Pharmacological targeting of chemokine (C-X-C motif) receptor 4 in porcine polytrauma and hemorrhage models

Abstract

BACKGROUND Recent evidence suggests that chemokine receptor CXCR4 regulates vascular α1-adrenergic receptor function and that the noncognate CXCR4 agonist ubiquitin has therapeutic potential after trauma/hemorrhage. Pharmacologic properties of ubiquitin in large animal trauma models, however, are poorly characterized. Thus, the aims of the present study were to determine the effects of CXCR4 modulation on resuscitation requirements after polytrauma, to assess whether ubiquitin influences survival times after lethal polytrauma-hemorrhage, and to characterize its dose-effect profile in porcine models. METHODS Anesthetized pigs underwent polytrauma (PT, femur fractures/lung contusion) alone (Series 1) or PT/hemorrhage (PT/H) to a mean arterial blood pressure of 30 mmHg with subsequent fluid resuscitation (Series 2 and 3) or 40% blood volume hemorrhage within 15 minutes followed by 2.5% blood volume hemorrhage every 15 minutes without fluid resuscitation (Series 4). In Series 1, ubiquitin (175 and 350 nmol/kg), AMD3100 (CXCR4 antagonist, 350 nmol/kg), or vehicle treatment 60 minutes after PT was performed. In Series 2, ubiquitin (175, 875, and 1,750 nmol/kg) or vehicle treatment 60 minutes after PT/H was performed. In Series 3, ubiquitin (175 and 875 nmol/kg) or vehicle treatment at 60 and 180 minutes after PT/H was performed. In Series 4, ubiquitin (875 nmol/kg) or vehicle treatment 30 minutes after hemorrhage was performed. RESULTS In Series 1, resuscitation fluid requirements were significantly reduced by 40% with 350-nmol/kg ubiquitin and increased by 25% with AMD3100. In Series 2, median survival time was 190 minutes with vehicle, 260 minutes with 175-nmol/kg ubiquitin, and longer than 420 minutes with 875-nmol/kg and 1,750-nmol/kg ubiquitin (p < 0.05 vs. vehicle). In Series 3, median survival time was 288 minutes with vehicle and 336 minutes and longer than 420 minutes (p < 0.05 vs. vehicle) with 175-nmol/kg and 875-nmol/kg ubiquitin, respectively. In Series 4, median survival time was 147.5 minutes and 150 minutes with vehicle and ubiquitin, respectively (p > 0.05). CONCLUSION These findings further suggest CXCR4 as a drug target after PT/H. Ubiquitin treatment reduces resuscitation fluid requirements and provides survival benefits after PT/H. The pharmacological effects of ubiquitin treatment occur dose dependently.

Pharmacological modulation of C‐X‐C motif chemokine receptor 4 influences development of acute respiratory distress syndrome after lung ischaemia–reperfusion injury

“…In combination with the observation of increased histological lung injury with AMD3100 treatment, these findings imply that endogenous CXCR4 mediates lung protective effects in the pathophysiology of ARDS. Furthermore, our finding that AMD3100 treatment promotes ARDS development is in agreement with previous reports that CXCR4 blockade increases mortality and tissue injury in models of endotoxemia and polymicrobial sepsis, and that administration of AMD3100 impairs hemodynamic stability in models of traumatic‐haemorrhagic shock . Collectively, these data indicate that endogenous CXCR4 plays important roles in infectious and non‐infectious inflammation, and provides tissue/organ protection, including lung protection.…”

“…Protective and therapeutically relevant effects of natural and synthetic CXCR4 agonists have been reported in multiple previous pre‐clinical studies, including animal models of endotoxemia, sepsis, ischaemia–reperfusion injury, trauma and haemorrhagic shock . The findings of the present study confirm that CXCR4 agonists have therapeutic potential, demonstrate that administration of the non‐cognate CXCR4 agonist ubiquitin delays and attenuates development of ARDS after lung ischaemia–reperfusion injury and provide initial information on its dose‐effect profile.…”

“…Protective and therapeutically relevant effects of natural and synthetic CXCR4 agonists have been reported in multiple previous pre-clinical studies, including animal models of endotoxemia, sepsis, ischaemia-reperfusion injury, trauma and haemorrhagic shock. [23][24][25][26][27][32][33][34][38][39][40][41][42][43][44] The findings of the present study confirm that CXCR4 agonists have therapeutic potential, demonstrate that administration of the non-cognate CXCR4 agonist ubiquitin delays and attenuates development of ARDS after lung ischaemia-reperfusion injury and provide initial information on its dose-effect profile. This assumption is supported by previous observations suggesting enhanced pro-inflammatory responses after pharmacological CXCR4 blockade and enhanced anti-inflammatory responses following CXCR4 activation.…”

“…Furthermore, our finding that AMD3100 treatment promotes ARDS development is in agreement with previous reports that CXCR4 blockade increases mortality and tissue injury in models of endotoxemia and polymicrobial sepsis, and that administration of AMD3100 impairs hemodynamic stability in models of traumatic-haemorrhagic shock. [31][32][33][34][35][36] Collectively, these data indicate that endogenous CXCR4 plays important roles in infectious and non-infectious inflammation, and provides tissue/ organ protection, including lung protection. The observation that leukocyte counts at the end of the observation period were significantly higher with AMD3100 treatment, as compared with vehicle treatment, is in line with its known pharmacological properties.…”

“…Animals received vehicle (0.5 mL NS, n = 6), 0.7 μmol/kg ubiquitin (n = 6) or 3.5 μmol/kg ubiquitin (n = 5) intra‐arterially within 5 minutes of reperfusion following a 60 minute period of ischaemia. Dosing of AMD3100 and ubiquitin was selected based on our previous studies in other animal models …”