Inhibition of Bruton’s Tyrosine Kinase Activity Attenuates Hemorrhagic Shock-Induced Multiple Organ Dysfunction in Rats

Abstract

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.

The role of nitric oxide in sepsis-associated kidney injury

“…The inhibition of Bruton tyrosine kinase (BTK) has been shown to reduce iNOS and nitrotyrosine immunostaining in immune cells and oxidative stress in renal tissue, resulting in amelioration of renal dysfunction in LPS-induced AKI [ 106 ]. Similar findings were found in hemorrhagic shock rats treated with BTK inhibitor [ 107 ]. The protective effects of the indirect inhibition of iNOS in S-AKI is very extensive and it has been shown after treatment of septic animals with dexmedetomidine [ 108 ] and S-nitrosoglutathione [ 109 ], to name but a few.…”

Inhibition of Macrophage Migration Inhibitory Factor Activity Attenuates Haemorrhagic Shock-Induced Multiple Organ Dysfunction in Rats

“…Activation of the NLRP3 inflammasome stimulates IL-1β production which plays a crucial role in trauma-associated systemic inflammation and organ dysfunction/injury ( 36 ). Inhibition of MIF activity with ISO-1 reduced both the assembly and subsequent activation of the NLRP3 inflammasome in the kidney and liver of HS-rats ( Figure 4 ).…”

“…The pressure-controlled long-term follow-up acute HS model was performed as previously described ( 36 ). Briefly, thirty rats were administered analgesia with tramadol (10 mg/kg i.p.)…”

“…Semi-quantitative immunoblot analysis was carried out in kidney and liver samples as previously described ( 36 ). Detailed description of the method can be found in the supplemental.…”

“…Determination of myeloperoxidase activity in lung and liver tissue samples was performed as previously described ( 36 ). Detailed description of the method can be found in the supplemental.…”