title: Dose dependency of outcomes of intrapleural fibrinolytic therapy in new rabbit empyema models.
abstract: The incidence of empyema (EMP) is increasing worldwide; EMP generally occurs with pleural loculation and impaired drainage is often treated with intrapleural fibrinolytic therapy (IPFT) or surgery. A number of IPFT options are used clinically with empiric dosing and variable outcomes in adults. To evaluate mechanisms governing intrapleural fibrinolysis and disease outcomes, models of Pasteurella multocida and Streptococcus pneumoniae were generated in rabbits and the animals were treated with either human tissue (tPA) plasminogen activator or prourokinase (scuPA). Rabbit EMP was characterized by the development of pleural adhesions detectable by chest ultrasonography and fibrinous coating of the pleura. Similar to human EMP, rabbits with EMP accumulated sizable, 20- to 40-ml fibrinopurulent pleural effusions associated with extensive intrapleural organization, significantly increased pleural thickness, suppression of fibrinolytic and plasminogen-activating activities, and accumulation of high levels of plasminogen activator inhibitor 1, plasminogen, and extracellular DNA. IPFT with tPA (0.145 mg/kg) or scuPA (0.5 mg/kg) was ineffective in rabbit EMP (n = 9 and 3 for P. multocida and S. pneumoniae, respectively); 2 mg/kg tPA or scuPA IPFT (n = 5) effectively cleared S. pneumoniae-induced EMP collections in 24 h with no bleeding observed. Although intrapleural fibrinolytic activity for up to 40 min after IPFT was similar for effective and ineffective doses of fibrinolysin, it was lower for tPA than for scuPA treatments. These results demonstrate similarities between rabbit and human EMP, the importance of pleural fluid PAI-1 activity, and levels of plasminogen in the regulation of intrapleural fibrinolysis and illustrate the dose dependency of IPFT outcomes in EMP.
authors.affiliation: Department of Cellular and Molecular Biology of the University of Texas Health Science Center at Tyler, Tyler, Texas; andrey.komissarov@uthct.edu.
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Komissarov
authors.affiliation: Department of Cellular and Molecular Biology of the University of Texas Health Science Center at Tyler, Tyler, Texas;
authors.forename: Galina
authors.initials: G
authors.lastname: Florova
authors.affiliation: The University of Texas at Tyler, Tyler, Texas;
authors.forename: Ali O
authors.initials: AO
authors.lastname: Azghani
authors.affiliation: Department of Cellular and Molecular Biology of the University of Texas Health Science Center at Tyler, Tyler, Texas;
authors.forename: Ann
authors.initials: A
authors.lastname: Buchanan
authors.affiliation: Department of Cellular and Molecular Biology of the University of Texas Health Science Center at Tyler, Tyler, Texas;
authors.forename: Jake
authors.initials: J
authors.lastname: Boren
authors.affiliation: Department of Pathology, The University of Texas Medical Branch, Galveston, Texas; and.
authors.forename: Timothy
authors.initials: T
authors.lastname: Allen
authors.affiliation: Oxford Centre for Respiratory Medicine, Oxford University Hospitals, National Health Service Trust, Oxford, UK.
authors.forename: Najib M
authors.initials: NM
authors.lastname: Rahman
authors.affiliation: Department of Cellular and Molecular Biology of the University of Texas Health Science Center at Tyler, Tyler, Texas;
authors.forename: Kathleen
authors.initials: K
authors.lastname: Koenig
authors.affiliation: Department of Cellular and Molecular Biology of the University of Texas Health Science Center at Tyler, Tyler, Texas;
authors.forename: Mignote
authors.initials: M
authors.lastname: Chamiso
authors.affiliation: Department of Cellular and Molecular Biology of the University of Texas Health Science Center at Tyler, Tyler, Texas;
authors.forename: Sophia
authors.initials: S
authors.lastname: Karandashova
authors.affiliation: Department of Cellular and Molecular Biology of the University of Texas Health Science Center at Tyler, Tyler, Texas;
authors.forename: James
authors.initials: J
authors.lastname: Henry
authors.affiliation: Department of Cellular and Molecular Biology of the University of Texas Health Science Center at Tyler, Tyler, Texas;
authors.forename: Steven
authors.initials: S
authors.lastname: Idell
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D016724:Empyema, Pleural / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D006801:Humans; D010326:Pasteurella Infections / Q000188:drug therapy* / Q000382:microbiology; D016979:Pasteurella multocida / Q000502:physiology; D010994:Pleura / Q000000981:diagnostic imaging / Q000382:microbiology / Q000473:pathology; D011008:Pneumococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage; D013296:Streptococcus pneumoniae / Q000502:physiology; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*; D014568:Urokinase-Type Plasminogen Activator / Q000008:administration & dosage*
chemical_list: D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; C067551:saruplase
keywords: empyema; fibrinolysis; plasminogen activator inhibitor-1; single chain urokinase; tissue plasminogen activator