lipoteichoic-acid and Systemic-Inflammatory-Response-Syndrome

Nerve injury-induced protein (Ninjurin [Ninj]) 1 is an adhesion molecule originally identified in Schwann cells after nerve injury, whereas it is also expressed in leukocytes, epithelium, endothelium, and various organs, and is induced under inflammatory conditions. Its contribution to inflammation was so far restricted to the nervous system and exclusively attributed to its role during leukocyte migration. We hypothesized a proinflammatory role for Ninj1 also outside the nervous system. To elucidate its impact during inflammation, we analyzed expression levels and its contribution to inflammation in septic mice and studied its effect on inflammatory signaling in vitro. The effect on inflammation was analyzed by genetic (only in vitro) and pharmacologic repression in septic mice (cecal ligation and puncture) and cell culture, respectively. Repression of Ninj1 by an inhibitory peptide or small interfering RNA attenuated LPS-triggered inflammation in macrophages and endothelial cells by modulating p38 phosphorylation and activator protein-1 activation. Inhibition of Ninj1 in septic mice reduced systemic and pulmonary inflammation as well as organ damage, and ameliorated survival after 24 hours. Ninj1 is elevated under inflammatory conditions and contributes to inflammation not only by mediating leukocyte migration, but also by modulating Toll-like receptor 4-dependent expression of inflammatory mediators. We assume that, owing to both mechanisms, inhibition reduces systemic inflammation and organ damage in septic mice. Our data contribute to a better understanding of the complex inflammatory mechanisms and add a novel therapeutic target for inflammatory conditions such as sepsis.

Topics: Animals; Cell Adhesion Molecules, Neuronal; Cell Movement; Disease Models, Animal; Endothelial Cells; Gene Expression Regulation; Humans; Leukocytes, Mononuclear; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Nerve Growth Factors; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Poly I-C; Primary Cell Culture; Sepsis; Signal Transduction; Systemic Inflammatory Response Syndrome; Teichoic Acids; Toll-Like Receptor 4; Transcription Factor AP-1; Tumor Necrosis Factor-alpha

Preconditioning with bacterial wall fragments lipopolysaccharide (LPS) or lipoteichoic acid (LTA) reduce myocardial infarct size after ischaemia and reperfusion (I/R) in rats. Preconditioning with LTA reduces neutrophil accumulation during reperfusion and thereby ameliorates one of myocardial reperfusion injury's most important mechanisms. In this study, we use an ex vivo model of regional myocardial I/R to investigate LTA versus LPS induced preconditioning in a system devoid of leukocytes.. Rats were subjected to LTA or LPS with or without dexamethasone pre-treatment. Twenty-four hours after LTA or LPS challenge, hearts were removed and retrogradely perfused in a Langendorff set-up. Hearts underwent 20 min of regional ischaemia followed by 2 h of reperfusion. Ischaemic preconditioning (IPC) was performed as a positive control. Myocardial infarct size was determined as the primary end-point.. LTA and LPS preconditioning both lead to a marked reduction in infarct size similar to IPC, however, no significant differences were found between LTA and LPS. The reduction in infarct size was abrogated by dexamethasone pre-treatment.. We conclude that preconditioning with LTA and likewise with LPS confers myocardial protection in an ex vivo setting devoid of leukocytes. Dexamethasone inhibits preconditioning, suggesting that the underlying mechanism is dependent upon induction of a systemic inflammatory response to a LTA or LPS stimulus.

Topics: Animals; Anti-Inflammatory Agents; Dexamethasone; Disease Models, Animal; Endotoxins; Ischemic Preconditioning, Myocardial; Lipopolysaccharides; Male; Myocardial Infarction; Neutrophils; Rats; Rats, Wistar; Systemic Inflammatory Response Syndrome; Teichoic Acids

Phagocytes play a major role in host defense against staphylococci as well as in the pathophysiology of Gram-positive septic shock. In Gram negative sepsis, the main mediator, LPS exerts its effects as easily suspendable mediator. In Gram positive sepsis the main mediator is still not found, therefore we studied the interaction of soluble staphylococcal products with phagocytes. Staphylococcus aureus supernates (SaS) were harvested from several laboratory and clinical strains that were grown to late-log phase. These supernates upregulated CD11b/CD18 expression on human neutrophils even in a 100-fold dilution. SaS also induced the release of TNF-alpha and IL-1 beta by human monocytes. Control experiments excluded peptidoglycan, lipoteichoic acid, alpha and delta toxin, leucocidin, TSST-1 and all enterotoxins as sole mediators. Endotoxin contamination was also excluded. SaS was heat-stable; incubation for 45 minutes at 100 degrees C did not affect its activity. Compared to purified peptidoglycan and intact bacteria per bacterium, SaS had a higher potency in stimulating phagocytes. We hypothesize that there are more--yet unknown--soluble staphylococcal products which are very important in phagocyte stimulation.

Topics: Bacterial Toxins; CD18 Antigens; Humans; In Vitro Techniques; Interleukin-1; Lipopolysaccharides; Macrophage-1 Antigen; Monocytes; Neutrophils; Peptidoglycan; Phagocytes; Staphylococcal Infections; Staphylococcus aureus; Systemic Inflammatory Response Syndrome; Teichoic Acids; Tumor Necrosis Factor-alpha; Up-Regulation