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.

Ventilator-associated lung injury: a search for better therapeutic targets

“…Animal models further implicate abnormalities of fibrin turnover in the pathogenesis of acute inflammation and fibrotic repair [69][70][71][84][85][86][87]. As discussed earlier, the process of fibrin deposition may be a means for the lung to localise or ''wall off'' inflammation, thereby limiting the risk of dissemination to neighbouring lung regions and the systemic circulation [69].…”

Stress repair mechanism activity explains inflammation and apoptosis

“…Brain, lung, nerves, autonomic ganglia, cervix, blood vessel adventitia, epithelium, mucosa, glomeruli, and placenta are rich in tissue factor [139,144,210,213,301,547,548]. This explains why these tissues are "targets" for positive feedback in stress-related conditions.…”

Lung Diseases - Selected State of the Art Reviews

“…The parenchymal recoil also offers an additional load during airway narrowing because the lung parenchyma is progressively distorted as the ASM shortens. This load can be calculated from the shear modulus () of the lung parenchyma, which was estimated to be 0.7 time the transpulmonary pressure (124), and the changes in adventitial diameter during airway narrowing, which is geometrically related to the changes in ASM length during shortening (126). So in addition to keep the intraparenchymal airways patent prior constriction, the lung recoil imposes an afterload that further limits airway narrowing once the ASM begins to shorten.…”

“…Thrombin has been implicated in a number of pulmonary fibrotic diseases such as acute lung injury (ALI) 124,125 acute respiratory distress syndrome (ARDS) 126 , interstitial lung disease (ILD) 127,128 and IPF 127,[129][130][131][132] and IPF BAL fluid thrombin has been shown to promote fibroblast proliferation 131 . In COPD, elevated procoagulant activity has been observed in the serum of patients with moderate to severe disease 133 .…”