The time course of resolution of adhesions during fibrinolytic therapy in tetracycline-induced pleural injury in rabbits

• Published in: American journal of physiology. Lung cellular and molecular physiology 2015-09, Vol.309 (6), p.L562-L572
• Main Authors: Komissarov, Andrey A, Florova, Galina, Azghani, Ali O, Buchanan, Ann, Bradley, William M, Schaefer, Chris, Koenig, Kathleen, Idell, Steven
• Format: Article
• Language: English
• Subjects: Animals; Call for Papers; Cell adhesion & migration; Drug Evaluation, Preclinical; Female; Fibrinolytic Agents - pharmacology; Fibrinolytic Agents - therapeutic use; Kinases; Lung diseases; Lung Injury - chemically induced; Lung Injury - drug therapy; Lung Injury - pathology; Medical imaging; Rabbits; Tetracycline; Time; Tissue Adhesions - chemically induced; Tissue Adhesions - drug therapy
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00136.2015

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 Pleural fluids withdrawn at 0-240 min and 24 h after IPFT were assayed for PA and fibrinolytic activities, α-macroglobulin/fibrinolysin complexes, and active PA inhibitor 1 (PAI-1).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.