Inhibition of Bruton’s tyrosine kinase activity attenuates trauma-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 (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.

Inhibition of the JAK/STAT pathway with baricitinib reduces the multiple organ dysfunction caused by hemorrhagic shock in rats

“…IL-6) can further prolong the activation of both molecules 47 . Trauma leads to increased nuclear translocation of NF-κB 27,28,[30][31][32] . Inhibition of JAK2/STAT3 activity with baricitinib decreased NF-κB activation in both the liver and kidneys (Figure 3).…”

“…The JAK/STAT pathway has also been shown to be linked to the NLRP3 inflammasome, with pharmacological inhibition of JAK reducing the expression and activation of NLRP3 inflammasome components 50,51 . NLRP3 inflammasome activation drives the formation of IL-1β which plays a key role in the systemic inflammation and/or organ dysfunction associated with trauma 27,28 . Inhibition of JAK2/STAT3 activity with baricitinib decreased the assembly and successive activation of the NLRP3 inflammasome in the liver and kidneys (Figure 3).…”

“…The acute hemorrhagic shock model was performed as previously described 27,28 . Briefly, forty rats were anesthetized with sodium thiopentone (120 mg/kg i.p.…”

“…Semi-quantitative immunoblot analysis was carried out in liver and kidney tissue samples as previously described 27,28 . Detailed description of the method can be found in the supplemental.…”