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      Association of initial intracellular signalling pathway and cytokine level with early mortality in severe sepsis patients

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      1 , , 1 , 2 , 3 , 1
      Critical Care
      BioMed Central
      Sepsis 2014
      3-5 December 2014

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          Abstract

          Introduction Sepsis occurs as a result of systemic inflammatory process. The release of bacterial components to the systemic circulation leads to activation of inhibitor kappa B kinase (IKK)-β and nuclear factor kappa B (NF-κB) through phosphorylation and ubiquitination. Excessive inflammatory process with maladaptive host's immune response leads to organ dysfunctions and death [1,2]. This study was designed to investigate association of the initial level of intracellular signalling pathway and cytokine involved in sepsis pathophysiology (that is, IKK-β, NF-κB, tumour necrosis factor (TNF)α) and 72-hour (early) mortality in severe sepsis patients. Methods A prospective cohort study was conducted in severe sepsis patients (aged 18 years and older) admitted to the Emergency Unit of Cipto Mangunkusumo Hospital, Persahabatan Hospital, and Gatot Subroto Indonesia Central Army Hospital, Jakarta, Indonesia. All blood samples for intracellular signalling pathway (that is, IKK-β, total NF-κB, phospho NF-κB) and cytokine (that is, TNFα) were collected and measured using the ELISA method during first 24 hours of inclusion. Patients' outcome was observed during first 72 hours after inclusion. Mann-Whitney test was used to analyse the median difference of IKK-β, total NF-κB, phospho NF-κB level in two groups based on 72-hour survival. The t test was used to analyse the mean difference of TNFα levels in both groups. Results Subjects consisted of 90 patients. Early mortality developed in 27 subjects. Baseline characteristics of survival and death subjects are shown in Table 1. The initial intracellular signalling pathway and cytokine parameters level are shown in Table 2. There was a significant higher median first 24 hours IKK-β and total NF-κB level in survival subjects compared with death subjects (P = 0.025 for median IKK-β and P = 0.036 for median total NF-κB). There was no significant difference of initial phospho NF-κB and TNFα level in survival and death subjects. Table 1 Baseline characteristics of the subjects Characteristic Survival subjects (n = 63) Death subjects (n = 27) Mean age (years) 52.98 ± 15.38 50.19 ± 13.46 Sex   Male 23 (36.5) 12 (44.4)   Female 40 (63.5) 15 (55.6) Sepsis severity   Severe sepsis 42 (66.7) 13 (48.1)   Septic shock 21 (33.3) 14 (51.9) Mean APACHE II score 13.03 ± 5.27 14.37 ± 6.55 Comorbidity   Without comorbidity 4 (6.3) 2 (7.4)   With comorbidity(s) 59 (93.7) 25 (92.6) Source of infection   Respiratory tract 45 (71.4) 24 (88.9)   Intraabdominal 4 (6.3) 1 (3.7)   Skin and soft tissue 5 (7.9) 1 (3.7)   Urinary tract 2 (3.1) 1 (3.7)   ≥ 2 sources 7 (11.3) 0 Mean procalcitonin (pg/ml) 21.47 ± 44.30 30.26 ± 17.29 Mean baseline lactate (mmol/l) 3.10 ± 1.77 4.89 ± 2.57 Data presented as n (%) or mean ± standard deviation. APACHE, Acute physiology and chronic health evaluation. Table 2 Initial intracellular signalling pathway and cytokine level based on 72-hour survival Parameter Survived subjects (n = 63) Death subjects (n = 27) P value IKK-βa 0.10 (0.03) 0.12 (0,03) 0.025 Total NF-κBa 0.08 (0.08) 0.12 (0.08) 0.036 Phospho NF-κBa 0.10 (0.38) 0.33 (0.38) 0.579 TNFαb 9.10 (7.80) 10.91 (11.74) 0.393 aMedian (interquartile range) in optical density, Mann-Whitney test. bMean (standard deviation) in pg/ml, t test. Conclusion There is a significant lower initial IKK-β and total NF-κB level in severe sepsis patients surviving on 72-hour observation. There is a tendency of lower initial phospho NF-κB and TNFα level in severe sepsis patients surviving on 72-hour observation.

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          NF-kappa B activation as a pathological mechanism of septic shock and inflammation.

          The pathophysiology of sepsis and septic shock involves complex cytokine and inflammatory mediator networks. NF-kappaB activation is a central event leading to the activation of these networks. The role of NF-kappaB in septic pathophysiology and the signal transduction pathways leading to NF-kappaB activation during sepsis have been an area of intensive investigation. NF-kappaB is activated by a variety of pathogens known to cause septic shock syndrome. NF-kappaB activity is markedly increased in every organ studied, both in animal models of septic shock and in human subjects with sepsis. Greater levels of NF-kappaB activity are associated with a higher rate of mortality and worse clinical outcome. NF-kappaB mediates the transcription of exceptional large number of genes, the products of which are known to play important roles in septic pathophysiology. Mice deficient in those NF-kappaB-dependent genes are resistant to the development of septic shock and to septic lethality. More importantly, blockade of NF-kappaB pathway corrects septic abnormalities. Inhibition of NF-kappaB activation restores systemic hypotension, ameliorates septic myocardial dysfunction and vascular derangement, inhibits multiple proinflammatory gene expression, diminishes intravascular coagulation, reduces tissue neutrophil influx, and prevents microvascular endothelial leakage. Inhibition of NF-kappaB activation prevents multiple organ injury and improves survival in rodent models of septic shock. Thus NF-kappaB activation plays a central role in the pathophysiology of septic shock.
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            Inhibition of IκB kinase reduces the multiple organ dysfunction caused by sepsis in the mouse

            SUMMARY Nuclear factor κB (NF-κB) plays a pivotal role in sepsis. Activation of NF-κB is initiated by the signal-induced ubiquitylation and subsequent degradation of inhibitors of kappa B (IκBs) primarily via activation of the IκB kinase (IKK). This study was designed to investigate the effects of IKK inhibition on sepsis-associated multiple organ dysfunction and/or injury (MOD) and to elucidate underlying signaling mechanisms in two different in vivo models: male C57BL/6 mice were subjected to either bacterial cell wall components [lipopolysaccharide and peptidoglycan (LPS/PepG)] or underwent cecal ligation and puncture (CLP) to induce sepsis-associated MOD. At 1 hour after LPS/PepG or CLP, mice were treated with the IKK inhibitor IKK 16 (1 mg/kg body weight). At 24 hours, parameters of organ dysfunction and/or injury were assessed in both models. Mice developed a significant impairment in systolic contractility (echocardiography), and significant increases in serum creatinine, serum alanine aminotransferase and lung myeloperoxidase activity, thus indicating cardiac dysfunction, renal dysfunction, hepatocellular injury and lung inflammation, respectively. Treatment with IKK 16 attenuated the impairment in systolic contractility, renal dysfunction, hepatocellular injury and lung inflammation in LPS/PepG-induced MOD and in polymicrobial sepsis. Compared with mice that were injected with LPS/PepG or underwent CLP, immunoblot analyses of heart and liver tissues from mice that were injected with LPS/PepG or underwent CLP and were also treated with IKK 16 revealed: (1) significant attenuation of the increased phosphorylation of IκBα; (2) significant attenuation of the increased nuclear translocation of the NF-κB subunit p65; (3) significant attenuation of the increase in inducible nitric oxide synthase (iNOS) expression; and (4) a significant increase in the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS). Here, we report for the first time that delayed IKK inhibition reduces MOD in experimental sepsis. We suggest that this protective effect is (at least in part) attributable to inhibition of inflammation through NF-κB, the subsequent decrease in iNOS expression and the activation of the Akt-eNOS survival pathway.
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              Author and article information

              Conference
              Crit Care
              Crit Care
              Critical Care
              BioMed Central
              1364-8535
              1466-609X
              2014
              3 December 2014
              : 18
              : Suppl 2
              : P46
              Affiliations
              [1 ]Division of Tropical and Infectious Diseases, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
              [2 ]Department of Internal Medicine, Gatot Subroto Indonesia Central Army Hospital, Jakarta, Indonesia
              [3 ]Department of Internal Medicine, Persahabatan Hospital, Jakarta, Indonesia
              Article
              cc14049
              10.1186/cc14049
              4273876
              db467065-be0e-4aab-82cf-063fc85eaa69
              Copyright © 2014 Lie et al.; licensee BioMed Central Ltd.

              This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

              Sepsis 2014
              Paris, France
              3-5 December 2014
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              Emergency medicine & Trauma
              Emergency medicine & Trauma

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