276 Bums (1991) 17, (4), 276-278 Printed in zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Great zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Britain Platelet-activating factor induces intestinal necrosis, but not septic shock, in germ-free and specific- pathogen-free rodents E. J. Schiffrin, M. Trop, S. Schroeder and E. A. Carter Massachusetts General Hospital, Shriner Bums Hospital, Harvard Medical School, Boston, USA Plafelet-acfivating facfor (FM) was injecfed info convenfional mice, endotoxin-resistant mice(C3H/HE]], conventional ruQ germ-free rats and specific-pathogen-free (SPF) mice. The PAF resulted in significanf necrosis and damage to Ihe small intestines of all the animals tested. In general, the frequency and sever& of the lesions were similar in all groups. All the conventional rats and mice, as well as the endototin-resistant HE] mice, were dead zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 18 h affer the injection of fhe F!! while all fhe germ-free rak and the SPF mice survived. These data demonstrate that development of massive intestinal lesions, in theabsence of aerobic bacteria, is not suficient to cause the death of the host from septic shock and endofoxaemia. Introduction Gram-negative bacteria such as Enterobacteriaceae and Pseudomonadaceae are normal inhabitants of the intestines. Under normal conditions, these bacteria are prevented from entering the sterile environment of the host. However, when host intestinal barrier defense mechanisms are compromised by underlying diseases such as malignant neoplasms, renal insufficiency, extensive trauma, or immunosuppressive therapy, there is invasion of the blood stream by enteric microorganisms. Therefore, Gram- negative septicaemia remains a major cause of mortality and morbidity in burned patients (Burke et al., 1977; Rocco et al., 1989), postsurgical trauma patients (Oettinger and Beger, 1989), patients with multiple organ failure (Cerra et al., 1990), and patients on chemotherpay (Rolston et al., 1990). One possible source of contamination by Gram- negative organisms in these patients is the gastrointestinal tract. The aim of this paper is to determine if damage to the intestines, and the subsequent production of septic shock and death, is related to the luminal bacterial content of the gut. Our present data suggests that in the absence of Gram-negative bacteria, intestinal necrosis per se is not sufficient to produce sepsis and death. In order to produce alterations of the intestines, without first damaging this organ on the luminal surface, some form of mediator-induced response must be proposed. Lipo- polysaccharide (LPS) and tumour necrosis factor (TNF) 0 1991 Buttenvorth-Heinemann Ltd 0305-4179/91/040276-03 injection have been shown to result in the production of platelet-activating factor (PAF), which has been clearly demonstrated to cause small intestinal necrosis (Gonzalez- Crussi and Hsueh, 1983; Hsueh et al., 1987; Sun and Hsueh, 1988). This damage could be prevented by pretreatment with a PAF antagonist (Hsueh et al., 1987; Sun and Hsueh, 1988). LPS, from a distant site of tissue damage or infection, may trigger the release of PAF. Such intestinal damage would subsequently cause further release of more endotoxin or bacteria. When sufficient contamination by Gram- negative organisms occurs, as depicted in Fipre I, the final result of such a positive feedback cycle is a septic condition. In the present study, we have attempted to test the above hypotheses by systemically producing severe intestinal damage, by the injection of PAP, into mice resistant to LPS TNF - PAF /’ \ LPS INTESTINAL 1 LEAKAGE /GE BACTERIA LPS AND RELATED PRODUCTS 1 SEPSIS I + DEATH Figure 1. Schematic relationship between intestinal damage and sepsis.