The enigma of sepsis

Riedemann, Niels C.; Guo, Renfeng; Ward, Peter A.

doi:10.1172/jci200319523

Cited by 491 publications

(45 citation statements)

References 75 publications

(63 reference statements)

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“…In these models, anticoagulation alone does not reproduce the effects of TM infusion (32,33). Although the antiinflammatory properties of APC could and are likely to contribute, we suspected that TM itself might be involved.…”

Section: Discussionmentioning

confidence: 95%

The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism

Abeyama¹,

Stern²,

Ito³

et al. 2005

J. Clin. Invest.

197

248

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Thrombomodulin (TM) is an endothelial anticoagulant cofactor that promotes thrombin-mediated formation of activated protein C (APC). We have found that the N-terminal lectin-like domain (D1) of TM has unique antiinflammatory properties. TM, via D1, binds high-mobility group-B1 DNA-binding protein (HMGB1), a factor closely associated with necrotic cell damage following its release from the nucleus, thereby preventing in vitro leukocyte activation, in vivo UV irradiation-induced cutaneous inflammation, and in vivo lipopolysaccharide-induced lethality. Our data also demonstrate antiinflammatory properties of a peptide spanning D1 of TM and suggest its therapeutic potential. These findings highlight a novel mechanism, i.e., sequestration of mediators, through which an endothelial cofactor, TM, suppresses inflammation quite distinctly from its anticoagulant cofactor activity, thereby preventing the interaction of these mediators with cell surface receptors on effector cells in the vasculature.

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Section: Discussionmentioning

confidence: 95%

The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism

Abeyama¹,

Stern²,

Ito³

et al. 2005

J. Clin. Invest.

197

248

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“…Recent epidemiological studies have demonstrated the wide variation in etiologies of and risk factors for AKI [17-19]. AKI occurs in approximately 19% of patients with moderate sepsis, 23% of patients with severe sepsis and 51% of patients with septic shock [20]. Patients who have sepsis-related AKI have much higher mortality than patients with AKI who do not have sepsis [21].…”

Section: Discussionmentioning

confidence: 99%

Acute kidney injury in critical ill patients affected by influenza A (H1N1) virus infection

et al. 2011

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IntroductionLittle information exists about the impact of acute kidney injury (AKI) in critically ill patients with the pandemic 2009 influenza A (H1N1) virus infection.MethodsWe conducted a prospective, observational, multicenter study in 148 Spanish intensive care units (ICUs). Patients with chronic renal failure were excluded. AKI was defined according to Acute Kidney Injury Network (AKIN) criteria.ResultsA total of 661 patients were analyzed. One hundred eighteen (17.7%) patients developed AKI; of these, 37 (31.4%) of the patients with AKI were classified as AKI I, 15 (12.7%) were classified as AKI II and 66 (55.9%) were classified as AKI III, among the latter of whom 50 (75.7%) required continuous renal replacement therapy. Patients with AKI had a higher Acute Physiology and Chronic Health Evaluation II score (19.2 ± 8.3 versus 12.6 ± 5.9; P < 0.001), a higher Sequential Organ Failure Assessment score (8.7 ± 4.2 versus 4.8 ± 2.9; P < 0.001), more need for mechanical ventilation (MV) (87.3% versus 56.2%; P < 0.01, odds ratio (OR) 5.3, 95% confidence interval (CI) 3.0 to 9.4), a greater incidence of shock (75.4% versus 38.3%; P < 0.01, OR 4.9, 95% CI, 3.1 to 7.7), a greater incidence of multiorgan dysfunction syndrome (92.4% versus 54.7%; P < 0.01, OR 10.0, 95% CI, 4.9 to 20.21) and a greater incidence of coinfection (23.7% versus 14.4%; P < 0.01, OR 1.8, 95% CI, 1.1 to 3.0). In survivors, patients with AKI remained on MV longer and ICU and hospital length of stay were longer than in patients without AKI. The overall mortality was 18.8% and was significantly higher for AKI patients (44.1% versus 13.3%; P < 0.01, OR 5.1, 95% CI, 3.3 to 7.9). Logistic regression analysis was performed with AKIN criteria, and it demonstrated that among patients with AKI, only AKI III was independently associated with higher ICU mortality (P < 0.001, OR 4.81, 95% CI 2.17 to 10.62).ConclusionsIn our cohort of patients with H1N1 virus infection, only those cases in the AKI III category were independently associated with mortality.

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“…Bacterial LPS, the principal component in the pathogenesis of endotoxic shock, acts primarily on monocytes and evokes an acute phase response in vivo, resulting in excessive production of IL-1β, IL-6, and TNF-α. The amplification of these proximal cytokines has a broad array of proinflammatory and anorexigenic effects (12,13), contributing to pathogenesis of sepsis and multiple organ failure (30,31). In an effort to examine the ability of ghrelin to modulate inflammatory cytokine expression in vivo, we treated mice with ghrelin prior to and after LPS administration.…”

Section: Figurementioning

confidence: 99%

“…In spite of a large body of data, the causes of systemic inflammatory response syndrome (SIRS) remain unknown, and various therapeutic approaches have yielded minimal beneficial results (30,31). LPS directly acts on mononuclear cells, but the resultant…”

Section: Encephalomyelitis (Eae) In This Modelmentioning

confidence: 99%

Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells

Dixit¹,

Schaffer²,

Pyle³

et al. 2004

J. Clin. Invest.

661

207

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Ghrelin, a recently described endogenous ligand for the growth hormone secretagogue receptor (GHS-R), is produced by stomach cells and is a potent circulating orexigen, controlling energy expenditure, adiposity, and growth hormone secretion. However, the functional role of ghrelin in regulation of immune responses remains undefined. Here we report that GHS-R and ghrelin are expressed in human T lymphocytes and monocytes, where ghrelin acts via GHS-R to specifically inhibit the expression of proinflammatory anorectic cytokines such as IL-1β, IL-6, and TNF-α. Ghrelin led to a dose-dependent inhibition of leptin-induced cytokine expression, while leptin upregulated GHS-R expression on human T lymphocytes. These data suggest the existence of a reciprocal regulatory network by which ghrelin and leptin control immune cell activation and inflammation. Moreover, ghrelin also exerts potent anti-inflammatory effects and attenuates endotoxin-induced anorexia in a murine endotoxemia model. We believe this to be the first report demonstrating that ghrelin functions as a key signal, coupling the metabolic axis to the immune system, and supporting the potential use of ghrelin and GHS-R agonists in the management of disease-associated cachexia.

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The enigma of sepsis

Cited by 491 publications

References 75 publications

The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism

The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism

Acute kidney injury in critical ill patients affected by influenza A (H1N1) virus infection

Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells

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