title: Nebulized Recombinant Human Tissue Factor Pathway Inhibitor Attenuates Coagulation and Exerts Modest Anti-inflammatory Effects in Rat Models of Lung Injury.
abstract: BACKGROUND
  Critically ill patients are at a constant risk of direct (e.g., by pneumonia) or indirect lung injury (e.g., by sepsis). Excessive alveolar fibrin deposition is a prominent feature of lung injury, undermining pulmonary integrity and function.
  
  
  METHODS
  We examined the effect of local administration of recombinant human tissue factor pathway inhibitor (rh-TFPI), a natural anticoagulant, in two well-established models of lung injury in rats. Rats received intratracheal instillation of Pseudomonas aeruginosa, causing direct lung injury, or they received an intravenous injection of Escherichia coli lipopolysaccharide (LPS), causing indirect lung injury. Rats were randomized to local treatment with rh-TFPI or placebo through repeated nebulization.
  
  
  RESULTS
  Challenge with P. aeruginosa or LPS was associated with increased coagulation and decreased fibrinolysis in bronchoalveolar lavage fluid (BALF) and plasma. Rh-TFPI levels in BALF increased after nebulization, whereas plasma rh-TFPI levels remained low and systemic TFPI activity was not affected. Nebulization of rh-TFPI attenuated pulmonary and systemic coagulation in both models, without affecting fibrinolysis. Nebulization of rh-TFPI modestly reduced the inflammatory response and bacterial growth of P. aeruginosa in the alveolar compartment.
  
  
  CONCLUSIONS
  Local treatment with rh-TFPI does not alter systemic TFPI activity; however, it attenuates both pulmonary and systemic coagulopathy. Furthermore, nebulized rh-TFPI modestly reduces the pulmonary inflammatory response and allows increased bacterial clearance in rats with direct lung injury caused by P. aeruginosa.
authors.affiliation: 1 Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A), Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands .|2 Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands .|3 Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands .
authors.forename: Florry E
authors.initials: FE
authors.lastname: van den Boogaard
authors.affiliation: 1 Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A), Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands .|4 Department of Medical Microbiology, University of Amsterdam , Amsterdam, The Netherlands .
authors.forename: Jorrit J
authors.initials: JJ
authors.lastname: Hofstra
authors.affiliation: 1 Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A), Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands .|2 Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands .
authors.forename: Xanthe
authors.initials: X
authors.lastname: Brands
authors.affiliation: 5 Department of Internal Medicine, University of Amsterdam , Amsterdam, The Netherlands .
authors.forename: Marcel M
authors.initials: MM
authors.lastname: Levi
authors.affiliation: 6 Department of Pathology, University of Amsterdam , Amsterdam, The Netherlands .
authors.forename: Joris J T H
authors.initials: JJ
authors.lastname: Roelofs
authors.affiliation: 3 Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands .|4 Department of Medical Microbiology, University of Amsterdam , Amsterdam, The Netherlands .
authors.forename: Sebastiaan A J
authors.initials: SA
authors.lastname: Zaat
authors.affiliation: 2 Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands .|3 Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands .
authors.forename: Cornelis
authors.initials: C
authors.lastname: Van't Veer
authors.affiliation: 2 Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands .|3 Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands .|7 Department of Infectious Diseases, University of Amsterdam , Amsterdam, The Netherlands .
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.affiliation: 1 Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A), Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands .|8 Department of Intensive Care Medicine, Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands .
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Schultz
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid; D004195:Disease Models, Animal; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D008070:Lipopolysaccharides / Q000633:toxicity; D008074:Lipoproteins / Q000008:administration & dosage / Q000494:pharmacology*; D055370:Lung Injury / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D011550:Pseudomonas aeruginosa; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins
chemical_list: D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D008070:Lipopolysaccharides; D008074:Lipoproteins; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor
keywords: Pseudomonas aeruginosa; coagulation; endotoxemia; lung; pneumonia; tissue factor pathway inhibitor