TY - JOUR
T1 - Nebulized fibrinolytic agents improve pulmonary fibrinolysis but not inflammation in rat models of direct and indirect acute lung injury
AU - Hofstra, Jorrit J.
AU - Cornet, Alexander D.
AU - Declerck, Paul J.
AU - Dixon, Barry
AU - Aslami, Hamid
AU - Vlaar, Alexander P. J.
AU - Roelofs, Joris J.
AU - van der Poll, Tom
AU - Levi, Marcel
AU - Schultz, Marcus J.
PY - 2013
Y1 - 2013
N2 - 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. 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). 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. Local treatment with rtPA or anti-PA1-1 affects pulmonary fibrinolysis but not inflammation in models of direct or indirect ALI in rats
AB - 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. 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). 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. Local treatment with rtPA or anti-PA1-1 affects pulmonary fibrinolysis but not inflammation in models of direct or indirect ALI in rats
U2 - https://doi.org/10.1371/journal.pone.0055262
DO - https://doi.org/10.1371/journal.pone.0055262
M3 - Article
C2 - 23408962
SN - 1932-6203
VL - 8
SP - e55262
JO - PLOS ONE
JF - PLOS ONE
IS - 2
M1 - e55262
ER -