Severe Lung Lesions Caused by Salmonella Are Prevented by Inhibition of the Contact System

Abstract

Vascular damage induced by trauma, inflammation, or infection results in an alteration of the endothelium from a nonactivated to a procoagulant, vasoconstrictive, and proinflammatory state, and can lead to life-threatening complications. Here we report that activation of the contact system by Salmonella leads to massive infiltration of red blood cells and fibrin deposition in the lungs of infected rats. These pulmonary lesions were prevented when the infected animals were treated with H-D-Pro-Phe-Arg-chloromethylketone, an inhibitor of coagulation factor XII and plasma kallikrein, suggesting that inhibition of contact system activation could be used therapeutically in severe infectious disease.

The Conversion of Fibrinogen to Fibrin at the Surface of Curliated Escherichia coli Bacteria Leads to the Generation of Proinflammatory Fibrinopeptides

“…This mechanism leads to a hypocoagulative state as well as to the generation of proinflammatory kinins. In the case of a massive activation, infected animals suffer from serious complications, including infiltration of red blood cells and fibrin deposition in the lungs (12,15). Of note, the pulmonary lesions were prevented when the infected animals were treated with the same contact system inhibitor as used in the present study (12).…”

“…36). However, coagulation disorders during bacterial infection can also be induced locally, as exemplified by the ability of some bacterial species, such as E. coli, Salmonella, Staphylococcus aureus, and Streptococcus pyogenes, to assemble and activate the contact system (also known as the kallikrein/kinin system or intrinsic pathway of coagulation) at their surface (12,15,(37)(38)(39). This mechanism leads to a hypocoagulative state as well as to the generation of proinflammatory kinins.…”

“…Curli-induced Clotting Disturbances Are Prevented by Contact System Inhibition-Previous studies have shown that the assembly and activation of the contact system at the surface of curli-expressing bacteria triggers not only the release of bradykinin from the bacterium, it also influences normal clotting (12,15). Therefore, experiments were performed to address the question of how contact activation triggers the coagulation system on bacteria.…”

“…When injected into animals, curli-expressing bacteria disrupt the coagulation cascade by modulating the contact system and trigger inflammatory reactions by activating inducible nitricoxide synthase (12,15,16). Moreover, it has been observed that E. coli bacteria expressing curli and a mutant strain secreting soluble CsgA stimulate a human macrophage cell line to produce proinflammatory cytokines (17).…”

Immunological Mechanisms Underlying the Genetic Predisposition to Severe Staphylococcus aureus Infection in the Mouse Model

“…These higher levels of released vasoactive bradykinin in infected A/J mice may be responsible for the vascular leakage and hemorrhages observed in the lungs of these mice as already previously shown after intravenous Salmonella infections. 39 …”