scholarly journals HMGB1 Inhibition to Ameliorate Organ Failure and Increase Survival in Trauma

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 101
Author(s):  
Zhangsheng Yang ◽  
Milomir O. Simovic ◽  
Peter R. Edsall ◽  
Bin Liu ◽  
Tomas S. Cancio ◽  
...  

Several preclinical and clinical reports have demonstrated that levels of circulating high mobility group box 1 protein (HMGB1) are increased early after trauma and are associated with systemic inflammation and clinical outcomes. However, the mechanisms of the interaction between HMGB1 and inflammatory mediators that lead to the development of remote organ damage after trauma remain obscure. HMGB1 and inflammatory mediators were analyzed in plasma from 54 combat casualties, collected on admission to a military hospital in Iraq, and at 8 and 24 h after admission. In total, 45 (83%) of these patients had traumatic brain injury (TBI). Nine healthy volunteers were enrolled as controls. HMGB1 plasma levels were significantly increased in the first 8 h after admission, and were found to be associated with systemic inflammatory responses, injury severity score, and presence of TBI. These data provided the rationale for designing experiments in rats subjected to blast injury and hemorrhage, to explore the effect of HMGB1 inhibition by CX-01 (2-O, 3-O desulfated heparin). Animals were cannulated, then recovered for 5–7 days before blast injury in a shock tube and volume-controlled hemorrhage. Blast injury and hemorrhage induced an early increase in HMGB1 plasma levels that coincided with severity of tissue damage and mortality. CX-01 inhibited systemic HMGB1 activity, decreased local and systemic inflammatory responses, significantly reduced tissue and organ damage, and tended to increase survival. These data suggest that CX-01 has potential as an adjuvant treatment for traumatic hemorrhage.

Author(s):  
Zhangsheng Yang ◽  
Milomir O Simovic ◽  
Peter R Edsall ◽  
Bin Liu ◽  
Tomas S Cancio ◽  
...  

Several preclinical and clinical reports have demonstrated that levels of circulating high mobility group box 1 protein (HMGB1) are increased early after trauma and are associated with systemic inflammation and clinical outcomes. However, the mechanisms of the interaction between HMGB1 and inflammatory mediators that lead to the development of remote organ damage after trauma remain obscure. HMGB1 and inflammatory mediators were analyzed in plasma from 54 combat casualties, collected on admission to a military hospital in Iraq, and at 8 and 24 hours after admission. Forty-five (83%) of these patients had traumatic brain injury (TBI). Nine healthy volunteers were enrolled as controls. HMGB1 plasma levels were significantly increased in the first 8 hours after admission, and were found to be associated with systemic inflammatory responses, injury severity score, and presence of TBI. These data provided the rationale for designing experiments in rats subjected to blast injury and hemorrhage, to explore the effect of HMGB1 inhibition by CX-01. Animals were cannulated, then recovered for 5-7 days before blast injury in a shock tube and volume-controlled hemorrhage. Blast injury and hemorrhage induced an early increase in HMGB1 plasma levels that coincided with severity of tissue damage and mortality. CX-01 inhibited systemic HMGB1 release, decreased local and systemic inflammatory responses, significantly reduced tissue and organ damage, and tended to increase survival. These data suggest that CX-01 has potential as an adjuvant treatment for traumatic hemorrhage.


Author(s):  
Aaron R. Caldwell ◽  
Kentaro Oki ◽  
Shauna M. Ward ◽  
Jermaine A. Ward ◽  
Thomas A. Mayer ◽  
...  

The purpose of the study was to determine if repeated exertional heat injuries (EHIs) worsen the inflammatory response and subsequent organ damage. We assessed the impact of a single EHI bout (EHI0) or 2 separate EHI episodes separated by 1 (EHI1), 3 (EHI3), and 7 (EHI7) days in male C57BL/6J mice (N = 236). To induce EHI, mice underwent a forced running protocol until loss of consciousness or core temperature reached ≥ 42.7°C. Blood and tissue samples were obtained 30 minutes, 3 hours, 1 day or 7 days after the EHI. We observed that mice undergoing repeated EHI events (EHI1, EHI3, and EHI7) had longer running distances prior to collapse (~ 528 meters), tolerated higher core temperatures (~0.18°C) prior to collapse, and had higher minimum core temperature (indicative of injury severity) during recovery relative to EHI0 group (~2.18°C; all P < .05). Heat resilience was most pronounced when latency was shortest between EHI episodes (i.e., thermal load and running duration highest in EHI1), suggesting the response diminishes with longer recoveries between EHI events. Furthermore, mice experiencing a second EHI exhibited increased serum & liver HSP70, and lower corticosterone, FABP2, MIP-1β, MIP-2, and IP-10 relative to mice experiencing a single EHI at specific points during the recovery period (typically 30-min to 3-hr after the EHI). Our findings indicate that an EHI event may initiate some adaptive processes that provide acute heat resilience to subsequent EHI conditions. Data and code are available at Open Science Framework repository: https://osf.io/n5ahf/?view_only=bca7ccb1b1554e1192ae776e6a7584d3


2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S221-S221
Author(s):  
Laveta Stewart ◽  
Ping Li ◽  
Dana M Blyth ◽  
Dana M Blyth ◽  
Joseph Petfield ◽  
...  

Abstract Background Deep soft-tissue infections (DSTIs) are a common complication of combat-related extremity trauma. We present an epidemiologic assessment of combat-related DSTIs among wounded military personnel. Methods Wounded personnel were included in the analysis if they sustained an open combat-related extremity wound (2009–2014), were admitted to a participating US military hospital, had a DSTI as the first confirmed extremity wound infection (within 30 days post-injury), started antibiotics ±3 days of DSTI diagnosis, and received ≥5 days of directed antibiotic treatment. Results Among 1961 combat casualties with open extremity wounds, 259 had a DSTI diagnosis with 173 (67%) having only 1 index DSTI and 86 (33%) having >1 index DSTI diagnosed on the same day. Nearly all patients (95%) were injured via a blast mechanism. Patients with >1 index DSTI were more severely injured (median injury severity score: 35 vs. 33; P = 0.009) and required large volume blood transfusions within 24 hours of injury (median units: 23 vs. 17; P < 0.001). Initial empiric antibiotic treatment largely involved carbapenem and vancomycin (77% and 72% of patients, respectively). For diagnosis timing, 130 (50%) patients had an early DSTI diagnosis (≤7 days post-injury), while the remaining 129 (50%) patients had a delayed diagnosis (>7 days post-injury). Patients with early DSTI diagnoses more often had >1 index DSTI (47% vs. 19% with delayed DSTI; P < 0.001). Polymicrobial DSTIs were common (73% of early DSTIs; 58% of delayed DSTIs) with Enterococcus spp. most frequently identified (56% of early DSTIs; 31% of delayed DSTIs) as well as Enterobacter spp., Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter spp. Moreover, 26% and 39% of early and delayed DSTIs had multidrug-resistant Gram-negative bacteria. Receipt of >20 units of blood within 24 hours of injury and having >1 index DSTI were independently associated with an early DSTI diagnosis (odds ratio [OR]: 3.21; 95% CI: 1.47–7.02 and OR: 2.98; 95% CI: 1.63–5.42, respectively). Conclusion Multiple index DSTIs and massive blood transfusion requirement are associated with early infection onset post-injury. Awareness of wound microbiology findings relative to DSTI onset provides guidance on empiric antimicrobial therapy. Disclosures All authors: No reported disclosures.


2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Bolin Cai ◽  
Edwin A. Deitch ◽  
Luis Ulloa

The inflammatory responses in sepsis and hemorrhage remain a major cause of death. Clinically, it is generally accepted that shock in sepsis or hemorrhage differs in its mechanisms. However, the recognition of inflammatory cytokines as a common lethal pathway has become consent. Proinflammatory cytokines such as tumor necrosis factor (TNF) or high-mobility group box1 (HMGB1) are fanatically released and cause lethal multiorgan dysfunction. Inhibition of these cytokines can prevent the inflammatory responses and organ damage. In seeking potential anti-inflammatory strategies, we reported that ethyl pyruvate and alpha7 nicotinic acetylcholine receptor (alpha7nAChR) agonists effectively restrained cytokine production to provide therapeutic benefits in both experimental sepsis and hemorrhage. Here, we review the inflammatory responses and the anti-inflammatory strategies in experimental models of sepsis and hemorrhage, as they may have a consistent inflammatory pathway in spite of their different pathophysiological processes.


Cartilage ◽  
2020 ◽  
pp. 194760352093485 ◽  
Author(s):  
Shifeng Zhou ◽  
Guodan Liu ◽  
Zhenxing Si ◽  
Luanfei Yu ◽  
Limin Hou

Background High mobility group box 1 (HMGB1) is increased in osteoarthritis (OA) tissue and chondrocytes stimulated with interleukin-1β (IL-1β). Suppression of HMGB1 expression is correlated with reduced inflammatory responses induced by IL-1β. This study aimed to investigate how inhibition of HMGB1 by glycyrrhizin might affect inflammatory responses and viability of OA patient–derived chondrocytes treated with IL-1β. Design The amounts of HMGB1 in the cartilage tissue and synovial fluid in patients with OA were assessed by Western blot and enzyme-linked immunosorbent assay (ELISA). Chondrocytes were extracted from OA patients and maintained in culture. The impact of glycyrrhizin on IL-1β-induced cell toxicity and inflammatory mediators and cytokines, including prostaglandin E2 (PGE2), nitric oxide (NO), proinflammatory cytokines, and metalloproteases (MMPs), were assessed by ELISA, Western blot, quantitative real-time polymerase chain reaction, and the Griess reagent assay. Results We confirmed that HMGB1 was significantly upregulated in specimens acquired from patients with OA. HMGB1 inhibition by glycyrrhizin improved cell viability of chondrocytes treated with IL-1β. Glycyrrhizin suppressed IL-1β-induced upregulation of HMGB1 and inflammatory mediators and cytokines, including PGE2, NO, proinflammatory cytokines, and MMPs. Conclusion Our results indicate that glycyrrhizin may be a potential therapy for OA patients and these promising findings warrant further study for clinical application.


Immunity ◽  
2021 ◽  
Author(s):  
Anna Barkaway ◽  
Loïc Rolas ◽  
Régis Joulia ◽  
Jennifer Bodkin ◽  
Tchern Lenn ◽  
...  

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hongseok Yoo ◽  
Yunjoo Im ◽  
Ryoung-Eun Ko ◽  
Jin Young Lee ◽  
Junseon Park ◽  
...  

AbstractThe role of high-mobility group box-1 (HMGB1) in outcome prediction in sepsis is controversial. Furthermore, its association with necroptosis, a programmed cell necrosis mechanism, is still unclear. The purpose of this study is to identify the association between the plasma levels of HMGB1 and the severity and clinical outcomes of sepsis, and to examine the correlation between HMGB1 and key executors of necroptosis including receptor-interacting kinase 3 (RIPK3) and mixed lineage kinase domain-like- (MLKL) proteins. Plasma HMGB1, RIPK3, and MLKL levels were measured with the enzyme-linked immunosorbent assay from the derivation cohort of 188 prospectively enrolled, critically-ill patients between April 2014 and December 2016, and from the validation cohort of 77 patients with sepsis between January 2017 and January 2019. In the derivation cohort, the plasma HMGB1 levels of the control (n = 46, 24.5%), sepsis (n = 58, 30.9%), and septic shock (n = 84, 44.7%) groups were significantly increased (P < 0.001). A difference in mortality between high (≥ 5.9 ng/mL) and low (< 5.9 ng/mL) HMGB1 levels was observed up to 90 days (Log-rank test, P = 0.009). There were positive linear correlations of plasma HMGB1 with RIPK3 (R2 = 0.61, P < 0.001) and MLKL (R2 = 0.7890, P < 0.001). The difference in mortality and correlation of HMGB1 levels with RIPK3 and MLKL were confirmed in the validation cohort. Plasma levels of HMGB1 were associated with the severity and mortality attributed to sepsis. They were correlated with RIPK3 and MLKL, thus suggesting an association of HMGB1 with necroptosis.


2021 ◽  
Vol 14 (6) ◽  
pp. 558
Author(s):  
Verena Peek ◽  
Lois M. Harden ◽  
Jelena Damm ◽  
Ferial Aslani ◽  
Stephan Leisengang ◽  
...  

High mobility group box (HMGB)1 action contributes to late phases of sepsis, but the effects of increased endogenous plasma HMGB1 levels on brain cells during inflammation are unclear. Here, we aimed to further investigate the role of HMGB1 in the brain during septic-like lipopolysaccharide-induced inflammation in rats (LPS, 10 mg/kg, i.p.). HMGB-1 mRNA expression and release were measured in the periphery/brain by RT-PCR, immunohistochemistry and ELISA. In vitro experiments with disulfide-HMGB1 in primary neuro-glial cell cultures of the area postrema (AP), a circumventricular organ with a leaky blood–brain barrier and direct access to circulating mediators like HMGB1 and LPS, were performed to determine the direct influence of HMGB1 on this pivotal brain structure for immune-to-brain communication. Indeed, HMGB1 plasma levels stayed elevated after LPS injection. Immunohistochemistry of brains and AP cultures confirmed LPS-stimulated cytoplasmatic translocation of HMGB1 indicative of local HMGB1 release. Moreover, disulfide-HMGB1 stimulation induced nuclear factor (NF)-κB activation and a significant release of interleukin-6, but not tumor necrosis factor α, into AP culture supernatants. However, only a few AP cells directly responded to HMGB1 with increased intracellular calcium concentration. Interestingly, priming with LPS induced a seven-fold higher percentage of responsive cells to HMGB1. We conclude that, as a humoral and local mediator, HMGB1 enhances brain inflammatory responses, after LPS priming, linked to sustained sepsis symptoms.


2006 ◽  
Vol 203 (7) ◽  
pp. 1637-1642 ◽  
Author(s):  
Shixin Qin ◽  
Haichao Wang ◽  
Renqi Yuan ◽  
Hui Li ◽  
Mahendar Ochani ◽  
...  

Severe sepsis, a lethal syndrome after infection or injury, is the third leading cause of mortality in the United States. The pathogenesis of severe sepsis is characterized by organ damage and accumulation of apoptotic lymphocytes in the spleen, thymus, and other organs. To examine the potential causal relationships of apoptosis to organ damage, we administered Z-VAD-FMK, a broad-spectrum caspase inhibitor, to mice with sepsis. We found that Z-VAD-FMK–treated septic mice had decreased levels of high mobility group box 1 (HMGB1), a critical cytokine mediator of organ damage in severe sepsis, and suppressed apoptosis in the spleen and thymus. In vitro, apoptotic cells activate macrophages to release HMGB1. Monoclonal antibodies against HMGB1 conferred protection against organ damage but did not prevent the accumulation of apoptotic cells in the spleen. Thus, our data indicate that HMGB1 production is downstream of apoptosis on the final common pathway to organ damage in severe sepsis.


2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S.S Saeedi Saravi ◽  
N.R Bonetti ◽  
G.G Camici ◽  
T.F Luscher ◽  
J.H Beer

Abstract Background Aging is associated with alterations in the fecal microbiome composition. The microbiota-derived trimethylamine-N-oxide (TMAO) correlates with arterial thrombotic events, e.g. myocardial infarction and stroke, the leading causes of mortality worldwide. The omega-3 fatty acid (n-3 FA) α-linolenic acid (ALA) has been shown to be protective against thrombosis and associated pathologies. Therefore, we hypothesized that long-term dietary ALA supplementation protects against the aging-associated microbiome dysbiosis, and reduces inflammatory and thrombotic responses. Methods 24 week-old male C57BL/6 mice were fed either a high ALA (7.3g%) or low ALA (0.03g%) diet for 12 months. We examined the compositional changes of fecal microbiota of the animals treated with high vs. low ALA via 16S rRNA gene sequencing. The plasma levels of TMAO and its precursors choline and betaine, and LPS were measured by ELISA. Additionally, the platelet aggregation in response to thrombin, and thrombus formation on collagen under high-shear flow conditions of 3000/sec (to mimic blood flow in stenosed arteries) were investigated. Results Genomic analyses showed that the abundance of Phylum Proteobacteria and the family of desulfovibrio were reduced 71.72% and 51.73% in the aged high ALA-treated mice (p&lt;0.01 and p&lt;0.001, resp.) that may result in decrease in TAMO production and the subsequent inflammatory responses. However, microbial diversity of Bacteroidetes or Fermicutes and Bacteroidetes/Fermicutes ratio did not demonstrate a significant change between high vs. low ALA groups. Interestingly, the dietary intake of high ALA increased the abundance of Lachnospiraceae (p&lt;0.01) that may exert anti-inflammatory effects. Importantly, high ALA significantly decreased the plasma levels of TMAO (p&lt;0.01) and its precursor choline (P&lt;0.05), but not betaine. The pro-inflammatory cytokine TNF-α showed a significant reduction (p&lt;0.05), whereas plasma IL-1β did not change significantly following high ALA supplementation. An increased thrombus formation on collagen under high-shear flow (36.34%, p&lt;0.01) and thrombin-induced platelet aggregation (31.31%, p&lt;0.05) were found in the aged mice. Conclusion These studies demonstrate that an ALA-rich diet induces beneficial bacterial shifts in the aging-associated fecal microbiome that may lead to the suppression of inflammatory and thrombotic responses. Hence, long-term dietary ALA supplementation may be exploited as a nutritional antithrombotic strategy in the aging. Microbiome-Thrombosis-Aging Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Swiss National Science Foundation (SNSF)


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