Cachectin (tumor necrosis factor), a protein produced in large quantities by endotoxin-activated macrophages, has been implicated as an important mediator of the lethal effect of endotoxin. Recombinant human cachectin was infused into rats in an effort to determine whether cachectin, by itself, can elicit the derangements of host physiology caused by administration of endotoxin. When administered in quantities similar to those produced endogenously in response to endotoxin, cachectin causes hypotension, metabolic acidosis, hemoconcentration, and death within minutes to hours, as a result of respiratory arrest. Hyperglycemia and hyperkalemia were also observed after infusion. At necropsy, diffuse pulmonary inflammation and hemorrhage were apparent on gross and histopathologic examination, along with ischemic and hemorrhagic lesions of the gastrointestinal tract, and acute renal tubular necrosis. Thus, it appears that a single protein mediator (cachectin) is capable of inducing many of the deleterious effects of endotoxin.

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This study supports the specificity of cardiac troponins T and I as markers of myocardial injury after pediatric cardiac operations and defines the importance of age and ischemic time in determining their release. In comparison with previous data in adults, our results raise the possibility that the pediatric heart may be more vulnerable to the effects of ischemia and reperfusion. Cardiac troponins will permit comparison of new myocardial protective strategies or other potentially therapeutic myocardial interventions.

Invasive bacterial infection in mammals often stimulates a fatal syndrome of hypotension, organ dysfunction and somatic tissue edema (1). This systemic response to critical illness in man is associated with somatic cell injury, as measured by a decrease in skeletal muscle transmembrane potential difference (Em), increased cellular sodium and water levels, and depletion of cellular potassium stores (2). These alterations in plasma membrane function are not temporally related to inadequate tissue perfusion or to depletion of high-energy phosphate stores (3). To date. no direct mediator for this deterioration of plasma membrane and electrolyte homeostasis has been identified .Recent work (4, 5) has shown that cachectin/tumor necrosis factor (TNF) is an important mediator of the lethal effects of endotoxin/LPS (6), and is produced in large quantities by macrophages exposed to endotoxin (7,8). High-affinity receptors for cachectin (7) stimulate altered cellular energy metabolism both in vivo and in vitro, but the evaluation of target tissues thus far has not demonstrated any adverse influence on normal cell viability. Several host tissues possess cachectin receptors (muscle, adipose, liver) (7) and exhibit extracellular responses at low receptor occupancy, a characteristic of many systemic mediators.Since passive immunization against cachectin confers a survival advantage in endotoxin/LPS-treated animals (6), we hypothesized that this monokine might affect skeletal muscle plasma membrane function during endotoxemia and shock. In this study, we observed that cachectin stimulated skeletal muscle fiber depolarization in an isolated muscle model. The plasma membrane response was prevented by pretreatment of cachectin with specific antibody to cachectin, and was not due to endotoxin/LPS. Measurement of muscle En, in vivo showed a similar decline after cachectin infusion .Recombinant human cachectin was prepared from a yeast expression system by previously described methods (4) and diluted in Krebs-Ringer-bicarbonate buffer (KRB) to the