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wolters Kluwer
2022-05-01
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| Series: | Critical Care Explorations |
| Online Access: | http://journals.lww.com/10.1097/CCE.0000000000000701 |
| _version_ | 1811332003047407616 |
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| author | Anthony J. DeSantis, MD McWayne Weche, MD Garrett A. Enten, MS Xianlong Gao, MD, PhD Matthias Majetschak, MD, PhD |
| author_facet | Anthony J. DeSantis, MD McWayne Weche, MD Garrett A. Enten, MS Xianlong Gao, MD, PhD Matthias Majetschak, MD, PhD |
| author_sort | Anthony J. DeSantis, MD |
| collection | DOAJ |
| description | OBJECTIVES:. Clinical correlations suggest that systemic chemokine (C-C motif) ligand (CCL) 2 release may contribute to blood pressure regulation and the development of hemodynamic instability during the early inflammatory response to traumatic-hemorrhagic shock. Thus, we investigated whether blockade of the principal CCL2 receptor chemokine (C-C motif) receptor (CCR) 2 affects blood pressure in normal animals, and hemodynamics and resuscitation fluid requirements in hemorrhagic shock models.
DESIGN:. Randomized prospective treatment study.
SETTING:. University laboratory.
SUBJECTS:. Male Sprague-Dawley rats.
INTERVENTIONS:. First, treatment of healthy anesthetized rats with increasing doses of INCB3284 or vehicle. Second, rats were hemorrhaged for 30 minutes, followed by treatment with the CCR2 antagonist INCB3284 (1.1 and 5.5 μmol/kg), the CCR5 antagonist Maraviroc (=control, 5.5 μmol/kg) or vehicle, and subsequent fluid resuscitation to maintain blood pressure until t = 90 minutes. Third, treatment of rats with 5 μmol/kg INCB3284 or vehicle after hemorrhage and fluid resuscitation until t = 300 minutes.
MEASUREMENTS AND MAIN RESULTS:. INCB3284 did not affect intrinsic function of isolated rat resistance arteries in pressure myography experiments. Blood pressure in anesthetized vehicle-treated animals continuously decreased by 0.09 ± 0.01 mm Hg/min (p < 0.001) but remained constant after INCB3284 injections. Systemic concentrations of the CCR2 agonists CCL2, CCL5, and CCL11 increased during hemorrhage and fluid resuscitation. INCB3284 dose-dependently reduced fluid requirements by 58% ± 11% in short-term experiments, whereas Maraviroc and vehicle-treated animals were indistinguishable. When resuscitation was performed until t = 300 minutes, INCB3284 reduced fluid requirements by 62% ± 6%, prevented from hemodynamic decompensation, reduced mortality from 50% with vehicle treatment to zero, and reduced overall tissue wet-weight/dry-weight ratios.
CONCLUSIONS:. Our findings suggest that CCR2 is involved in the regulation of normal cardiovascular function and during the cardiovascular stress response to hemorrhagic shock and fluid resuscitation. The present study identifies CCR2 as a drug target to reduce fluid requirements and to prevent death from hemodynamic decompensation during resuscitation from hemorrhagic shock. |
| first_indexed | 2024-04-13T16:29:26Z |
| format | Article |
| id | doaj.art-112e5460702a4fdf96f1b6d272f7f10b |
| institution | Directory Open Access Journal |
| issn | 2639-8028 |
| language | English |
| last_indexed | 2024-04-13T16:29:26Z |
| publishDate | 2022-05-01 |
| publisher | Wolters Kluwer |
| record_format | Article |
| series | Critical Care Explorations |
| spelling | doaj.art-112e5460702a4fdf96f1b6d272f7f10b2022-12-22T02:39:37ZengWolters KluwerCritical Care Explorations2639-80282022-05-0145e070110.1097/CCE.0000000000000701202205000-00021The Chemokine (C-C Motif) Receptor 2 Antagonist INCB3284 Reduces Fluid Requirements and Protects From Hemodynamic Decompensation During Resuscitation From Hemorrhagic ShockAnthony J. DeSantis, MD0McWayne Weche, MD1Garrett A. Enten, MS2Xianlong Gao, MD, PhD3Matthias Majetschak, MD, PhD41 Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL.1 Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL.1 Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL.1 Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL.1 Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL.OBJECTIVES:. Clinical correlations suggest that systemic chemokine (C-C motif) ligand (CCL) 2 release may contribute to blood pressure regulation and the development of hemodynamic instability during the early inflammatory response to traumatic-hemorrhagic shock. Thus, we investigated whether blockade of the principal CCL2 receptor chemokine (C-C motif) receptor (CCR) 2 affects blood pressure in normal animals, and hemodynamics and resuscitation fluid requirements in hemorrhagic shock models. DESIGN:. Randomized prospective treatment study. SETTING:. University laboratory. SUBJECTS:. Male Sprague-Dawley rats. INTERVENTIONS:. First, treatment of healthy anesthetized rats with increasing doses of INCB3284 or vehicle. Second, rats were hemorrhaged for 30 minutes, followed by treatment with the CCR2 antagonist INCB3284 (1.1 and 5.5 μmol/kg), the CCR5 antagonist Maraviroc (=control, 5.5 μmol/kg) or vehicle, and subsequent fluid resuscitation to maintain blood pressure until t = 90 minutes. Third, treatment of rats with 5 μmol/kg INCB3284 or vehicle after hemorrhage and fluid resuscitation until t = 300 minutes. MEASUREMENTS AND MAIN RESULTS:. INCB3284 did not affect intrinsic function of isolated rat resistance arteries in pressure myography experiments. Blood pressure in anesthetized vehicle-treated animals continuously decreased by 0.09 ± 0.01 mm Hg/min (p < 0.001) but remained constant after INCB3284 injections. Systemic concentrations of the CCR2 agonists CCL2, CCL5, and CCL11 increased during hemorrhage and fluid resuscitation. INCB3284 dose-dependently reduced fluid requirements by 58% ± 11% in short-term experiments, whereas Maraviroc and vehicle-treated animals were indistinguishable. When resuscitation was performed until t = 300 minutes, INCB3284 reduced fluid requirements by 62% ± 6%, prevented from hemodynamic decompensation, reduced mortality from 50% with vehicle treatment to zero, and reduced overall tissue wet-weight/dry-weight ratios. CONCLUSIONS:. Our findings suggest that CCR2 is involved in the regulation of normal cardiovascular function and during the cardiovascular stress response to hemorrhagic shock and fluid resuscitation. The present study identifies CCR2 as a drug target to reduce fluid requirements and to prevent death from hemodynamic decompensation during resuscitation from hemorrhagic shock.http://journals.lww.com/10.1097/CCE.0000000000000701 |
| spellingShingle | Anthony J. DeSantis, MD McWayne Weche, MD Garrett A. Enten, MS Xianlong Gao, MD, PhD Matthias Majetschak, MD, PhD The Chemokine (C-C Motif) Receptor 2 Antagonist INCB3284 Reduces Fluid Requirements and Protects From Hemodynamic Decompensation During Resuscitation From Hemorrhagic Shock Critical Care Explorations |
| title | The Chemokine (C-C Motif) Receptor 2 Antagonist INCB3284 Reduces Fluid Requirements and Protects From Hemodynamic Decompensation During Resuscitation From Hemorrhagic Shock |
| title_full | The Chemokine (C-C Motif) Receptor 2 Antagonist INCB3284 Reduces Fluid Requirements and Protects From Hemodynamic Decompensation During Resuscitation From Hemorrhagic Shock |
| title_fullStr | The Chemokine (C-C Motif) Receptor 2 Antagonist INCB3284 Reduces Fluid Requirements and Protects From Hemodynamic Decompensation During Resuscitation From Hemorrhagic Shock |
| title_full_unstemmed | The Chemokine (C-C Motif) Receptor 2 Antagonist INCB3284 Reduces Fluid Requirements and Protects From Hemodynamic Decompensation During Resuscitation From Hemorrhagic Shock |
| title_short | The Chemokine (C-C Motif) Receptor 2 Antagonist INCB3284 Reduces Fluid Requirements and Protects From Hemodynamic Decompensation During Resuscitation From Hemorrhagic Shock |
| title_sort | chemokine c c motif receptor 2 antagonist incb3284 reduces fluid requirements and protects from hemodynamic decompensation during resuscitation from hemorrhagic shock |
| url | http://journals.lww.com/10.1097/CCE.0000000000000701 |
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