Background: 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.
Methods: 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.
Results: 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-α, interleukin-1β, 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.
Conclusion: On the basis of these observations, we developed a monitoring system to recognize
early signs of infection.
