The novel inosine analogue INO-2002 exerts an anti-inflammatory effect in a murine model of acute lung injury.

Endogenous purines, including inosine, have been shown to exert immunomodulatory and anti-inflammatory effects in a variety of disease models. The dosage of inosine required for these effects has been shown to be between 200 and 600 mg kg(-1) because of the rapid metabolism of inosine in vivo. The aim of this study was to determine whether a metabolic resistant purine analog, INO-2002, exerts anti-inflammatory effects in an animal model of acute respiratory distress syndrome.

Lung-protective effects of the metalloporphyrinic peroxynitrite decomposition catalyst WW-85 in interleukin-2 induced toxicity.

Recombinant interleukin-2 (IL-2) therapy for malignancy is associated with a pulmonary vascular leakage syndrome (VLS) similar to that seen in sepsis. We investigated the possibility that the IL-2-induced VLS may be associated with the release of peroxynitrite (ONOO(-)), and used a model of IL-2-induced VLS in sheep to test the effects of the ONOO(-) decomposition catalyst WW-85. Eighteen sheep were chronically instrumented and randomly divided into three groups (n=6 per group): sham: lactated Ringer's solution, control: IL-2, and treatment: IL-2 and WW-85.

The novel inosine analogue, INO-2002, protects against diabetes development in multiple low-dose streptozotocin and non-obese diabetic mouse models of type I diabetes.

Endogenous purines including inosine have been shown to exert immunomodulatory and anti-inflammatory effects in a variety of disease models. The dosage of inosine required for protection is very high because of the rapid metabolism of inosine in vivo. The aim of this study was to determine whether a metabolic-resistant purine analogue, INO-2002, exerts anti-inflammatory effects in two animal models of type I diabetes.

Gender differences in the endotoxin-induced inflammatory and vascular responses: potential role of poly(ADP-ribose) polymerase activation.

Activation of poly(ADP-ribose) polymerase (PARP) is an important factor in the pathogenesis of various cardiovascular and inflammatory diseases. Here, we report that the gender-specific inflammatory response is preferentially down-regulated by PARP in male animals. Female mice produce less tumor necrosis factor-alpha and macrophage inflammatory protein-1alpha in response to systemic inflammation induced by endotoxin than male mice and are resistant to endotoxin-induced mortality.

Antibodies raised against N'-terminal Pseudomonas aeruginosa flagellin prevent mortality in lethal murine models of infection.

The goal of this study was to investigate if antibodies raised against N'-terminal Pseudomonas aeruginosa (Pa) flagellin could afford protection in two lethal mouse models of Pa infection. To that end, rabbit polyclonal antibodies were generated against the N'-terminal domains (amino acids 1-156) of recombinant Pa01 or Salmonella muenchen flagellins, termed anti-N'-fla-b and anti-N'-fla-Sm, respectively. In vitro, anti-N'-fla-b but not anti-N'-fla-Sm IgG specifically recognized recombinant and Pa endogenous flagellin type b proteins, total bacterial lysates of Pa type b, and inhibited Pa01 invasion into A549 cells.

Activation of poly(ADP-ribose) polymerase in circulating leukocytes during myocardial infarction.

Myocardial ischemia-reperfusion can lead to increased oxidative stress both locally and in circulating leukocytes. Oxidant-mediated DNA single strand breaks are known to activate the nuclear enzyme poly(ADP-ribose) polymerase (PARP) in various forms of shock, inflammation, and ischemia-reperfusion injury. The aim of the current study was to investigate whether a local insult such as myocardial ischemia-reperfusion is sufficient to lead to activation of PARP in circulating leukocytes.

Identification of conserved domains in Salmonella muenchen flagellin that are essential for its ability to activate TLR5 and to induce an inflammatory response in vitro.

The bacterial surface protein flagellin is widely distributed and well conserved among distant bacterial species. We and other investigators have reported recently that purified flagellin from Salmonella dublin or recombinant flagellin of Salmonella muenchen origin binds to the eukaryotic toll receptor TLR5 and activates the nuclear translocation of NF-kappaB and mitogen-activated protein kinase, resulting in the release of a host of pro-inflammatory mediators in vitro and in vivo. The amino acid sequence alignment of flagellins from various Gram-negative bacteria shows that the C and N termini are well conserved.

The Flagellin-TLR5 Axis: Therapeutic Opportunities.

Motile bacteria synthesize large-sized surface structures known as flagella through the ordered polymerization of protein subunits. Flagellin, a protein of 40-60 kDa, is the principal constituent of the flagellum; each flagellum consists of approximately 20,000 flagellin molecules. An alignment of the amino acid sequences from different Gram-negative species shows a high degree of similarity in the amino and carboxy terminal domains.

Requirements of the RNA polymerase II C-terminal domain for reconstituting pre-mRNA 3' cleavage.

RNA polymerase II (RNAP II) has previously been shown to be required for the pre-mRNA polyadenylation cleavage reaction in vitro. This activity was found to reside solely in the C-terminal domain (CTD) of the enzyme's largest subunit. Using a deletion analysis of glutathione S-transferase-CTD fusion proteins, we searched among the CTD's 52 imperfectly repetitive heptapeptides for the minimal subset that possesses this property.

Comparison of inflammation, organ damage, and oxidant stress induced by Salmonella enterica serovar Muenchen flagellin and serovar Enteritidis lipopolysaccharide.

Gram-negative sepsis is related to the activation of interconnected inflammatory cascades in response to bacteria and their products. Recent work showed that flagellin, the monomeric subunit of bacterial flagella, triggers innate immune responses mediated by Toll-like receptor 5. Here, we compared the effects of Salmonella enterica serovar Enteritidis lipopolysaccharide (LPS) and recombinant Salmonella enterica serovar Muenchen flagellin administered intravenously (100 microg) to mice.