Tissue factor pathway inhibitor prevents airway obstruction, respiratory failure and death due to sulfur mustard analog inhalation

Toxicol Appl Pharmacol. 2013 Oct 1;272(1):86-95. doi: 10.1016/j.taap.2013.05.020. Epub 2013 May 30.


Sulfur mustard (SM) inhalation causes airway injury, with enhanced vascular permeability, coagulation, and airway obstruction. The objective of this study was to determine whether recombinant tissue factor pathway inhibitor (TFPI) could inhibit this pathogenic sequence.

Methods: Rats were exposed to the SM analog 2-chloroethyl ethyl sulfide (CEES) via nose-only aerosol inhalation. One hour later, TFPI (1.5mg/kg) in vehicle, or vehicle alone, was instilled into the trachea. Arterial O2 saturation was monitored using pulse oximetry. Twelve hours after exposure, animals were euthanized and bronchoalveolar lavage fluid (BALF) and plasma were analyzed for prothrombin, thrombin-antithrombin complex (TAT), active plasminogen activator inhibitor-1 (PAI-1) levels, and fluid fibrinolytic capacity. Lung steady-state PAI-1 mRNA was measured by RT-PCR analysis. Airway-capillary leak was estimated by BALF protein and IgM, and by pleural fluid measurement. In additional animals, airway cast formation was assessed by microdissection and immunohistochemical detection of airway fibrin.

Results: Airway obstruction in the form of fibrin-containing casts was evident in central conducting airways of rats receiving CEES. TFPI decreased cast formation, and limited severe hypoxemia. Findings of reduced prothrombin consumption, and lower TAT complexes in BALF, demonstrated that TFPI acted to limit thrombin activation in airways. TFPI, however, did not appreciably affect CEES-induced airway protein leak, PAI-1 mRNA induction, or inhibition of the fibrinolytic activity present in airway surface liquid.

Conclusions: Intratracheal administration of TFPI limits airway obstruction, improves gas exchange, and prevents mortality in rats with sulfur mustard-analog-induced acute lung injury.

Keywords: Airway; Coagulation; Inhalation; Lung injury; Sulfur mustard; TFPI.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Inhalation
  • Airway Obstruction / chemically induced*
  • Airway Obstruction / pathology
  • Airway Obstruction / prevention & control*
  • Animals
  • Blotting, Western
  • Bronchoalveolar Lavage Fluid / chemistry
  • Chemical Warfare Agents / pharmacokinetics
  • Chemical Warfare Agents / toxicity*
  • Enzyme-Linked Immunosorbent Assay
  • Fibrin / metabolism
  • Fibrinolysis / drug effects
  • Immunoglobulin M / metabolism
  • Immunohistochemistry
  • Indicators and Reagents
  • Lipoproteins / pharmacology*
  • Male
  • Microdissection
  • Mustard Gas / analogs & derivatives*
  • Mustard Gas / pharmacokinetics
  • Mustard Gas / toxicity
  • Proteins / pharmacology
  • Prothrombin / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / pharmacology
  • Respiratory Insufficiency / chemically induced*
  • Respiratory Insufficiency / pathology
  • Respiratory Insufficiency / prevention & control*


  • Chemical Warfare Agents
  • Immunoglobulin M
  • Indicators and Reagents
  • Lipoproteins
  • Proteins
  • Recombinant Proteins
  • lipoprotein-associated coagulation inhibitor
  • Tifacogin
  • 2-chloroethyl ethyl sulfide
  • Prothrombin
  • Fibrin
  • Mustard Gas