A cell wall component from pathogenic and non-pathogenic gram-positive bacteria (peptidoglycan) synergises with endotoxin to cause the release of tumour necrosis factor-alpha, nitric oxide production, shock, and multiple organ injury/dysfunction in the rat

Abstract

The incidence of sepsis and septic shock due to gram-positive organisms has increased dramatically over the last two decades. Interestingly, many patients with sepsis/septic shock have both gram-positive and gram-negative bacteria present in the bloodstream and these polymicrobial or "mixed" infections often have a higher mortality than infection due to a single organism. The reason for this observation is unclear. The aim of this study was to investigate whether cell wall fragments from gram-positive and gram-negative bacteria could synergise to cause the release of cytokines, shock, and organ injury/ dysfunction in vivo. Male Wistar rats were anaesthetised and received an intravenous bolus of vehicle (saline), lipopolysaccharide (LPS) from Escherichia coli (0.1 mg/kg), peptidoglycan (Pep G) from Staphylococcus aureus (S10 mg/kg), co-administration of LPS (0.1 mg/kg) and PepG from S. aureus (10 mg/kg), LPS (10 mg/kg), PepG from Bacillus subtilis, or co-administration of LPS and PepG from B. subtilis. Blood pressure and heart rate were monitored for 6 h before plasma samples were taken for the measurement of TNF-alpha, total nitrite, and biochemical indices of organ injury. Peptidoglycan from both pathogenic (S. aureus) and non-pathogenic (B. subtilis) gram-positive bacteria synergised with endotoxin to cause formation of TNF-alpha, nitrite, shock, and organ injury. Synergism between PepG and LPS may partly explain the high mortality associated with mixed bacterial infections, as well as the deleterious effects of translocation of bacteria, or their cell wall components from the gut lumen in patients with sepsis.