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

Blood ◽  
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.

scholarly journals Targeting neutrophil extracellular traps in severe acute pancreatitis treatment

2020 ◽  
Vol 13 ◽  
pp. 175628482097491
Author(s):  
Jing Hu ◽  
Hongxin Kang ◽  
Huan Chen ◽  
Jiaqi Yao ◽  
Xiaolin Yi ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Severe Acute Pancreatitis ◽  
Inflammatory Cells ◽  
Neutrophil Extracellular Traps ◽  
Multiple Organ ◽  
Organ Injury ◽  
Normal Tissues ◽  
Pathogen Invasion ◽  
Extracellular Traps ◽  
Abdominal Disease

Severe acute pancreatitis (SAP) is a critical abdominal disease associated with high death rates. A systemic inflammatory response promotes disease progression, resulting in multiple organ dysfunction. The functions of neutrophils in the pathology of SAP have been presumed traditionally to be activation of chemokine and cytokine cascades accompanying the inflammatory process. Recently, since their discovery, a new type of antimicrobial mechanism, neutrophil extracellular traps (NETs), and their role in SAP, has attracted widespread attention from the scientific community. Significantly different from phagocytosis and degranulation, NETs kill extracellular microorganisms by releasing DNA fibers decorated with granular proteins. In addition to their strong antimicrobial functions, NETs participate in the pathophysiological process of many noninfectious diseases. In SAP, NETs injure normal tissues under inflammatory stress, which is associated with the activation of inflammatory cells, to cause an inflammatory cascade, and SAP products also trigger NET formation. Thus, due to the interaction between NET generation and SAP, a treatment targeting NETs might become a key point in SAP therapy. In this review, we summarize the mechanism of NETs in protecting the host from pathogen invasion, the stimulus that triggers NET formation, organ injury associated with SAP involving NETs, methods to interrupt the harmful effects of NETs, and different therapeutic strategies to preserve the organ function of patients with SAP by targeting NETs.

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

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.

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

2022 ◽  
Author(s):  
Nikita M Patel ◽  
Debora Collotta ◽  
Eleonora Aimaretti ◽  
Gustavo Ferreira Alves ◽  
Sarah Kröller ◽  
...  
Keyword(s):  
Hemorrhagic Shock ◽  
Organ Dysfunction ◽  
Rat Model ◽  
Multiple Organ ◽  
Janus Kinase ◽  
Organ Injury ◽  
High Morbidity ◽  
Multiple Organ Dysfunction ◽  
Severe Hemorrhage ◽  
Stat Pathway

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.

Disseminated intravascular coagulation in meningococcal sepsis

2003 ◽  
Vol 23 (03) ◽  
pp. 125-130 ◽  
Author(s):  
S. Zeerleder ◽  
R. Zürcher Zenklusen ◽  
C. E. Hack ◽  
W. A. Wuillemin
Keyword(s):  
Organ Dysfunction ◽  
Disseminated Intravascular Coagulation ◽  
Skin Necrosis ◽  
Multiple Organ ◽  
Meningococcal Sepsis ◽  
Multiple Organ Dysfunction ◽  
Intravascular Coagulation ◽  
Therapeutic Concepts ◽  
New Therapeutic Concepts ◽  
Coagulation And Fibrinolysis

SummaryWe report on a man (age: 49 years), who died from severe meningococcal sepsis with disseminated intravascular coagulation (DIC), multiple organ dysfunction syndrome and extended skin necrosis. We discuss in detail the pathophysiology of the activation of coagulation and fibrinolysis during sepsis. The article discusses new therapeutic concepts in the treatment of disseminated intravascular coagulation in meningococcal sepsis, too.

Multiple Organ Dysfunction Syndrome of Alcoholic Origin in an 18-Year-Old Patient

2018 ◽  
Vol 2 (12) ◽  
Author(s):  
Francesco Gazia ◽  
Giacomo De Luca ◽  
Imbalzano Gabriele ◽  
Vincenzo Pellicanò
Keyword(s):  
Organ Dysfunction ◽  
Multiple Organ Dysfunction Syndrome ◽  
Multiple Organ ◽  
Multiple Organ Dysfunction

IMPACT probability of poor outcome and plasma cytokine concentrations are associated with multiple organ dysfunction syndrome following traumatic brain injury

2019 ◽  
Vol 131 (6) ◽  
pp. 1931-1937 ◽  
Author(s):  
Sungho Lee ◽  
Hyunsoo Hwang ◽  
Jose-Miguel Yamal ◽  
J. Clay Goodman ◽  
Imoigele P. Aisiku ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Organ Dysfunction ◽  
Multiple Organ Dysfunction Syndrome ◽  
Sofa Score ◽  
Plasma Concentrations ◽  
Multiple Organ ◽  
Multiple Organ Dysfunction ◽  
Poor Outcome ◽  
Initial Plasma

OBJECTIVETraumatic brain injury (TBI) is a major cause of morbidity and mortality. Multiple organ dysfunction syndrome (MODS) occurs frequently after TBI and independently worsens outcome. The present study aimed to identify potential admission characteristics associated with post-TBI MODS.METHODSThe authors performed a secondary analysis of a recent randomized clinical trial studying the effects of erythropoietin and blood transfusion threshold on neurological recovery after TBI. Admission clinical, demographic, laboratory, and imaging parameters were used in a multivariable Cox regression analysis to identify independent risk factors for MODS following TBI, defined as maximum total Sequential Organ Failure Assessment (SOFA) score > 7 within 10 days of TBI.RESULTSTwo hundred patients were initially recruited and 166 were included in the final analysis. Respiratory dysfunction was the most common nonneurological organ system dysfunction, occurring in 62% of the patients. International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) probability of poor outcome at admission was significantly associated with MODS following TBI (odds ratio [OR] 8.88, 95% confidence interval [CI] 1.94–42.68, p < 0.05). However, more commonly used measures of TBI severity, such as the Glasgow Coma Scale, Injury Severity Scale, and Marshall classification, were not associated with post-TBI MODS. In addition, initial plasma concentrations of interleukin (IL)–6, IL-8, and IL-10 were significantly associated with the development of MODS (OR 1.47, 95% CI 1.20–1.80, p < 0.001 for IL-6; OR 1.26, 95% CI 1.01–1.58, p = 0.042 for IL-8; OR 1.77, 95% CI 1.24–2.53, p = 0.002 for IL-10) as well as individual organ dysfunction (SOFA component score ≥ 1). Finally, MODS following TBI was significantly associated with mortality (OR 5.95, 95% CI 2.18–19.14, p = 0.001), and SOFA score was significantly associated with poor outcome at 6 months (Glasgow Outcome Scale score < 4) when analyzed as a continuous variable (OR 1.21, 95% CI 1.06–1.40, p = 0.006).CONCLUSIONSAdmission IMPACT probability of poor outcome and initial plasma concentrations of IL-6, IL-8, and IL-10 were associated with MODS following TBI.

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