Low levels of tissue factor lead to alveolar haemorrhage, potentiating murine acute lung injury and oxidative stress
- Julie A Bastarache1,
- Sara C Sebag1,
- Jennifer K Clune1,
- Brandon S Grove1,
- William E Lawson1,2,
- David R Janz1,
- L Jackson Roberts II3,
- Ryszard Dworski1,
- Nigel Mackman4,
- Lorraine B Ware1,5
- 1Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- 2Department of Veterans Affairs Medical Center, Nashville, Tennessee, USA
- 3Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- 4Division of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
- 5Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Correspondence to Dr Julie A Bastarache, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, TN 37232-2650, USA;
- Received 16 February 2012
- Accepted 1 September 2012
- Published Online First 2 October 2012
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 (3.4×105 wild-type (WT) LPS vs 3.3×105 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 (F2 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.