Overexpression of activated protein C hampers bacterial dissemination during pneumococcal pneumonia.

BACKGROUND: During pneumonia, inflammation and coagulation are activated as part of anti-bacterial host defense. Activated protein C (APC) has anticoagulant and anti-inflammatory properties and until recently was a registered drug for the treatment of severe sepsis. Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia. METHODS: We aimed to investigate the effect of high APC levels during experimental pneumococcal pneumonia. Wild type (WT) and APC overexpressing (APC(high))-mice were intranasally infected with S. pneumoniae and sacrificed after 6, 24 or 48 hours, or followed in a survival study. RESULTS: In comparison to WT mice, APC(high)-mice showed decreased bacterial dissemination to liver and spleen, while no differences in bacterial loads were detected at the primary site of infection. Although no differences in the extent of lung histopathology were seen, APC(high)-mice showed a significantly decreased recruitment of neutrophils into lung tissue and bronchoalveolar lavage fluid. Activation of coagulation was not altered in APC(high)-mice. No differences in survival were observed between WT and APC(high)-mice (P =0.06). CONCLUSION: APC overexpression improves host defense during experimental pneumococcal pneumonia. This knowledge may add to a better understanding of the regulation of the inflammatory and procoagulant responses during severe Gram-positive pneumonia.

The effect of inflammation on coagulation and vice versa.

PURPOSE OF REVIEW: In infection, inflammation is frequently accompanied by a disturbance of the normal hemostatic balance provided by procoagulant and anticoagulant mechanisms. This review summarizes recently acquired knowledge on the bimodal interactions between coagulation and inflammation in infection. RECENT FINDINGS: Infection elicits inflammation-induced coagulation via tissue factor. A net procoagulant state is further produced by impaired functioning of anticoagulant mechanisms among which is the protein C system. Protease activated receptors (PARs) form the molecular link between coagulation and inflammation. PAR1 mediates both detrimental (induced by thrombin) and protective (induced by activated protein C) cellular effects. Activated protein C protects against mortality in experimental endotoxemia and sepsis by effects that rely on PAR1, not on the anticoagulant properties of this protein. SUMMARY: Recent data provide new insights into how inflammation impacts on coagulation and vice versa, identifying crucial roles for PARs. This knowledge may assist in designing novel interventions targeted at the perpetuation of inflammation by mediators traditionally implicated in coagulation.