Objective: The aim of this study was to investigate (a) the potential of the Bruton's tyrosine kinase (BTK) inhibitors acalabrutinib and fenebrutinib to reduce multiple organ dysfunction syndrome (MODS) in acute (short-term and long-term follow-up) hemorrhagic shock (HS) rat models and (b) whether treatment with either acalabrutinib or fenebrutinib attenuates BTK, NF-κB and NLRP3 activation in HS. Background: The MODS caused by an excessive systemic inflammatory response following trauma is associated with a high morbidity and mortality. The protein BTK is known to play a role in the activation of the NLRP3 inflammasome, which is a key component of the innate inflammatory response. However, its role in trauma-hemorrhage is unknown. Methods: Acute HS rat models were performed to determine the influence of acalabrutinib or fenebrutinib on MODS. The activation of BTK, NF-κB and NLRP3 pathways were analyzed by western blot in the kidney. Results: We demonstrated that (a) HS caused organ injury and/or dysfunction and hypotension (post-resuscitation) in rats, while (b) treatment of HS-rats with either acalabrutinib or fenebrutinib attenuated the organ injury and dysfunction in acute HS models and (c) reduced the activation of BTK, NF- kB and NLRP3 pathways in the kidney. Conclusion: Our results point to a role of BTK in the pathophysiology of organ injury and dysfunction caused by trauma/hemorrhage and indicate that BTK inhibitors may be repurposed as a potential therapeutic approach for MODS after trauma and/or hemorrhage.

Objective: The aim of this study was to investigate (a) the potential of the Bruton's tyrosine kinase (BTK) inhibitors (BTKi) acalabrutinib and fenebrutinib to reduce multiple organ dysfunction syndrome (MODS) in acute and chronic hemorrhagic shock (HS) rat models and (b) whether treatment with either acalabrutinib or fenebrutinib attenuates BTK, NF-κB and NLRP3 activation in HS. Background: The MODS caused by an excessive systemic inflammatory response following trauma is associated with a high morbidity and mortality. The protein BTK is known to play a role in the activation of the NLRP3 inflammasome, which is a key component of the innate inflammatory response. However, its role in trauma-hemorrhage is unknown. Methods: Acute and chronic HS rat models were performed to determine the influence of acalabrutinib or fenebrutinib on MODS. The activation of BTK, NF-κB and NLRP3 pathways were analyzed by western blot in the kidney. Results: We demonstrated that (a) HS caused organ injury and/or dysfunction and hypotension (post resuscitation) in rats, while (b) treatment of HS-rats with either acalabrutinib or fenebrutinib attenuated the organ injury and dysfunction in acute and chronic HS models and (c) reduced the activation of BTK, NF-κB and NLRP3 pathways in the kidney. Conclusion: Our results point to a role of BTK in the pathophysiology of organ injury and dysfunction caused by trauma/hemorrhage and indicate that BTK inhibitors may be repurposed as a potential therapeutic approach for MODS after trauma and/or hemorrhage.

ObjectiveThe aim of this study was to investigate (a) macrophage migration inhibitory factor (MIF) levels in polytrauma patients and rats after haemorrhagic shock (HS), (b) the potential of the MIF inhibitor ISO-1 to reduce multiple organ dysfunction syndrome (MODS) in acute (short-term and long-term follow-up) HS rat models and (c) whether treatment with ISO-1 attenuates NF-κB and NLRP3 activation in HS.BackgroundThe MODS caused by an excessive systemic inflammatory response following trauma is associated with a high morbidity and mortality. MIF is a pleiotropic cytokine which can modulate the inflammatory response, however, its role in trauma is unknown.MethodsThe MIF levels in plasma of polytrauma patients and serum of rats with HS were measured by ELISA. Acute HS rat models were performed to determine the influence of ISO-1 on MODS. The activation of NF-κB and NLRP3 pathways were analysed by western blot in the kidney and liver.ResultsWe demonstrated that (a) MIF levels are increased in polytrauma patients on arrival to the emergency room and in rats after HS, (b) HS caused organ injury and/or dysfunction and hypotension (post-resuscitation) in rats, while (c) treatment of HS-rats with ISO-1 attenuated the organ injury and dysfunction in acute HS models and (d) reduced the activation of NF-κB and NLRP3 pathways in the kidney and liver.ConclusionOur results point to a role of MIF in the pathophysiology of trauma-induced organ injury and dysfunction and indicate that MIF inhibitors may be used as a potential therapeutic approach for MODS after trauma and/or haemorrhage.