title: The time course of resolution of adhesions during fibrinolytic therapy in tetracycline-induced pleural injury in rabbits.
abstract: The time required for the effective clearance of pleural adhesions/organization after intrapleural fibrinolytic therapy (IPFT) is unknown. Chest ultrasonography and computed tomography (CT) were used to assess the efficacy of IPFT in a rabbit model of tetracycline-induced pleural injury, treated with single-chain (sc) urokinase plasminogen activators (scuPAs) or tissue PAs (sctPA). IPFT with sctPA (0.145 mg/kg; n = 10) and scuPA (0.5 mg/kg; n = 12) was monitored by serial ultrasonography alone (n = 12) or alongside CT scanning (n = 10). IPFT efficacy was assessed with gross lung injury scores (GLIS) and ultrasonography scores (USS). Pleural fluids withdrawn at 0-240 min and 24 h after IPFT were assayed for PA and fibrinolytic activities, α-macroglobulin/fibrinolysin complexes, and active PA inhibitor 1 (PAI-1). scuPA and sctPA generated comparable steady-state fibrinolytic activities by 20 min. PA activity in the scuPA group decreased slower than the sctPA group (kobs = 0.016 and 0.042 min(-1)). Significant amounts of bioactive uPA/α-macroglobulin (but not tPA; P < 0.05) complexes accumulated at 0-40 min after IPFT. Despite the differences in intrapleural processing, IPFT with either fibrinolysin was effective (GLIS ≤ 10) in animals imaged with ultrasonography only. USS correlated well with postmortem GLIS (r(2) = 0.85) and confirmed relatively slow intrapleural fibrinolysis after IPFT, which coincided with effective clearance of adhesions/organization at 4-8 h. CT scanning was associated with less effective (GLIS > 10) IPFT and higher levels of active PAI-1 at 24 h following therapy. We concluded that intrapleural fibrinolysis in tetracycline-induced pleural injury in rabbits is relatively slow (4-8 h). In CT-scanned animals, elevated PAI-1 activity (possibly radiation induced) reduced the efficacy of IPFT, buttressing the major impact of active PAI-1 on IPFT outcomes.
authors.affiliation: The Department of Cellular and Molecular Biology and the Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler (UTHSCT), Tyler, Texas; andrey.komissarov@uthct.edu.
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Komissarov
authors.affiliation: The Department of Cellular and Molecular Biology and the Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler (UTHSCT), Tyler, Texas;
authors.forename: Galina
authors.initials: G
authors.lastname: Florova
authors.affiliation: The Department of Biology at the University of Texas at Tyler, Tyler, Texas;
authors.forename: Ali O
authors.initials: AO
authors.lastname: Azghani
authors.affiliation: UTHSCT Vivarium, The University of Texas Health Science Center at Tyler, Tyler, Texas;
authors.forename: Ann
authors.initials: A
authors.lastname: Buchanan
authors.affiliation: The Department of Radiation Oncology, The University of Texas Health Science Center at Tyler, Tyler, Texas.
authors.forename: William M
authors.initials: WM
authors.lastname: Bradley
authors.affiliation: The Department of Cellular and Molecular Biology and the Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler (UTHSCT), Tyler, Texas;
authors.forename: Chris
authors.initials: C
authors.lastname: Schaefer
authors.affiliation: The Department of Cellular and Molecular Biology and the Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler (UTHSCT), Tyler, Texas;
authors.forename: Kathleen
authors.initials: K
authors.lastname: Koenig
authors.affiliation: The Department of Cellular and Molecular Biology and the Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler (UTHSCT), Tyler, Texas;
authors.forename: Steven
authors.initials: S
authors.lastname: Idell
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D055370:Lung Injury / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D011817:Rabbits; D013752:Tetracycline; D000267:Tissue Adhesions / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D005343:Fibrinolytic Agents; D013752:Tetracycline
keywords: fibrinolysis; fibrinolytic therapy; plasminogen activator inhibitor 1; pleural injury; tissue plasminogen activator; urokinase