Stratification is the key: Inflammatory biomarkers accurately direct immunomodulatory therapy in experimental sepsis*

Osuchowski, Marcin F.; Connett, Judith M.; Welch, Kathleen B.; Granger, Jill; Remick, Daniel G.

doi:10.1097/ccm.0b013e31819df06b

Cited by 122 publications

(107 citation statements)

References 44 publications

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“…In a murine cecal ligation and puncture model of septic shock, levels of IL-6 at 6 hours following onset of sepsis were predictive of outcome [34]. Whilst the effect of Il-6 on cardiac myoctes has largely been assumed to be due to transignaling from binding of IL-6 to soluble receptor in serum and subsequent activation via cell surface gp130 receptor, our data in both rat and human cardiac myocytes show a direct negative inotropic effect of IL-6 in the absence of the soluble receptor [12], suggesting that classical signaling via a cell surface IL-6 receptor also occurs.…”

Section: Discussionmentioning

confidence: 99%

Myocardial depressant effects of interleukin 6 in meningococcal sepsis are regulated by p38 mitogen-activated protein kinase*

Pathan

Franklin

Eleftherohorinou

et al. 2011

Critical Care Medicine

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2 At a glance commentary: Myocardial dysfunction is a major feature in the pathophysiology of septic shock. IL-6 has been identified as a key mediator of a negative inotropic state in meningococcal sepsis. In this study we demonstrate that the p38MAPK pathway is a central regulator in the negative inotropic activity of interleukin 6 and is highly dysregulated in meningococcal septic shock. Modulators of the p38MAPK pathway could have therapeutic potential for patients with cardiac dysfunction in meningococcal and other forms of septic shock. 2 Abstract: Objectives: Myocardial failure, leading to inotrope-unresponsive shock, is the predominant cause of death in meningococcal and other forms of septic shock. Pro-inflammatory cytokines released in septic shock are known to have myocardial depressant effects. We previously showed that Interleukin 6 (IL-6) is a major myocardial depressant factor in children with meningococcal septicaemia. In the current study, we aimed to investigate the mechanisms by which IL-6 induces myocardial failure in meningococcal sepsis, and to identify potential novel therapeutic targets. Design: Laboratory based study Setting: University hospital and laboratories Patients: Children with a clinical diagnosis of meningococcal septic shock Methods: We studied IL-6-induced signaling events, both in vitro using isolated rat ventricular cardiac myocytes as a model of myocardial contractility, and in whole blood from children with meningococcal sepsis. Measurements and Main results: We demonstrated involvement of JAK2, PI3K, Akt and p38MAPK in IL-6-induced negative inotropy in isolated cardiac myocytes. Inhibition of p38MAPK not only reversed IL-6-induced myocardial depression in both rat and human myocytes, but restored inotrope responsiveness. Cardiomyocytes transduced with dominant-negative p38MAPK showed no IL-6-induced myocardial depression. To investigate p38MAPK in vivo, we profiled global RNA expression patterns in peripheral blood of children with meningococcal septicaemia. Transcripts for genes mapping to the p38MAPK pathway showed significantly altered levels of abundance, with a high proportion of genes of this pathway affected. Conclusions: Our findings demonstrate an integral role of the p38MAPK pathway in IL-6-mediated cardiac contractile dysfunction and inotrope insensitivity. Dysregulation of the p38MAPK pathway in meningococcal septicemia suggests that this pathway may be an important target for novel therapies to 3 reverse myocardial dysfunction in patients with meningococcal septic shock who are not responsive to inotropic support. (273 words) 4 Introduction: Sepsis and septic shock remain major causes of morbidity and mortality worldwide, with reported mortality rates of 10-50% [1-4]. An important feature in the pathophysiology of septic shock is the development of progressive hemodynamic and cardiovascular instability and depressed myocardial contractility [5, 6]. Over the past three decades, intense efforts to develop immunomodulatory treatments for septic shock have target...

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Section: Discussionmentioning

confidence: 99%

Myocardial depressant effects of interleukin 6 in meningococcal sepsis are regulated by p38 mitogen-activated protein kinase*

Pathan

Franklin

Eleftherohorinou

et al. 2011

Critical Care Medicine

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“…Although our results were adjusted for multiple comparisons, relevant covariates, and population stratification, and although we used functional assays to demonstrate in vitro effects of SNPs, we underscore the limitations of our sample size and the need for replication in independent studies. The early tailoring of treatments has been beneficial for outcomes of sepsis in animal models (47). Therefore, an early classification of patients, based on their genetics to predict immunomodulatory status, may offer benefits in more specific therapeutic interventions.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-1 Receptor–Associated Kinase 3 Gene Associates with Susceptibility to Acute Lung Injury

Pino-Yanes

Fan

Sun

et al. 2011

Am J Respir Cell Mol Biol

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Sepsis is the most common cause of acute lung injury (ALI), leading to organ dysfunction and death in critically ill patients. Previous studies associated variants of interleukin-1 receptor-associated kinase genes (IRAKs) with differential immune responses to pathogens and with outcomes during sepsis, and revealed that increased expression levels of the IRAK3 gene were correlated with poor outcomes during sepsis. Here we explored whether common variants of the IRAK3 gene were associated with susceptibility to, and outcomes of, severe sepsis. After our discovery of polymorphism, we genotyped a subset of seven single-nucleotide polymorphisms (SNPs) in 336 population-based control subjects and 214 patients with severe sepsis, collected as part of a prospective study of adults from a Spanish network of intensive care units. Whereas IRAK3 SNPs were not associated with susceptibility to severe sepsis, rs10506481 showed a significant association with the development of ALI among patients with sepsis (P 5 0.007). The association remained significant after adjusting for multiple comparisons, population stratification, and clinical variables (odds ratio, 2.50; 95% confidence interval, 1.15-5.47; P 5 0.021). By imputation, we revealed three additional SNPs independently associated with ALI (P , 0.01). One of these (rs1732887) predicted the disruption of a putative human-mouse conserved transcription factor binding site, and demonstrated functional effects in vitro (P 5 0.017). Despite the need for replication in independent studies, our data suggest that common SNPs in the IRAK3 gene may be determinants of sepsis-induced ALI.

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“…Animal studies, as well as recent human studies, have highlighted the importance of delayed sepsis-induced immunosuppression and its contribution to the mortality of the syndrome (14). Several researchers have shown that the levels of both proinflammatory and anti-inflammatory cytokines can be correlated with the severity of illness (26,27,29). For example, IL-10, a potent anti-inflammatory cytokine, has been shown to predict poor prognosis in patients with sepsis, and modulation of IL-10 in selected animal models of sepsis improved survival (15,16,34; M. Ariefdjohan, K. Queensland, L. Weitzel, D. Heyland, and P. Wischmeyer, presented at the 32nd Annual Conference on Shock, San Antonio, TX, 2009).…”

mentioning

confidence: 99%

Characterization and Modulation of the Immunosuppressive Phase of Sepsis

Muenzer¹,

Davis²,

Chang³

et al. 2010

Infect Immun

185

149

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Sepsis continues to cause significant morbidity and mortality in critically ill patients. Studies of patients and animal models have revealed that changes in the immune response during sepsis play a decisive role in the outcome. Using a clinically relevant two-hit model of sepsis, i.e., cecal ligation and puncture (CLP) followed by the induction of Pseudomonas aeruginosa pneumonia, we characterized the host immune response. Second, AS101 [ammonium trichloro(dioxoethylene-o,o)tellurate], a compound that blocks interleukin 10 (IL-10), a key mediator of immunosuppression in sepsis, was tested for its ability to reverse immunoparalysis and improve survival. Mice subjected to pneumonia following CLP had different survival rates depending upon the timing of the secondary injury. Animals challenged with P. aeruginosa at 4 days post-CLP had ϳ40% survival, whereas animals challenged at 7 days had 85% survival. This improvement in survival was associated with decreased lymphocyte apoptosis, restoration of innate cell populations, increased proinflammatory cytokines, and restoration of gamma interferon (IFN-␥) production by stimulated splenocytes. These animals also showed significantly less P. aeruginosa growth from blood and bronchoalveolar lavage fluid. Importantly, AS101 improved survival after secondary injury 4 days following CLP. This increased survival was associated with many of the same findings observed in the 7-day group, i.e., restoration of IFN-␥ production, increased proinflammatory cytokines, and decreased bacterial growth. Collectively, these studies demonstrate that immunosuppression following initial septic insult increases susceptibility to secondary infection. However, by 7 days post-CLP, the host's immune system has recovered sufficiently to mount an effective immune response. Modulation of the immunosuppressive phase of sepsis may aid in the development of new therapeutic strategies.

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Stratification is the key: Inflammatory biomarkers accurately direct immunomodulatory therapy in experimental sepsis*

Cited by 122 publications

References 44 publications

Myocardial depressant effects of interleukin 6 in meningococcal sepsis are regulated by p38 mitogen-activated protein kinase*

Myocardial depressant effects of interleukin 6 in meningococcal sepsis are regulated by p38 mitogen-activated protein kinase*

Interleukin-1 Receptor–Associated Kinase 3 Gene Associates with Susceptibility to Acute Lung Injury

Characterization and Modulation of the Immunosuppressive Phase of Sepsis

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