Liesbeth M Kager1, W Joost Wiersinga, Joris J T H Roelofs, Onno J de Boer, Joost C M Meijers, Berend Isermann, Cornelis van't Veer, Tom Van der Poll. 1. 1Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, the Netherlands. 2Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, the Netherlands. 3Department of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands. 4Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands. 5Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands. 6Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands. 7Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke University, Magdeburg, Germany.
Abstract
OBJECTIVE: The interplay between inflammation and blood coagulation is an essential part of host defense during severe pneumosepsis. Melioidosis, instigated by the Gram-negative bacterium Burkholderia pseudomallei, is a frequent cause of pneumosepsis in Southeast Asia. Patients with severe pneumosepsis, including melioidosis, have decreased circulating levels of protein C. Activated protein C has anticoagulant and anti-inflammatory properties. In this study, we aimed to investigate the effect of sustained elevated activated protein C levels on the host response during melioidosis. DESIGN: Animal study. SETTING: University research laboratory. SUBJECTS: Wild type and activated protein C overexpressing C57BL/6 mice. INTERVENTIONS: Mice were intranasally infected with viable B. pseudomallei and killed after 24, 48, or 72 hours for harvesting of lungs, liver, spleen, and blood. Additionally, survival studies were performed. MEASUREMENTS AND MAIN RESULTS: Plasma activated protein C concentrations in activated protein C overexpressing mice (median 18.1 ng/mL) were in the same range as previously measured in patients treated with recombinant human activated protein C. Activated protein C overexpressing mice demonstrated enhanced susceptibility to B. pseudomallei infection compared with wild type mice as evidenced by a strongly increased mortality accompanied by enhanced bacterial loads in the lungs, blood, and distant organs 48 hours after infection. Additionally, at this time point, activated protein C overexpressing mice showed elevated levels of proinflammatory cytokines in lungs and plasma, together with increased pulmonary histopathology scores and neutrophil influx. At 72 hours postinfection, decreased levels of thrombin-antithrombin complexes, reflecting inhibition of coagulation, were measured in lungs of activated protein C overexpressing mice. CONCLUSION: Constitutively enhanced expression of activated protein C impairs host defense during severe Gram-negative sepsis caused by B. pseudomallei.
OBJECTIVE: The interplay between inflammation and blood coagulation is an essential part of host defense during severe pneumosepsis. Melioidosis, instigated by the Gram-negative bacterium Burkholderia pseudomallei, is a frequent cause of pneumosepsis in Southeast Asia. Patients with severe pneumosepsis, including melioidosis, have decreased circulating levels of protein C. Activated protein C has anticoagulant and anti-inflammatory properties. In this study, we aimed to investigate the effect of sustained elevated activated protein C levels on the host response during melioidosis. DESIGN: Animal study. SETTING: University research laboratory. SUBJECTS: Wild type and activated protein C overexpressing C57BL/6 mice. INTERVENTIONS:Mice were intranasally infected with viable B. pseudomallei and killed after 24, 48, or 72 hours for harvesting of lungs, liver, spleen, and blood. Additionally, survival studies were performed. MEASUREMENTS AND MAIN RESULTS: Plasma activated protein C concentrations in activated protein C overexpressing mice (median 18.1 ng/mL) were in the same range as previously measured in patients treated with recombinant human activated protein C. Activated protein C overexpressing mice demonstrated enhanced susceptibility to B. pseudomallei infection compared with wild type mice as evidenced by a strongly increased mortality accompanied by enhanced bacterial loads in the lungs, blood, and distant organs 48 hours after infection. Additionally, at this time point, activated protein C overexpressing mice showed elevated levels of proinflammatory cytokines in lungs and plasma, together with increased pulmonary histopathology scores and neutrophil influx. At 72 hours postinfection, decreased levels of thrombin-antithrombin complexes, reflecting inhibition of coagulation, were measured in lungs of activated protein C overexpressing mice. CONCLUSION: Constitutively enhanced expression of activated protein C impairs host defense during severe Gram-negative sepsis caused by B. pseudomallei.
Authors: Liesbeth M Kager; W Joost Wiersinga; Joris J T H Roelofs; Onno J de Boer; Hartmut Weiler; Cornelis van 't Veer; Tom van der Poll Journal: PLoS Negl Trop Dis Date: 2014-04-24
Authors: Johannes Daan de Boer; Liesbeth M Kager; Joris J T H Roelofs; Joost C M Meijers; Onno J de Boer; Hartmut Weiler; Berend Isermann; Cornelis van 't Veer; Tom van der Poll Journal: BMC Infect Dis Date: 2014-11-04 Impact factor: 3.090
Authors: Cong Lin; Jan von der Thüsen; Berend Isermann; Hartmut Weiler; Tom van der Poll; Keren Borensztajn; Chris A Spek Journal: J Cell Mol Med Date: 2016-06-14 Impact factor: 5.310