Low levels of tissue factor lead to alveolar haemorrhage, potentiating murine acute lung injury and oxidative stress.

Bastarache JA, Sebag SC, Clune JK, Grove BS, Lawson WE, Janz DR, Roberts LJ, Dworski R, Mackman N, Ware LB
Thorax. 2012 67 (12): 1032-9

PMID: 23033361 · PMCID: PMC3652432 · DOI:10.1136/thoraxjnl-2012-201781

BACKGROUND - Systemic blockade of tissue factor (TF) attenuates acute lung injury (ALI) in animal models of sepsis but the effects of global TF deficiency are unknown. We used mice with complete knockout of mouse TF and low levels (∼1%) of human TF (LTF mice) to test the hypothesis that global TF deficiency attenuates lung inflammation in direct lung injury.

METHODS - LTF mice were treated with 10 μg of lipopolysaccharide (LPS) or vehicle administered by direct intratracheal injection and studied at 24 h.

RESULTS - Contrary to our hypothesis, LTF mice had increased lung inflammation and injury as measured by bronchoalveolar lavage cell count (3.4×10(5) wild-type (WT) LPS vs 3.3×10(5) LTF LPS, p=0.947) and protein (493 μg/ml WT LPS vs 1014 μg/ml LTF LPS, p=0.006), proinflammatory cytokines (TNF-α, IL-10, IL-12, p<0.035 WT LPS vs LTF LPS) and histology compared with WT mice. LTF mice also had increased haemorrhage and free haemoglobin in the airspace accompanied by increased oxidant stress as measured by lipid peroxidation products (F(2) isoprostanes and isofurans).

CONCLUSIONS - These findings indicate that global TF deficiency does not confer protection in a direct lung injury model. Rather, TF deficiency causes increased intra-alveolar haemorrhage following LPS leading to increased lipid peroxidation. Strategies to globally inhibit TF may be deleterious in patients with ALI.

MeSH Terms (20)

Acute Lung Injury Analysis of Variance Animals Blotting, Western Bronchoalveolar Lavage Cytokines Electrophoresis, Polyacrylamide Gel Furans Hemoglobins Hemorrhage Inflammation Isoprostanes Lipopolysaccharides Mice Mice, Knockout Oxidative Stress Pulmonary Alveoli Real-Time Polymerase Chain Reaction Statistics, Nonparametric Thromboplastin

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