Abstract
Objective The aim of this study was to investigate (a) the effects of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway inhibitor (baricitinib) on the multiple organ dysfunction syndrome (MODS) in a rat model of hemorrhagic shock (HS) and (b) whether treatment with baricitinib attenuates the activation of JAK/STAT, NF-κB and NLRP3 caused by HS.
Background Post-traumatic MODS, which is in part due to excessive systemic inflammation, is associated with high morbidity and mortality. The JAK/STAT pathway is a regulator of numerous growth factor and cytokine receptors and, hence, is considered a potential master regulator of many inflammatory signaling processes. However, its role in trauma-hemorrhage is unknown.
Methods An acute HS rat model was performed to determine the effect of baricitinib on MODS. The activation of JAK/STAT, NF-κB and NLRP3 pathways were analyzed by western blotting in the kidney and liver.
Results We demonstrate here for the first time that treatment with baricitinib (during resuscitation following severe hemorrhage) attenuates the organ injury and dysfunction and the activation of JAK/STAT, NF-κB and NLRP3 pathways caused by HS in the rat.
Conclusions Our results point to a role of the JAK/STAT pathway in the pathophysiology of the organ injury and dysfunction caused by trauma/hemorrhage and indicate that JAK inhibitors, such as baricitinib, may be repurposed for the treatment of the MODS after trauma and/or hemorrhage.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Sources of support: NMP was funded by the William Harvey Research Foundation.
- Abbreviations
- ALT
- alanine aminotransferase
- AST
- aspartate aminotransferase
- CK
- creatine kinase
- DAMP
- damage-associated molecular pattern
- HS
- hemorrhagic shock
- JAK
- Janus kinase
- LDH
- lactate dehydrogenase
- MAP
- mean arterial pressure
- MODS
- multiple organ dysfunction syndrome
- STAT
- signal transducer and activator of transcription
