Polymorphonuclear Leukocyte Dysfunction Syndrome in Patients With Increasing Sepsis Severity

Kaufmann, Inès; Hoelzl, Alwin; Schliephake, Florian; Hummel, Theresia; Choukèr, Alexander; Peter, K.; Thiel, Manfred

doi:10.1097/01.shk.0000223131.64512.7a

Cited by 81 publications

(79 citation statements)

References 35 publications

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“…Similarly, in a rat model of peritonitis, neutrophils have been associated with liver failure (21). Recently, Kaufmann et al (15) reported neutrophil dysfunction in patients with severe sepsis (15). Neutrophils from severely septic patients exhibited a compromised phagocytic function; however, they produced higher amounts of ROS on activation by soluble stimuli (like fMLP, TNF-α, and TPA) compared with healthy subjects (15).…”

Section: Discussionmentioning

confidence: 99%

Preclinical Evaluation of Targeting the Nrf2 Pathway by Triterpenoids (CDDO-Im and CDDO-Me) for Protection from LPS-Induced Inflammatory Response and Reactive Oxygen Species in Human Peripheral Blood Mononuclear Cells and Neutrophils

Thimmulappa

Fuchs

Malhotra

et al. 2007

Antioxidants & Redox Signaling

134

116

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Sepsis is characterized by an inappropriate host immune-inflammatory response and sustained oxidative damage. Nrf2, a bZIP oxidant-responsive transcription factor, regulates a battery of cytoprotective genes including antioxidants and maintains cellular redox homeostasis. Mouse studies have demonstrated a critical role of Nrf2 in improving survival during sepsis. This preclinical ex vivo study using neutrophils and peripheral blood mononuclear cells (PBMCs) as a surrogate cells evaluates the efficacy of CDDO-Im and CDDO-Me [imidazole and methyl ester derivative of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO)] to activate the Nrf2 pathway and protect from lipopolysaccharide (LPS)-induced inflammatory response in humans. CDDO-Im treatment significantly induced Nrf2-dependent antioxidative genes (HO-1, GCLC, GCLM, and NQO1) in PBMCs isolated from six normal subjects. CDDO-Im increased nuclear accumulation of Nrf2 protein. Pretreatment of PBMC by CDDO-Im significantly attenuated LPS-induced cytokine expression. Similar increases in levels of antioxidant genes and suppression of LPS-induced cytokine expression was observed after CDDO-Me pretreatment. CDDO-Im also greatly inhibited LPS, fMLP, TNF-α, and TPA-induced ROS generation in neutrophils. In conclusion, these results demonstrate that activation of the Nrf2-dependent antioxidative pathway by CDDO-Im or CDDO-Me protects against the LPS-induced inflammatory response and suggest that they can be potential therapeutic candidates for intervening sepsis syndrome.

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Section: Discussionmentioning

confidence: 99%

Preclinical Evaluation of Targeting the Nrf2 Pathway by Triterpenoids (CDDO-Im and CDDO-Me) for Protection from LPS-Induced Inflammatory Response and Reactive Oxygen Species in Human Peripheral Blood Mononuclear Cells and Neutrophils

Thimmulappa

Fuchs

Malhotra

et al. 2007

Antioxidants & Redox Signaling

134

116

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“…Several clinical studies have demonstrated low antioxidants and elevated levels of oxidative stress markers, such as lipid hydroperoxides and plasma nitrite, in septic patients (6,15). Recently, Kaufmann et al (12) reported neutrophil dysfunction in patients with severe sepsis. Neutrophils from patients with severe sepsis exhibited compromised phagocytic function; however, they produced higher amounts of ROS on activation by soluble stimuli (such as fMLP, TNF-α, and TPA) compared with healthy subjects (12).…”

mentioning

confidence: 99%

“…Recently, Kaufmann et al (12) reported neutrophil dysfunction in patients with severe sepsis. Neutrophils from patients with severe sepsis exhibited compromised phagocytic function; however, they produced higher amounts of ROS on activation by soluble stimuli (such as fMLP, TNF-α, and TPA) compared with healthy subjects (12). ROS/RNS can cause DNA-strand breakage, triggering the activation of poly(ADP-ribose) polymerase (PARP).…”

mentioning

confidence: 99%

Sepsis: Redox Mechanisms and Therapeutic Opportunities

Biswal

Remick

2007

Antioxidants & Redox Signaling

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DESPITE ADVANCEMENTS IN THE treatment of critically ill patients, sepsis remains the leading cause of death in the ICU-an estimated 175,000 deaths per year (2). The incidence of sepsis in the United States ranges from 400,000 to 750,000 cases per year. Mortality due to sepsis is around 30% and increases with age from 10% in children to 40% in the elderly; mortality is 50% or greater in patients with the more severe syndrome, septic shock, and a recent study reported a 70% increase in the number of severe sepsis cases from 1993 to 2003 (2,5).Sepsis is a complex syndrome characterized by hyperinflammation, oxidative damage, hypercoagulation, tissue hypoperfusion and hypoxia, immune suppression, as well as multiorgan dysfunction. The pathogenesis of sepsis involves cumulative dysfunction of immune cells (macrophages, neutrophils, and lymphocytes), endothelial cells, and epithelial cells. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) significantly contribute to the dysfunction of these cells during sepsis.ROS/RNS play a key role in physiologic cellular functions, including signal transduction involved in expression of several cytokines, growth factors, and hormones. Additionally, ROS produced by the NADPH oxidase complex during phagocytosis is essential for microbicidal activity. However, excess production of ROS/RNS represents a key element in the cascade of deleterious processes in sepsis. Recent studies indicated that ROS can affect the pathogenesis of sepsis by two mechanisms: (a) modulating the innate immune signaling cascade, and (b) causing pathologic damage to cells and organs (1,4,6,11,13,16). ROS can alter LPS-TLR4 signaling at multiple levels and prime the innate immune cell for increased responsiveness to subsequent stimuli (14,17). ROS, such as superoxide and hydrogen peroxide, enhance NF-κB activation (3). More recently, ROS were shown to mediate trafficking of the TLR4 receptor to lipid rafts (16,17). Oxidative stress generated during hemorrhagic shock caused increase translocation of TLR4 receptor to the lipid rafts in the plasma membrane of macrophages that increased responsiveness to subsequent stimuli (17). Choi's group (16) also showed that carbon monoxide generated from heme oxygenase inhibits LPS-induced translocation of TLR4 to lipid rafts, as well as its downstream signaling adapter molecules (MYD88, TRIF, TRAF6, IRAK) through suppression of NADPH oxidase-dependent ROS generation (16).Superoxide anion and peroxynitrite play key roles in the pathogenesis of hemodynamic instability and organ dysfunction during septic shock. A growing body of evidence relates neutrophil dysfunction with the severity of sepsis and is linked with end-organ failure and mortality (8). Excessive release of proinflammatory mediators, ROS, and proteases by activated neutrophils exacerbates sepsis by increasing inflammation, oxidative tissue damage, Address reprint requests to:

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“…4,5 The consequences of impaired immune function include enhanced susceptibility to nosocomial infection 6 or death from sepsis. 7 Neutrophils are the major front-line cellular defense against bacterial pathogens, and acquired defects in neutrophil function have been identified in both animal and human sepsis 8,9 as well as sterile SIRS. 10,11 However, the mediators driving these defects, and the mechanisms involved, remain uncertain.…”

Section: Introductionmentioning

confidence: 99%

C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients

Morris

Brittan

Wilkinson

et al. 2011

Blood

150

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Critically ill patients are at heightened risk for nosocomial infections. The anaphylatoxin C5a impairs phagocytosis by neutrophils. However, the mechanisms by which this occurs and the relevance for acquisition of nosocomial infection remain undetermined. We aimed to characterize mechanisms by which C5a inhibits phagocytosis in vitro and in critically ill patients, and to define the relationship between C5a-mediated dysfunction and acquisition of nosocomial infection. In healthy human neutrophils, C5a significantly inhibited RhoA activation, preventing actin polymerization and phagocytosis. RhoA inhibition was mediated by PI3K␦. The effects on RhoA, actin, and phagocytosis were fully reversed by GM-CSF. Parallel observations were made in neutrophils from critically ill patients, that is, impaired phagocytosis was associated with inhibition of RhoA and actin polymerization, and reversed by GM-CSF. Among a cohort of 60 critically ill patients, C5a-mediated neutrophil dysfunction (as determined by reduced CD88 expression) was a strong predictor for subsequent acquisition of nosocomial infection (relative risk, 5.8; 95% confidence interval, 1.5-22; P ‫؍‬ .0007), and remained independent of time effects as assessed by survival analysis (hazard ratio, 5.0; 95% confidence interval, 1.3-8.3; P ‫؍‬ .01). In conclusion, this study provides new insight into the mechanisms underlying immunocompromise in critical illness and suggests novel avenues for therapy and prevention of nosocomial infection. (Blood. 2011;117(19):5178-5188) IntroductionThe systemic inflammatory response syndrome (SIRS) is classically characterized by profound immune activation, accompanying massive cytokinemia and organ damage. 1,2 However, SIRS is accompanied by a counter-regulatory immune suppression sometimes termed the compensatory anti-inflammatory response syndrome (CARS). 3 This relative immune suppression is considered important for effective resolution of inflammation but may extend to maladaptive counter-regulatory anti-inflammatory responses. 4,5 The consequences of impaired immune function include enhanced susceptibility to nosocomial infection 6 or death from sepsis. 7 Neutrophils are the major front-line cellular defense against bacterial pathogens, and acquired defects in neutrophil function have been identified in both animal and human sepsis 8,9 as well as sterile SIRS. 10,11 However, the mediators driving these defects, and the mechanisms involved, remain uncertain.Animal studies have implicated uncontrolled activation of the complement system in the pathogenesis of sepsis and sterile SIRS. [12][13][14] The key components mediating vasodilatation and vascular leak-the hallmarks of septic shock-are the anaphylatoxins. These are activated forms of complement factors 3 (C3a) and 5 (C5a). 14,15 Animal models of sepsis have also implicated C5a in neutrophil dysfunction. 8 Because of the rapid clearance (2-to 3-minute half life) of C5a from the circulation, measurement of plasma concentrations gives an imprecise account of neutrophil expos...

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Polymorphonuclear Leukocyte Dysfunction Syndrome in Patients With Increasing Sepsis Severity

Cited by 81 publications

References 35 publications

Preclinical Evaluation of Targeting the Nrf2 Pathway by Triterpenoids (CDDO-Im and CDDO-Me) for Protection from LPS-Induced Inflammatory Response and Reactive Oxygen Species in Human Peripheral Blood Mononuclear Cells and Neutrophils

Preclinical Evaluation of Targeting the Nrf2 Pathway by Triterpenoids (CDDO-Im and CDDO-Me) for Protection from LPS-Induced Inflammatory Response and Reactive Oxygen Species in Human Peripheral Blood Mononuclear Cells and Neutrophils

Sepsis: Redox Mechanisms and Therapeutic Opportunities

C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients

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