Induction of endotoxin (ET) tolerance by atoxic endotoxin - a new prophylactic concept to the septic syndrome

Abstract

Repeated, small doses of ET induces resistance to subsequent larger doses of ET in both animals and men. This preconditioning, termed ET tolerance is a well-controlled active response that is orchestrated to prevent excessive inflammation. The ET of distantly related Gram-negative bacterial species like the sulfur-containing or the sulfur-free purple bacteria appear to have low endotoxicity or to be completely non-toxic but maintain many of the beneficial immunomodulatory activities. The present experiment was designed to test the response to the non-toxic ET of Rhodopseudomonas sphaeroides to protect the animals after 5 days of immunization against a continuous ET challenge-dose of 250 ng/kg BW/h over a 12 h observation period. Results are summarized in the Table below. Clinical signs of endotoxemia could be observed in both groups within the first hour of the experiment. However, in contrast to the tolerant animals which appeared cardiorespiratorily stable for most of the observation period, the control animals sustained serious reductions in MAP, CO and arterial PaO2 (see Table). While only one animal survived in the control group only one animal died in the tolerant group during the observation period. The encouraging results of this study emphasize the potential role of atoxic ET as a therapeutic agent. As a new prophylactic approach ET tolerance as such seems interesting — as prophylaxis in high-risk patients it may prevent septic complications. The tolerance state however is relative and never complete — it can be overcome by raising the ET challenge dose or adding other negative stimuli like second or subsequent hit. Table