Massive alveolar thrombin activation in Pseudomonas aeruginosa-induced acute lung injury.

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.

Ventilation-induced lung injury is associated with an increase in gut permeability.

Mechanical ventilation is associated with several harmful effects mainly related to high tidal volumes (Vt). Ventilator-induced lung injury can be responsible for an increased production of inflammatory mediators. We evaluated remote consequences on the gut of lung triggered inflammatory response, neutralizing anti-tumor necrosis factor (TNF) antibody was administered to assess the role of TNF in lung and gut permeability changes. Rats were anesthetized and ventilated for 2 h. A control group (Con: Vt = 10 mL/kg) was compared with a high Vt group (HV: Vt = 30 ml/kg). One microCi of I125-labeled human serum albumin was injected to measure extravascular albumin space. Gut permeability was evaluated by plasma-to-lumen ratio leakage of I125 human serum albumin. Extravascular albumin space increased in the HV group from 446 +/- 50 microL to 2783 +/- 887 microL. Gut index of permeability increased from 5.1 +/- 1.2 to 14.2 +/- 4.9. Anti-TNF antibody prevented both lung and gut increase in permeability. High tidal volume ventilation resulted in an increase in lung edema and gut permeability, antagonism of TNF with neutralizing antibodies abrogated the increase in gut permeability as well as lung edema.