Mediator Responses in Surgical Infections

Abstract

Surgical infections, and sepsis in particular, are characterized by extensive release of mediators. Our laboratories have been interested in understanding how these substances contribute to morbidity and mortality during various stages of surgical infections in order to develop new and more effective therapeutics and treatment strategies. In a series of in vitro studies, human plasma was exposed to lipopolysaccharide (LPS), and whole blood was treated with peptidoglycan from Staphylococcus aureus. The activity of peptidoglycan also was studied in the rat, and LPS infusion was tested in dog and pig models. In a clinical study, the relation of serum LPS to multiple organ dysfunction and failure was studied in patients in the surgical intensive care unit. Exposure of plasma to LPS led to formation of bradykinin, activation of the plasma kallikrein-kinin system, and reduction of kallikrein inhibitor capacity. The coagulation, fibrinolysis, and complement cascades were activated. Peptidoglycan caused rapid release of tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 from macrophages and activation of the genes encoding pro-inflammatory and anti-inflammatory cytokines. In the rat, peptidoglycan induced cytokine release, caused liver and kidney dysfunction, and induced matrix metalloproteinase-9 (MMP-9) activity in the liver and lung. In the dog and pig, LPS caused substantial activation of plasma proteases. Clinically, a finding of LPS in the plasma was associated with multiple organ dysfunction and failure. These patients also revealed substantial activation of the plasma cascade systems, as well as systemic cytokine release. On the basis of these observations, we developed a monitoring system to recognize early signs of infection.