title: Massive alveolar thrombin activation in Pseudomonas aeruginosa-induced acute lung injury.
abstract: In acute lung injury (ALI), a coagulation/fibrinolysis imbalance leads to fibrin deposition, persistence of which contributes to fibrotic evolution. Our study evaluated the effects of early inhibition of coagulation in Pseudomonas aeruginosa (Pa)-induced ALI through the use of recombinant human antithrombin (rhAT). The study was conducted in vivo on a murine model of Pa-induced ALI. Intravenous rhAT was administered simultaneously with intratracheal Pa. Four experimental groups were compared: CTR, intratracheal saline (0.5 mL/kg)/intravenous saline (1 mL); PNP, intratracheal Pa (0.5 mL/kg of 2 x 10(9) cfu)/intravenous saline; AT, intratracheal saline/intravenous rhAT (500 IU/kg); ATPNP, intratracheal Pa/intravenous rhAT. Epithelial and endothelial permeabilities were evaluated with radiolabeled albumin flux across the alveolar barrier (125I- and 131I-labeled albumin). Thrombin-antithrombin (TAT) complexes levels were used as markers of coagulation activation in blood samples and in BAL fluid. Epithelial and endothelial protein permeability were increased in Pa-induced ALI versus control. Intravenous rhAT administration led to further permeability disorders. Administration of rhAT in Pa ALI led to a rise in TAT complexes in ATPNP blood serum and BAL fluids compared with the other groups. In Pa-induced ALI the administration intravenous rhAT leads to major histologic damage, alveolar capillary barrier injury, and permeability increase. Such effects of the inhibition of thrombin activation by rhAT lead to the hypothesis of a probable beneficial role of early coagulation activation in ALI as a factor limiting both the extent of injury and permeability disorders. Our study suggests that inhibition of this initial procoagulative imbalance is potentially dangerous.
authors.affiliation: Faculté de Médecine de Lille, Lille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Kipnis
authors.forename: Benoît P
authors.initials: BP
authors.lastname: Guery
authors.forename: Antoine
authors.initials: A
authors.lastname: Tournoys
authors.forename: Xavier
authors.initials: X
authors.lastname: Leroy
authors.forename: Laurent
authors.initials: L
authors.lastname: Robriquet
authors.forename: Patrice
authors.initials: P
authors.lastname: Fialdes
authors.forename: Remi
authors.initials: R
authors.lastname: Neviere
authors.forename: François
authors.initials: F
authors.lastname: Fourrier
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000378:metabolism; D001777:Blood Coagulation; D001794:Blood Pressure; D001992:Bronchoalveolar Lavage Fluid; D005260:Female; D005337:Fibrin / Q000378:metabolism; D005342:Fibrinolysis; D006801:Humans; D008168:Lung / Q000473:pathology; D055370:Lung Injury; D010100:Oxygen / Q000378:metabolism; D011552:Pseudomonas Infections / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000382:microbiology* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000209:etiology* / Q000382:microbiology; D013917:Thrombin / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000991:Antithrombins; D005337:Fibrin; D013917:Thrombin; D010100:Oxygen