Delayed Neutralization of Interleukin 6 Reduces Organ Injury, Selectively Suppresses Inflammatory Mediator, and Partially Normalizes Immune Dysfunction Following Trauma and Hemorrhagic Shock

Zhang, Yong; Zhang, Jinxiang; Korff, Sebastian; Ayoob, Faez; Vodovotz, Yoram; Billiar, Timothy R.

doi:10.1097/shk.0000000000000211

Cited by 32 publications

(31 citation statements)

References 39 publications

(57 reference statements)

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“…The use of monoclonal antibodies against TNF-α attenuated the cardiovascular consequences and improved the survival rate in HS (36), and a monoclonal antibody against IL-6 reduced organ dysfunction and inflammation in HS (37). Our results are in line with these studies, because we also report an association between high levels of TNF-α and IL-6 and the development of organ injury and dysfunction.…”

Section: K K I N H I B I T I O N I M P R O V E S O R G a N I N J U supporting

confidence: 90%

“…The proinflammatory cytokines TNF-α and IL-6 are important mediators of alterations associated with organ dysfunction and even lethality following hemorrhage and resuscitation (3,15,36,37). The use of monoclonal antibodies against TNF-α attenuated the cardiovascular consequences and improved the survival rate in HS (36), and a monoclonal antibody against IL-6 reduced organ dysfunction and inflammation in HS (37).…”

Section: K K I N H I B I T I O N I M P R O V E S O R G a N I N J U mentioning

confidence: 99%

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Inhibition of IκB Kinase Attenuates the Organ Injury and Dysfunction Associated with Hemorrhagic Shock

Chiazza

Johnson

Patel

et al. 2015

Mol Med

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Nuclear factor-kappa B (NF-κB) activation is widely implicated in multiple organ failure (MOF); however, a direct inhibitor of IκB kinase (IKK), which plays a pivotal role in the activation of NF-κB, has not been investigated in shock. Thus, the aim of the present work was to investigate the effects of an IKK inhibitor on the MOF associated with hemorrhagic shock (HS). Therefore, rats were subjected to HS and were resuscitated with the shed blood. Rats were treated with the inhibitor of IKK or vehicle at resuscitation. Four hours later, blood and organs were assessed for organ injury and signaling events involved in the activation of NF-κB. Additionally, survival following serum deprivation was assessed in HK-2 cells treated with the inhibitor of IKK. HS resulted in renal dysfunction, lung, liver and muscular injury, and increases in serum inflammatory cytokines. Kidney and liver tissue from HS rats revealed increases in phosphorylation of IKKαβ and IκBα, nuclear translocation of NF-κB and expression of inducible isoform of nitric oxide synthase (iNOS). IKK16 treatment upon resuscitation attenuated NF-κB activation and activated the Akt survival pathway, leading to a significant attenuation of all of the above parameters. Furthermore, IKK16 exhibited cytoprotective effects in human kidney cells. In conclusion, the inhibitor of IKK complex attenuated the MOF associated with HS. This effect may be due to the inhibition of the NF-κB pathway and activation of the survival kinase Akt. Thus, the inhibition of the IKK complex might be an effective strategy for the prevention of MOF associated with HS.

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Section: K K I N H I B I T I O N I M P R O V E S O R G a N I N J U supporting

confidence: 90%

Section: K K I N H I B I T I O N I M P R O V E S O R G a N I N J U mentioning

confidence: 99%

Inhibition of IκB Kinase Attenuates the Organ Injury and Dysfunction Associated with Hemorrhagic Shock

Chiazza

Johnson

Patel

et al. 2015

Mol Med

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“…8 Together, these studies suggest that certain components of the innate immune response are severely impaired in aged patients. Although experimental studies have established that high levels of IL-6 early after injury contribute to organ injury, 34,35 the consequence of inadequate IL-6 levels cannot be determined from our studies.…”

Section: Discussionmentioning

confidence: 83%

Young and Aged Blunt Trauma Patients Display Major Differences in Circulating Inflammatory Mediator Profiles after Severe Injury

Lamparello

Namas

Abdul-Malak

et al. 2019

Journal of the American College of Surgeons

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BACKGROUND: Aging is accompanied by alterations in immune functions. How these changes translate into levels of circulating inflammatory mediators and network expression after severe trauma is not well characterized. To address this, we compared time-dependent changes in the levels of an extensive biomarker panel in cohorts of severely injured young and aged adults. STUDY DESIGN: Cohorts of young (18 to 30 years old, n ¼ 115) and aged (65 to 90 years old, n ¼ 101) blunt trauma patients admitted to the ICU with plasma sampled 3 times within the first 24 hours and daily from day 1 to day 7 were assayed for 30 inflammatory biomarkers using Luminex analyzer. Stringently matched groups controlling for sex ratio and Injury Severity Score (n ¼ 56 young vs n ¼ 56 aged) were generated. Data were analyzed using 2-way ANOVA, area under the curve analysis, Dynamic Bayesian Network inference, and Dynamic Network Analysis. RESULTS: In the overall cohorts, the young group had a significantly higher Injury Severity Score, which was associated with higher circulating levels of 18 inflammatory mediators from admission to day 7. The aged group had higher levels of C-X-C motif chemokine ligand 10/interferon gamma-induced protein 10 and C-X-C motif chemokine ligand 9/monokine induced by gamma interferon. In groups that were matched for Injury Severity Score, the significantly higher levels of interferon gamma-induced protein 10 and monokine induced by gamma interferon persisted in the aged. Dynamic Bayesian Network revealed interferon gammainduced protein 10 and monokine induced by gamma interferon as key mediators in the aged, and Dynamic Network Analysis revealed higher network complexity in the aged. CONCLUSIONS: These findings indicate that differences in the early inflammatory networks between young and aged trauma patients are not simply a suppression of pro-inflammatory responses in the aged, but are characterized by a major shift in the mediator profile patterns with high levels of CXC chemokines in the aged.

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“…In recent years, several experimental studies have focused on the protective effects of PEGs. In lung endothelial cells, treatment with 15-20 kDa molecular weight PEG (PEG [15][16][17][18][19][20] was found to enhance cell function by activating endothelial cell-barrier signal transduction pathways and by contributing to cytoskeleton reorganization [8]. In addition, pre-treatment with PEG 15-20 in cultured ventricular myocytes subjected to hypoxia-reoxygenation reduced oxidative stress and apoptosis and increased cell survival [9].…”

Section: Introductionmentioning

confidence: 99%

Polyethylene Glycol 35 (PEG35) Protects against Inflammation in Experimental Acute Necrotizing Pancreatitis and Associated Lung Injury

Ferrero-Andrés

Panisello‐Roselló

Serafín

et al. 2020

IJMS

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Acute pancreatitis is an inflammatory disorder of the pancreas. Its presentation ranges from self-limiting disease to acute necrotizing pancreatitis (ANP) with multiorgan failure and a high mortality. Polyethylene glycols (PEGs) are non-immunogenic, non-toxic, and water-soluble chemicals composed of repeating units of ethylene glycol. The present article explores the effect of PEG35 administration on reducing the severity of ANP and associated lung injury. ANP was induced by injection of 5% sodium taurocholate into the biliopancreatic duct. PEG35 was administered intravenously either prophylactically or therapeutically. Three hours after ANP induction, pancreas and lung tissue samples and blood were collected and ANP severity was assessed. To evaluate the inflammatory response, gene expression of pro-inflammatory cytokines and chemokine and the changes in the presence of myeloperoxidase and adhesion molecule levels were determined in both the pancreas and the lung. To evaluate cell death, lactate dehydrogenase (LDH) activity and apoptotic cleaved caspase-3 localization were determined in plasma and in both the pancreatic and lung tissue respectively. ANP-associated local and systemic inflammatory processes were reduced when PEG35 was administered prophylactically. PEG35 pre-treatment also protected against acute pancreatitis-associated cell death. Notably, the therapeutic administration of PEG35 significantly decreased associated lung injury, even when the pancreatic lesion was equivalent to that in the untreated ANP-induced group. Our results support a protective role of PEG35 against the ANP-associated inflammatory process and identify PEG35 as a promising tool for the treatment of the potentially lethal complications of the disease.

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Delayed Neutralization of Interleukin 6 Reduces Organ Injury, Selectively Suppresses Inflammatory Mediator, and Partially Normalizes Immune Dysfunction Following Trauma and Hemorrhagic Shock

Cited by 32 publications

References 39 publications

Inhibition of IκB Kinase Attenuates the Organ Injury and Dysfunction Associated with Hemorrhagic Shock

Inhibition of IκB Kinase Attenuates the Organ Injury and Dysfunction Associated with Hemorrhagic Shock

Young and Aged Blunt Trauma Patients Display Major Differences in Circulating Inflammatory Mediator Profiles after Severe Injury

Polyethylene Glycol 35 (PEG35) Protects against Inflammation in Experimental Acute Necrotizing Pancreatitis and Associated Lung Injury

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