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Updated: Oct 4, 2025
Author Spotlight: Developing Innovative Therapeutic Strategies for Hemorrhagic Shock Research
Published on: March 22, 2024
Inhibition of Bruton's Tyrosine Kinase Activity Attenuates Hemorrhagic Shock-Induced Multiple Organ Dysfunction in
Nikita M Patel1, Filipe R M B Oliveira2, Hanna Pillmann Ramos2
1William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
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.
Insights
Bruton
Area of Science:
- Biomedical research
- Inflammation and immunology
- Trauma and critical care medicine
Background:
- Multiple organ dysfunction syndrome (MODS) following trauma leads to high mortality.
- Bruton's tyrosine kinase (BTK) is implicated in NLRP3 inflammasome activation, a key inflammatory pathway.
- The specific role of BTK in trauma-hemorrhage (HS) induced MODS remains unclear.
Purpose of the Study:
- To evaluate the efficacy of BTK inhibitors (acalabrutinib, fenebrutinib) in mitigating MODS in rat models of acute hemorrhagic shock (HS).
- To determine if these inhibitors reduce BTK, NF-κB, and NLRP3 activation following HS.
- To explore the therapeutic potential of BTK inhibitors for MODS post-trauma/hemorrhage.
Main Methods:
- Establishment of acute hemorrhagic shock (HS) rat models.
- Administration of acalabrutinib or fenebrutinib to HS rats.
- Assessment of organ injury and dysfunction post-resuscitation.
- Analysis of BTK, NF-κB, and NLRP3 pathway activation in kidney tissue via western blot.
Main Results:
- Hemorrhagic shock (HS) induced significant organ injury, dysfunction, and hypotension in rats.
- Treatment with acalabrutinib or fenebrutinib attenuated HS-induced organ injury and dysfunction.
- BTK inhibitor treatment reduced the activation of BTK, NF-κB, and NLRP3 pathways in the kidney.
Conclusions:
- BTK plays a significant role in the pathophysiology of organ injury and dysfunction resulting from trauma and hemorrhage.
- BTK inhibitors demonstrate potential as a therapeutic strategy for managing MODS after trauma and hemorrhage.
- Targeting BTK may offer a novel approach to reduce inflammation and organ damage in critical care settings.
