An N-terminal fragment of bactericidal/permeability-increasing protein protects against hemodynamic and metabolic derangements in rat Gram-negative sepsis

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.

In this chapter, current concepts about the mechanisms of action of endotoxin are reviewed. Particular attention is focused upon endotoxin-induced production of soluble mediators from macrophages and mononuclear cells and on the potential contribution of these mediators to endotoxin shock. In many cases, the interrelationships between these mediators as primary and/or secondary consequences of endotoxin stimulation of mononuclear phagocytes are discussed. Final comments address the relevance of these mediators to the therapy of endotoxin shock.