title: Effects of intra-abdominal administration of recombinant tissue plasminogen activator on coagulation, fibrinolysis and inflammatory responses in experimental polymicrobial peritonitis.
abstract: Peritonitis represents a procoagulant state because of activated coagulation and inhibited fibrinolysis. Intra-abdominal fibrin deposition-entrapping bacteria-prevents bacterial spread but impairs bacterial clearance. Activating intra-abdominal fibrinolysis by recombinant tissue-type plasminogen activator (r-tPA) early during peritonitis may enhance bacterial clearance and reduce inflammation. This study examines effects of abdominal r-tPA lavage on local and distant coagulation, fibrinolysis, and inflammatory responses in experimental polymicrobial peritonitis. Twenty-four hours after cecal ligation and puncture, mice were exposed to therapeutic abdominal lavage with varying doses of r-tPA or saline (controls). Coagulation, fibrinolysis, and inflammation were assessed in abdominal, systemic, and pulmonary compartments (n = 6 per group per time point). Survival was assessed during 96 h (n = 16 per group). Highest-dose (2 mg/mL) r-tPA lavage caused immediate death. High-dose (0.5 mg/mL) r-tPA lavage increased fibrinolysis, demonstrated by low abdominal plasminogen activator inhibitor 1 levels and elevated pulmonary tPA levels, resulting in reduced abdominal bacterial load, chemokine levels, leukocyte influx, and thrombin generation, along with less pulmonary fibrin depositions and organ damage on histological examination (P < 0.05 vs. saline lavage). Low-dose (0.05 mg/mL) r-tPA lavage showed hardly any effect compared with saline lavage. Adversely, abdominal and plasma interleukin (IL) 12 were elevated, whereas IL-10 levels were decreased after high-dose r-tPA lavage (P < 0.05 vs. saline). Survival rate was not affected by any dose of r-tPA lavage compared with saline lavage. Delayed local stimulation of fibrinolysis by peritoneal r-tPA lavage enhanced intra-abdominal bacterial clearance and reduced intra- and extra-abdominal coagulation responses in a dose-dependent manner. Survival rate was unaffected likely due to adverse changes in IL-12 and IL-10 levels.
authors: Department of Surgery, Surgical Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Suzanne Q
authors: SQ
authors: van Veen
authors: Joost C M
authors: JC
authors: Meijers
authors: Marcel
authors: M
authors: Levi
authors: Thomas M
authors: TM
authors: van Gulik
authors: Marja A
authors: MA
authors: Boermeester
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D002432:Cecum / Q000293:injuries; D018925:Chemokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005337:Fibrin / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects*; D007150:Immunohistochemistry; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010533:Peritoneal Lavage; D010538:Peritonitis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012965:Sodium Chloride / Q000008:administration & dosage / Q000494:pharmacology; D015996:Survival Rate; D013917:Thrombin / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D018925:Chemokines; D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; D016753:Interleukin-10; D018664:Interleukin-12; D012965:Sodium Chloride; D005337:Fibrin; D013917:Thrombin; D010959:Tissue Plasminogen Activator