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.

• Authors: Nikita M Patel, Filipe R M B Oliveira, Hanna Pillmann Ramos, Eleonora Aimaretti, Gustavo Ferreira Alves, Sina M Coldewey, Massimo Collino, Regina Sordi, Christoph Thiemermann
• Journal: Annals of surgery (Ann Surg) Vol. 277 Issue 3 Pg. e624-e633 (03 01 2023) ISSN: 1528-1140 [Electronic] United States
• PMID: 35129479 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.

Chemical References

• acalabrutinib
• Agammaglobulinaemia Tyrosine Kinase
• NF-kappa B
• NLR Family, Pyrin Domain-Containing 3 Protein

Topics

• Animals
• Rats
• Shock, Hemorrhagic (complications, drug therapy)
• Agammaglobulinaemia Tyrosine Kinase
• NF-kappa B
• Multiple Organ Failure (etiology, prevention & control)
• NLR Family, Pyrin Domain-Containing 3 Protein