title: Nebulized fibrinolytic agents improve pulmonary fibrinolysis but not inflammation in rat models of direct and indirect acute lung injury.
abstract: BACKGROUND
  Critically ill patients frequently develop acute lung injury (ALI). Disturbed alveolar fibrin turnover, a characteristic feature of ALI, is the result of both activation of coagulation and inhibition of fibrinolysis. Nebulized fibrinolytic agents could exert lung-protective effects, via promotion of fibrinolysis as well as anti-inflammation.
  
  
  METHODS
  Rats were challenged intratracheally with Pseudomonas aeruginosa, resulting in pneumonia as a model for direct ALI, or received an intravenous bolus infusion of lipopolysaccharide, as a model for indirect ALI. Rats were randomized to nebulization of normal saline (placebo), recombinant tissue plasminogen activator (rtPA), or monoclonal antibodies against plasminogen activator inhibitor-type 1 (anti-PAI-1).
  
  
  RESULTS
  Nebulized rtPA or anti-PA1-1 enhanced the bronchoalveolar fibrinolytic system, as reflected by a significant reduction of PAI-1 activity levels in bronchoalveolar lavage fluid, and a consequent increase in plasminogen activator activity (PAA) levels to supranormal values. Both treatments also significantly affected systemic fibrinolysis as reflected by a significant increase in PAA levels in plasma to supranormal levels. Neither nebulized rtPA nor anti-PA1-1 affected pulmonary inflammation. Neither treatment affected bacterial clearance of P. aeruginosa from the lungs in case of pneumonia.
  
  
  CONCLUSIONS
  Local treatment with rtPA or anti-PA1-1 affects pulmonary fibrinolysis but not inflammation in models of direct or indirect ALI in rats.
authors: Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. j.j.hofstra@amc.uva.nl
authors: Jorrit J
authors: JJ
authors: Hofstra
authors: Alexander D
authors: AD
authors: Cornet
authors: Paul J
authors: PJ
authors: Declerck
authors: Barry
authors: B
authors: Dixon
authors: Hamid
authors: H
authors: Aslami
authors: Alexander P J
authors: AP
authors: Vlaar
authors: Joris J
authors: JJ
authors: Roelofs
authors: Tom
authors: T
authors: van der Poll
authors: Marcel
authors: M
authors: Levi
authors: Marcus J
authors: MJ
authors: Schultz
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D004195:Disease Models, Animal; D005342:Fibrinolysis / Q000187:drug effects*; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy*; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008297:Male; D009330:Nebulizers and Vaporizers; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005343:Fibrinolytic Agents