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John Arcaroli

Publications and source records attributed to John Arcaroli.

10 recordsLinked to original sources
PubMed2006

Variant IRAK-1 haplotype is associated with increased nuclear factor-kappaB activation and worse outcomes in sepsis.

RATIONALE: The IL-1 receptor-associated kinase (IRAK-1) plays a central role in TLR2- and TLR4-induced activation of nuclear factor (NF)-kappaB, a critical event in the transcriptional regulation of many sepsis-associated proinflammatory mediators. There are two haplotypes for the IRAK-1 gene in Caucasians, with the variant haplotype consisting of five intron single-nucleotide polymorphisms (SNPs) and three exon SNPs. OBJECTIVES: To examine the functional significance of the IRAK-1 variant haplotype in modifying nuclear translocation of NF-kappaB and affecting outcomes from sepsis. MEASUREMENTS AND MAIN RESULTS: One hundred fifty-five Caucasian patients with sepsis were included. Twenty-one (14%) were homozygous for the IRAK-1 variant haplotype as determined by a SNP in which T is replaced with C at nucleotide 1,595 within exon 12 of the IRAK-1 gene. The IRAK-1 variant haplotype was associated with increased nuclear levels of NF-kappaB in LPS-stimulated peripheral blood neutrophils from patients with sepsis compared with that found in patients with wild-type IRAK-1 haplotype (p=0.0009). There was an increased incidence of shock (p=0.047) (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.1-7.7), greater requirement for more prolonged mechanical ventilator support (p=0.04) (OR, 2.7; 95% CI, 1.05-6.9), and higher 60-d mortality (p=0.05) (OR, 2.7; 95% CI, 1.0-6.8) in patients with the IRAK-1 variant haplotype compared with wild type. CONCLUSIONS: These results indicate that the IRAK-1 variant haplotype is functionally significant in patients with sepsis, being associated with increased nuclear translocation of NF-kappaB, more severe organ dysfunction, and higher mortality.

Adolescent↗
PubMed2005

Genetic polymorphisms and sepsis.

Sepsis is a polygenic and complex syndrome that is initiated by infection and is characterized by a systemic inflammatory response. Genetic polymorphisms in the immune response to infection have been shown to be associated with clinical outcomes. Functional and association studies involving genetic polymorphisms in essential genes, including Toll-like receptors, cytokines, and coagulation factors, have provided important insights into the mechanisms involved in the pathogenesis of sepsis-induced organ dysfunction. The advancement of high-throughput single nucleotide polymorphism (SNP) genotyping will provide valuable information on the interaction of multiple allelic variants and clinical outcome. More precise categorization of patients based on genetic background is likely to lead to individualized targeted treatment. Future therapeutic trials as well as actual treatment regimens for patients with sepsis are likely to be designed to target specific genotypes and associated cellular responses, maximizing clinical response and patient safety.

Animals↗
PubMed2004

Hemorrhage-induced acute lung injury is TLR-4 dependent.

Toll-like receptor 4 (TLR-4), initially identified as an LPS receptor, is critical to the signaling of a variety of danger signals, including heat shock protein 60, fibrinogen, and fibronectin. Recent data also suggest that TLR-4 plays a role in determining survival in both endotoxemia and hemorrhagic shock. We hypothesized that a functional TLR-4 would be required for hemorrhage and endotoxin-induced acute lung injury. Hemorrhage- and endotoxin-induced lung TNF-alpha mRNA and protein production, neutrophil accumulation, and protein permeability were dependent on a functional TLR-4. Hemorrhage-induced nuclear factor (NF)-kappaB activation was independent of functional TLR-4, whereas endotoxin-induced activation of NF-kappaB requires a functional TLR-4 for full response. Therefore, we conclude that 1) hemorrhage-induced acute lung injury is TLR-4 dependent and 2) hemorrhage has a different and distinct TLR-4-dependent intracellular activation mechanism compared with endotoxemia.

Acute Disease↗
PubMed2003

Modulation of bone marrow-derived neutrophil signaling by H2O2: disparate effects on kinases, NF-kappaB, and cytokine expression.

Reactive oxygen species (ROS), including hydrogen peroxide (H2O2), are generated in increased amounts in pathological, biological processes and can play a role in signal transduction. Neutrophils often accumulate in acute inflammatory reactions, at sites where elevated concentrations of ROS are present. ROS have been demonstrated to participate in the activation of intracellular signaling pathways, including those involved in modulating nuclear accumulation and transcriptional activity of NF-kappaB. However, the role of ROS in affecting such events in neutrophils has not been examined. Using exposure of murine bone marrow neutrophils to H2O2 as a model of oxidative stress, we found both strong and persistent activation of ERK1/2, p38, JNK, and PKB, but not the p21-activated kinase. Stimulating the bone marrow-derived neutrophils with H2O2 did not affect nuclear translocation of NF-kappaB. However, production and secretion of the proinflammatory cytokine TNF-alpha in LPS-stimulated neutrophils were inhibited by H2O2. Exposure of LPS- or TNF-alpha-stimulated neutrophils to H2O2 decreased nuclear translocation of NF-kappaB. LPS-induced activation of the transcriptional factor AP-1 was also inhibited by H2O2. This inhibition of nuclear accumulation of NF-kappaB by H2O2 was not caused by an impaired capacity of LPS to stimulate the IKK pathway or to direct oxidative effects on NF-kappaB but rather reflected diminished degradation of IkappaB-alpha. These results indicate that oxidative stress, despite being able to selectively activate intracellular kinases in bone marrow-derived neutrophils, also inhibits NF-kappaB activation and associated TNF-alpha expression. Such inhibitory effects on neutrophil activation may limit tissue damage produced by oxidative stress.

Animals↗
PubMed2003

Urokinase-type plasminogen activator potentiates lipopolysaccharide-induced neutrophil activation.

Urokinase plasminogen activator (uPA) is a serine protease that catalyzes the conversion of plasminogen to plasmin. Although increased circulating levels of uPA are present in endotoxemia and sepsis, conditions in which activated neutrophils contribute to the development of acute organ dysfunction, the ability of uPA to participate directly in LPS-induced neutrophil activation has not been examined. In the present experiments, we show that uPA can enhance activation of neutrophils exposed to submaximal stimulatory doses of LPS. In particular, uPA increased LPS-induced activation of intracellular signaling pathways, including Akt and c-Jun N-terminal kinase, nuclear translocation of the transcriptional regulatory factor NF-kappa B, and expression of proinflammatory cytokines, including IL-1 beta, macrophage-inflammatory protein-2, and TNF-alpha. There was no effect of uPA on LPS-induced activation of p38 mitogen-activated protein kinase in neutrophils. Transgenic mice unable to produce uPA (uPA(-/-)) were protected from endotoxemia-induced lung injury, as determined by development of lung edema, pulmonary neutrophil accumulation, lung IL-1 beta, macrophage-inflammatory protein-2, and TNF-alpha cytokine levels. These results demonstrate that uPA can potentiate LPS-induced neutrophil responses and also suggest that such effects are sufficiently important in vivo to play a major contributory role in neutrophil-mediated inflammatory responses, such as the development of acute lung injury.

Active Transport, Cell Nucleus↗
PubMed2003

Evidence for extracellular superoxide dismutase as a mediator of hemorrhage-induced lung injury.

Hemorrhage results in excessive production of superoxide that is associated with severe lung injury. We examined whether the superoxide dismutase (SOD) mimetic manganese(III) mesotetrakis (di-N-ethylimidazole) porphyrin (AEOL 10150) could attenuate this lung injury and whether extracellular (EC)-SOD-deficient mice would have increased hemorrhage-induced lung injury. Compared with wild-type mice, EC-SOD-deficient mice had increased lung neutrophil accumulation, a 3.9-fold increase in myeloperoxidase activity, a 1.5-fold increase in nuclear factor (NF)-kappaB activation, and a 1.5-fold increase in lipid peroxidation 1 h after hemorrhage. Pretreatment with AEOL 10150 did not attenuate neutrophil accumulation but significantly reduced NF-kappaB activation and lipid peroxidation in both wild-type and EC-SOD-deficient mice. The increase in hemorrhage-induced neutrophil accumulation in the lungs of EC-SOD-deficient mice suggests that EC-SOD might play a role in mediating neutrophil recruitment to the lung.

Aconitate Hydratase↗
PubMed2003

Involvement of phosphatidylinositol 3-kinase gamma in neutrophil apoptosis.

Although phosphoinositide 3-kinases (PI3-K) are known to participate in anti-apoptotic pathways, their importance in modulating neutrophil apoptosis in vivo has not been examined. In these studies, we used neutrophils from mice lacking the PI3-Kgamma isoform (PI3-Kgamma-/-) to determine the role that PI3-Kgamma occupies in neutrophil apoptosis under in vivo conditions. We found that neutrophil apoptosis under basal and LPS-stimulated conditions was increased in PI3-Kgamma-/- mice compared to that present in control PI3-Kgamma+/+ animals. Neutrophils from PI3-Kgamma-/- mice demonstrated decreased amounts of active, serine 473 phosphorylated Akt, phosphorylated CREB, and diminished nuclear translocation of NF-kappaB. Levels of the CREB-dependent anti-apoptotic protein Mcl-1 and of the NF-kappaB-dependent anti-apoptotic mediator Bcl-x(L) were significantly decreased in PI3-Kgamma-/- neutrophils. In contrast, PI3-Kgamma-/- neutrophils contained diminished amounts of phosphorylated, inactive forms of the pro-apoptotic mediators, Bad, FKHR, and GSK-3beta. These results demonstrate that PI3-Kgamma directly participates in multiple in vivo pathways involved in regulating neutrophil apoptosis.

Animals↗
PubMed2003

Activation of gene expression in human neutrophils by high mobility group box 1 protein.

High mobility group box 1 (HMGB1) protein, a DNA binding protein that stabilizes nucleosomes and facilitates transcription, was recently identified as a late mediator of endotoxin lethality. High serum HMGB1 levels in patients with sepsis are associated with increased mortality, and administration of HMGB1 produces acute inflammation in animal models of lung injury and endotoxemia. Neutrophils occupy a critical role in mediating the development of endotoxemia-associated acute lung injury, but previously it was not known whether HMGB1 could influence neutrophil activation. In the present experiments, we demonstrate that HMGB1 increases the nuclear translocation of NF-kappaB and enhances the expression of proinflammatory cytokines in human neutrophils. These proinflammatory effects of HMGB1 in neutrophils appear to involve the p38 MAPK, phosphatidylinositol 3-kinase/Akt, and ERK1/2 pathways. The mechanisms of HMGB1-induced neutrophil activation are distinct from endotoxin-induced signals, because HMGB1 leads to a different profile of gene expression, pattern of cytokine expression, and kinetics of p38 activation compared with LPS. These findings indicate that HMGB1 is an effective stimulus of neutrophil activation that can contribute to development of a proinflammatory phenotype in diseases characterized by excessively high levels of HMGB1.

Biological Transport↗
PubMed2002

Effects of catecholamines on kinase activation in lung neutrophils after hemorrhage or endotoxemia.

Catecholamines are released in high levels after hemorrhage or endotoxemia and have been shown to modulate immune function, including cellular release of inflammatory mediators. In the present experiments, we examined the effects of endogenous and exogenous catecholamines on neutrophil accumulation and activation in the lungs using pretreatment with alpha- or beta-antagonists or alpha-adrenergic agonists before hemorrhage or endotoxemia. These studies showed that alpha-, but not beta-adrenergic stimuli, modulated the severity of acute lung injury after hemorrhage or endotoxemia, and alpha-adrenergic stimuli was proinflammatory after hemorrhage but anti-inflammatory after endotoxemia. The observed alpha-adrenergic effects on lung neutrophil activation appeared to involve primarily the extracellular signal-regulated kinase pathway at the upstream kinase Raf, but not Ras. Although p38 and protein kinase A were activated in lung neutrophils after hemorrhage or endotoxemia, these kinases were not affected by alpha- or beta-adrenergic modulation. These results demonstrate that catecholamines have important immunomodulatory effects in vivo that affect intracellular signaling pathways in neutrophils and neutrophil-driven, inflammatory processes such as the development of acute lung injury.

Adrenergic alpha-Agonists↗