Cell Walls of Saccharomyces cerevisiae Differentially Modulated Innate Immunity and Glucose Metabolism during Late Systemic Inflammation

BACKGROUND: Salmonella causes acute systemic inflammation by using its virulence factors to invade the intestinal epithelium. But, prolonged inflammation may provoke severe body catabolism and immunological diseases. Salmonella has become more life-threatening due to emergence of multiple-antibiotic resistant strains. Mannose-rich oligosaccharides (MOS) from cells walls of Saccharomyces cerevisiae have shown to bind mannose-specific lectin of Gram-negative bacteria including Salmonella, and prevent their adherence to intestinal epithelial cells. However, whether MOS may potentially mitigate systemic inflammation is not investigated yet. Moreover, molecular events underlying innate immune responses and metabolic activities during late inflammation, in presence or absence of MOS, are unknown. METHODS AND PRINCIPAL FINDINGS: Using a Salmonella LPS-induced systemic inflammation chicken model and microarray analysis, we investigated the effects of MOS and virginiamycin (VIRG, a sub-therapeutic antibiotic) on innate immunity and glucose metabolism during late inflammation. Here, we demonstrate that MOS and VIRG modulated innate immunity and metabolic genes differently. Innate immune responses were principally mediated by intestinal IL-3, but not TNF-α, IL-1 or IL-6, whereas glucose mobilization occurred through intestinal gluconeogenesis only. MOS inherently induced IL-3 expression in control hosts. Consequent to LPS challenge, IL-3 induction in VIRG hosts but not differentially expressed in MOS hosts revealed that MOS counteracted LPS's detrimental inflammatory effects. Metabolic pathways are built to elucidate the mechanisms by which VIRG host's higher energy requirements were met: including gene up-regulations for intestinal gluconeogenesis (PEPCK) and liver glycolysis (ENO2), and intriguingly liver fatty acid synthesis through ATP citrate synthase (CS) down-regulation and ATP citrate lyase (ACLY) and malic enzyme (ME) up-regulations. However, MOS host's lower energy demands were sufficiently met through TCA citrate-derived energy, as indicated by CS up-regulation. CONCLUSIONS: MOS terminated inflammation earlier than VIRG and reduced glucose mobilization, thus representing a novel biological strategy to alleviate Salmonella-induced systemic inflammation in human and animal hosts

Selective iNOS inhibition for the treatment of sepsis-induced acute kidney injury.

Contains fulltext : 81592.pdf (publisher's version ) (Closed access)The incidence and mortality of sepsis and the associated development of acute kidney injury (AKI) remain high, despite intense research into potential treatments. Targeting the inflammatory response and/or sepsis-induced alterations in the (micro)circulation are two therapeutic strategies. Another approach could involve modulating the downstream mechanisms that are responsible for organ system dysfunction. Activation of inducible nitric oxide (NO) synthase (iNOS) during sepsis leads to elevated NO levels that influence renal hemodynamics and cause peroxynitrite-related tubular injury through the local generation of reactive nitrogen species. In many organs iNOS is not constitutively expressed; however, it is constitutively expressed in the kidney and, in humans, a relationship between the upregulation of renal iNOS and proximal tubular injury during systemic inflammation has been demonstrated. For these reasons, the selective inhibition of renal iNOS might have important implications for the treatment of sepsis-induced AKI. Various animal studies have demonstrated that selective iNOS inhibition-in contrast to nonselective NOS inhibition-attenuates sepsis-induced renal dysfunction and improves survival, a finding that warrants investigation in clinical trials. In this Review, the selective inhibition of iNOS as a potential novel treatment for sepsis-induced AKI is discussed