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

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.

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Pyruvate alleviates lipid peroxidation and multiple-organ dysfunction in rats with hemorrhagic shock

The American Journal of Emergency Medicine ◽

10.1016/j.ajem.2015.12.040 ◽

2016 ◽

Vol 34 (3) ◽

pp. 525-530 ◽

Cited By ~ 9

Author(s):

Rui Liu ◽

Shu-Ming Wang ◽

Xian-Qi Liu ◽

Si-Jia Guo ◽

Hai-Bin Wang ◽

...

Keyword(s):

Lipid Peroxidation ◽

Hemorrhagic Shock ◽

Organ Dysfunction ◽

Multiple Organ ◽

Multiple Organ Dysfunction

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Increased Serum Endotoxin and Elevated CD14 and IL-1β Expression in a Rat Model of Cerebrogenic Multiple Organ Dysfunction Syndrome

Medicinal Chemistry ◽

10.2174/157340609789117903 ◽

2009 ◽

Vol 5 (5) ◽

pp. 462-467 ◽

Cited By ~ 4

Author(s):

Qu Chuanqiang ◽

Guo Shougang ◽

Guo Hongzhi ◽

Wang Chunjuan ◽

Ma Lin ◽

...

Keyword(s):

Organ Dysfunction ◽

Multiple Organ Dysfunction Syndrome ◽

Rat Model ◽

Multiple Organ ◽

Multiple Organ Dysfunction

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Inhibition of Bruton's tyrosine kinase activity attenuates trauma-induced multiple organ dysfunction in rats

10.1101/2021.09.23.460775 ◽

2021 ◽

Author(s):

Nikita M Patel ◽

Filipe RMB Oliveira ◽

Hanna Pillmann Ramos ◽

Eleonora Aimaretti ◽

Gustavo Ferreira Alves ◽

...

Keyword(s):

Inflammatory Response ◽

Tyrosine Kinase ◽

Organ Dysfunction ◽

Multiple Organ ◽

Organ Injury ◽

Bruton’S Tyrosine Kinase ◽

Multiple Organ Dysfunction ◽

Bruton's Tyrosine Kinase ◽

Rat Models ◽

Btk Inhibitors

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.

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Erratum to “Pyruvate alleviates lipid peroxidation and multiple organ dysfunction in rats with hemorrhagic shock” (Am J Emerg Med 34[3]:525-530)

The American Journal of Emergency Medicine ◽

10.1016/j.ajem.2016.04.035 ◽

2016 ◽

Vol 34 (7) ◽

pp. 1330 ◽

Cited By ~ 3

Author(s):

Rui Liu ◽

Shu-Ming Wang ◽

Xian-Qi Liu ◽

Si-Jia Guo ◽

Hai-Bin Wang ◽

...

Keyword(s):

Lipid Peroxidation ◽

Hemorrhagic Shock ◽

Organ Dysfunction ◽

Multiple Organ ◽

Multiple Organ Dysfunction

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Stress and Redox Regulation. Heat shock response in a rat model of septic multiple organ dysfunction syndrome.

Folia Pharmacologica Japonica ◽

10.1254/fpj.114.295 ◽

1999 ◽

Vol 114 (5) ◽

pp. 295-302 ◽

Cited By ~ 5

Author(s):

Toru TAKAHASHI ◽

Tsutomu SUZUKI ◽

Akira YAMASAKI ◽

Takashi TSUKIJI ◽

Masahisa HIRAKAWA ◽

...

Keyword(s):

Heat Shock ◽

Organ Dysfunction ◽

Multiple Organ Dysfunction Syndrome ◽

Rat Model ◽

Heat Shock Response ◽

Redox Regulation ◽

Multiple Organ ◽

Multiple Organ Dysfunction ◽

Shock Response

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Inhibition of Bruton's Tyrosine Kinase Activity Attenuates Hemorrhagic Shock-Induced Multiple Organ Dysfunction in Rats

Annals of Surgery ◽

10.1097/sla.0000000000005357 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Nikita M. Patel ◽

Filipe R. M. B. Oliveira ◽

Hanna Pillmann Ramos ◽

Eleonora Aimaretti ◽

Gustavo Ferreira Alves ◽

...

Keyword(s):

Tyrosine Kinase ◽

Hemorrhagic Shock ◽

Organ Dysfunction ◽

Kinase Activity ◽

Multiple Organ ◽

Bruton’S Tyrosine Kinase ◽

Multiple Organ Dysfunction ◽

Tyrosine Kinase Activity ◽

Bruton's Tyrosine Kinase

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Gasdermin D inhibition prevents multiple organ dysfunction during sepsis by blocking NET formation

Blood ◽

10.1182/blood.2021011525 ◽

2021 ◽

Author(s):

Camila Meirelles Silva ◽

Carlos W. S. Wanderley ◽

Flavio P Veras ◽

Fabiane Sonego ◽

Daniele Carvalho Nascimento ◽

...

Keyword(s):

Organ Dysfunction ◽

Neutrophil Extracellular Traps ◽

Multiple Organ ◽

Organ Injury ◽

Multiple Organ Dysfunction ◽

Extracellular Traps ◽

Highly Correlated ◽

Net Release ◽

Worse Prognosis ◽

Novel Therapeutic

Multiple organ dysfunction is the most severe outcome of sepsis progression and is highly correlated with a worse prognosis. Excessive neutrophil extracellular traps (NETs) are critical players in the development of organ failure during sepsis. Therefore, interventions targeting NET release would likely effectively prevent NET-based organ injury associated with this disease. Herein, we demonstrate that the pore-forming protein gasdermin D (GSDMD) is active in neutrophils from septic humans and mice and plays a crucial role in NET release. Inhibition of GSDMD with disulfiram or genic deletion abrogated NET formation, reducing multiple organ dysfunction and sepsis lethality. Mechanistically, we demonstrate that during sepsis, activation of the caspase-11/GSDMD pathway controls NET release by neutrophils during sepsis. In summary, our findings uncover a novel therapeutic use for disulfiram and suggest that GSDMD is a therapeutic target to improve sepsis treatment.

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