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-kappa B, and NLRP3 caused by HS. Background:Posttraumatic 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-kappa B, 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-kappa B, 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.

Inhibition of the JAK/STAT Pathway With Baricitinib Reduces the Multiple Organ Dysfunction Caused by Hemorrhagic Shock in Rats

Collotta, Debora;Aimaretti, Eleonora;Ferreira Alves, Gustavo;Collino, Massimo;
2023-01-01

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-kappa B, and NLRP3 caused by HS. Background:Posttraumatic 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-kappa B, 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-kappa B, 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.
2023
278
1
e137
e146
baricitinib; hemorrhagic shock; ischemia-reperfusion; janus kinase; multiorgan dysfunction syndrome; trauma
Patel, Nikita M; Collotta, Debora; Aimaretti, Eleonora; Ferreira Alves, Gustavo; Kröller, Sarah; Coldewey, Sina M; Collino, Massimo; Thiemermann, Christoph
File in questo prodotto:
File Dimensione Formato  
2023 Annals of Surgery Bricitinib HS.pdf

Accesso aperto

Tipo di file: PDF EDITORIALE
Dimensione 1.08 MB
Formato Adobe PDF
1.08 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1931870
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 3
  • ???jsp.display-item.citation.isi??? 3
social impact