INTERFERON -y, A MEDIATOR OF LETHAL LIPOPOLYSACCHARIDE-INDUCED SHWARTZMAN-LIKE

LPS, a cell wall component of all Gram-negative bacteria, is well known to be responsible for a large part of the toxic manifestations associated with infections by such bacteria. When administered to experimental animals, LPSinduces pathophysiologic changes that vary with the experimental conditions . A generalized and potentially lethal inflammatory reaction, known as the generalized Shwartzman reaction, can be elicited in several animal species, especially in rabbits (1), but also in mice (2). Typically, the reaction requires two consecutive, relatively low doses of LPS and is clinically manifested as a shock syndrome . The occurrence ofthe syndrome always requires careful dosage and timing (2). This reaction is of particular interest, since it shares pathogenetic elements with septic shock in humans, a condition that occurs with increasing frequency, and is a major cause of death among hospitalized patients in intensive care units . Evidence from many studies indicates that the complex pathogenesis of septic shock and of the LPS-induced reactions is orchestrated by a complex network of endogenous mediators, whose release is triggered by the interaction of LPS with various cell types, especially phagocytes and endothelial cells . In recent years one particular group of mediators, the cytokines, has elicited considerable interest for their role in the LPS-induced inflammatory responses. Direct as well as indirect observations indicate that TNFa and IL-1, two cytokines mainly produced by macrophages/monocytes, maybe the principal mediators ofthe endotoxin-induced lethality. Thus, both these cytokines are released into the blood stream in humans (3, 4) or animals (3, 5) after intentional exposure to endotoxin, as well as during septic shock or meningococcal infection in patients (6-8) . Furthermore, TNF induces profound shock, tissue injury, and death when infused into experimental animals (9-13) . Moreover, a very strong synergism between TNF and bacteria or their products in causing a generalized Shwartzman-like reaction has been observed (14, 15). Finally, lethality