Peptidoglycan of Staphylococcus aureus causes inflammation and organ injury in the rat.

OBJECTIVE

Previous studies have implicated a role of peptidoglycan in the pathophysiology of organ injury in sepsis. However, the systemic response to, and organ injury caused by, peptidoglycan have been scarcely studied in vivo.

DESIGN

Prospective, randomized study.

SETTING

University-based research laboratory.

SUBJECTS: Fifty-seven anesthetized, male Wistar rats.

INTERVENTIONS: After surgical preparation, anaesthetized rats were administered 3 mg/kg Staphylococcus aureus peptidoglycan (n = 9), 10 mg/kg S. aureus peptidoglycan (n = 14), or an equal volume of saline (sham, n = 12) in the jugular vein over a 10-min period.

MEASUREMENTS AND MAIN

RESULTS

Injection of low-dose peptidoglycan (3 mg/kg) had no measurable effects on the rats. In contrast, high-dose peptidoglycan (10 mg/kg) caused increased serum values of aspartate aminotransferase (p < or =.005), alanine aminotransferase (p < or =.001), gamma-glutamyltransferase, and bilirubin (p < or =.05) (indicators of liver injury/dysfunction) as well as a moderate, but significant, increase in serum creatinine and urea (p < or =.05) (indicators of renal dysfunction). Plasma analyses showed a substantial increase in plasma values of tumor necrosis factor-alpha, interleukin-6, and interleukin-10 (p < or =.05 for all vs. sham) at 1 and 3 hrs (enzyme-linked immunosorbent assay). This was accompanied by accumulation of messenger RNAs for tumor necrosis factor-alpha, interleukin-6, and interleukin-10 in both the liver and the lung (p < or =.05 for all cytokines vs. sham) (real-time polymerase chain reaction). Peptidoglycan also caused increased DNA binding of nuclear factor-kappaB (band-shift assays) and phosphorylation of c-Jun and Jun N-terminal kinase (Western blots). In the kidney, interleukin-6 messenger RNA was increased, whereas Toll-like receptor 4 messenger RNA was significantly decreased.

CONCLUSIONS

These results demonstrate that injection of peptidoglycan alone causes organ injury/dysfunction, organ inflammation, and systemic inflammation in the rat, involving nuclear factor-kappaB and possibly activator protein 1. These data support the contention that peptidoglycan is a contributing factor in the pathophysiology of organ injury in sepsis.