Bacterial infection of the mammalian bloodstream can lead to overwhelming sepsis, a potentially fatal syndrome of irreversible cardiovascular collapse (shock) and critical organ failure. Cachectin, also known as tumour necrosis factor, is a macrophage-derived peptide hormone released in response to bacterial lipopolysaccharide, and it has been implicated as a principal mediator of endotoxic shock, although its function in bacterial sepsis is not known. Anaesthetized baboons were passively immunized against endogenous cachectin and subsequently infused with an LD100 dose of live Escherichia coli. Control animals (not immunized against cachectin) developed hypotension followed by lethal renal and pulmonary failure. Neutralizing monoclonal anti-cachectin antibody fragments (F(ab')2) administered to baboons only one hour before bacterial challenge protected against shock, but did not prevent critical organ failure. Complete protection against shock, vital organ dysfunction, persistent stress hormone release and death was conferred by administration of antibodies 2 h before bacterial infusion. These results indicate that cachectin is a mediator of fatal bacteraemic shock, and suggest that antibodies against cachectin offer a potential therapy of life-threatening infection.

Severe weight loss and debilitative wasting of lean body mass frequently complicate the treatment of patients suffering from malignancy or chronic infection. Termed cachexia, this syndrome of anorexia, anemia, and weakness further increases cancer mortality; some data indicate that as many as 30% of cancer patients die from cachexia, rather than tumor burden (1-3). The severity of cachexia may be unrelated to tumor size or parasite load, and profound wasting has been observed in patients with tumor burdens of only 0.01-5.0% body mass (4). If not reversed, cachexia-associated derangements of homeostasis lead to immunological deficiencies, organ failure, and multiple metabolic abnormalities . While it is clear that a variety of mechanisms participate in the pathogenesis of cachexia, and that cachexia adversely affects prognosis, the etiology of this syndrome is not known.For a number of years we have been searching for endogenous, humoral mediators of cachexia, beginning with the characterization of metabolic changes in trypanosome-infected rabbits that develop profound cachexia and lose up to 50% of lean body mass within weeks. In later stages of disease a paradoxical increase in circulating triglycerides occurs, attributable to systemic suppression of lipoprotein lipase (LPL)t (5). A bacterial LPS-inducible serum factor which suppresses LPL in mice, and several other key lipogenic enzymes in the adipocyte cell line 3T3-L1, was isolated and named cachectin (6, 7). Cachectin evokes a state of cellular cachexia by suppressing the expression of several mRNAs encoding essential lipogenic enzymes (8, 9). Myocytes also show changes in cellular metabolism after exposure to cachectin in vitro, including a prompt decrease in resting transmembrane potential difference and depletion of intracellular glycogen stores with increased lactate efflux, and a later increase in hexose transporters (10,11). It has been suggested that cachectin may play a

Cytokines secreted in response to invading micro-organisms are important mediators of detrimental hemodynamic and metabolic changes in the host. To test whether cachectin/TNF plays a role in triggering release of other cytokines in the setting of infection, anesthetized baboons were passively immunized against systemic cachectin/TNF before infusion of a LD100 dose of live Escherichia coli. Bacteremia led to significant increases in circulating levels of cachectin/TNF, IL-1 beta, and IL-6. Although bacterial endotoxin/lipopolysaccharide is a potent stimulus for the synthesis and release of IL-1 and IL-6 in vitro, specific neutralization of cachectin/TNF in vivo with mAb pretreatment significantly attenuated both the IL-1 beta and the IL-6 responses despite fulminant overwhelming bacteremia. These data suggest that cachectin/TNF is essential for the initiation or amplification of IL-1 and IL-6 release during lethal gram-negative septic shock syndrome.