title: Natural anticoagulants limit lipopolysaccharide-induced pulmonary coagulation but not inflammation.
abstract: Pulmonary coagulopathy and hyperinflammation may contribute to an adverse outcome in sepsis. The present study determines the effects of natural inhibitors of coagulation on bronchoalveolar haemostasis and inflammation in a rat model of endotoxaemia. Male Sprague-Dawley rats were randomised to treatment with normal saline, recombinant human activated protein C (APC), plasma-derived antithrombin (AT), recombinant human tissue factor pathway inhibitor (TFPI), heparin or recombinant tissue plasminogen activator (tPA). Rats were intravenously injected with lipopolysaccharide (LPS), which induced a systemic inflammatory response and pulmonary inflammation. Blood and bronchoalveolar lavage were obtained at 4 and 16 h after LPS injection, and markers of coagulation and inflammation were measured. LPS injection caused an increase in the levels of thrombin-AT complexes, whereas plasminogen activator activity was attenuated, both systemically and within the bronchoalveolar compartment. Administration of APC, AT and TFPI significantly limited LPS-induced generation of thrombin-AT complexes in the lungs, and tPA stimulated pulmonary fibrinolytic activity. However, none of the agents had significant effects on the production of pulmonary cytokines, chemokines, neutrophil influx and myeloperoxidase activity. Natural inhibitors of coagulation prevent bronchoalveolar activation of coagulation, but do not induce major alterations of the pulmonary inflammatory response in rat endotoxaemia.
authors.affiliation: Department of Intensive Care Medicine, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. godachoi@mail.com
authors.forename: G
authors.initials: G
authors.lastname: Choi
authors.forename: A P J
authors.initials: AP
authors.lastname: Vlaar
authors.forename: M
authors.initials: M
authors.lastname: Schouten
authors.forename: C
authors.initials: C
authors.lastname: Van't Veer
authors.forename: T
authors.initials: T
authors.lastname: van der Poll
authors.forename: M
authors.initials: M
authors.lastname: Levi
authors.forename: M J
authors.initials: MJ
authors.lastname: Schultz
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D000990:Antithrombin III / Q000378:metabolism; D000991:Antithrombins / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D019446:Endotoxemia / Q000276:immunology*; D004926:Escherichia coli / Q000276:immunology*; D005342:Fibrinolysis / Q000187:drug effects*; D006493:Heparin / Q000494:pharmacology; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000276:immunology*; D008074:Lipoproteins / Q000494:pharmacology; D008168:Lung / Q000276:immunology; D008297:Male; D009504:Neutrophils / Q000276:immunology; D010447:Peptide Hydrolases / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010960:Plasminogen Activators / Q000378:metabolism; D011486:Protein C / Q000494:pharmacology; D011655:Pulmonary Embolism / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D012128:Respiratory Distress Syndrome / Q000276:immunology*; D018746:Systemic Inflammatory Response Syndrome / Q000276:immunology*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D008074:Lipoproteins; D011486:Protein C; D011994:Recombinant Proteins; C046193:antithrombin III-protease complex; C051928:lipoprotein-associated coagulation inhibitor; D000990:Antithrombin III; D006493:Heparin; D009195:Peroxidase; D010447:Peptide Hydrolases; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator