title: Thrombomodulin protects against lung damage created by high level of oxygen with large tidal volume mechanical ventilation in rats.
abstract: BACKGROUND
  Ventilator-induced lung injury (VILI) is associated with inflammatory responses in the lung. Thrombomodulin (TM), a component of the coagulation system, has anticoagulant and anti-inflammatory effects. We hypothesized that the administration of recombinant human soluble TM (rhsTM) would block the development of lung injury.
  
  
  METHODS
  Lung injury was induced by high tidal volume ventilation for 2 h with 100% oxygen in rats. Rats were ventilated with a tidal volume of 35 ml/kg with pretreatment via a subcutaneous injection of 3 mg/kg rhsTM (HV (high tidal volume)/TM) or saline (HV/SAL) 12 h before mechanical ventilation. Rats ventilated with a tidal volume of 6 ml/kg under 100% oxygen with rhsTM (LV (low tidal volume)/TM) or saline (LV/SAL) were used as controls. Lung protein permeability was determined by Evans blue dye (EBD) extravasation.
  
  
  RESULTS
  Lung injury was successfully induced in the HV/SAL group compared with the LV/SAL group, as shown by the significant decrease in arterial oxygen pressure (PaO2), increased protein permeability, and increase in mean pulmonary artery pressure (mPAP) and ratio of mean pulmonary artery pressure to mean artery pressure (Pp/Ps). Treatment of rats with lung injury with rhsTM (HV/TM) significantly attenuated the decrease in PaO2 and the increase in both mPAP and Pp/Ps, which was associated with a decrease in the lung protein permeability. Lung tissue mRNA expressions of interleukin (IL)-1α, IL-1β, IL-6, tumor necrosis factor-α, and macrophage inflammatory protein (MIP)-2 were significantly higher in HV than in LV rats. Rats with VILI treated with rhsTM (HV/TM) had significantly lower mRNA expressions of IL-1α, IL-1β, IL-6, and MIP-2 than those expressions in HV/SAL rats.
  
  
  CONCLUSIONS
  Administration of rhsTM may prevent the development of lung injury created by high level of oxygen with large tidal volume mechanical ventilation, which has concomitant decrease in proinflammatory cytokine and chemokine expression in the lung.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie 5148507 Japan ; Department of Emergency Critical Care Center, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507 Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Iwashita
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie 5148507 Japan.
authors.forename: Erquan
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie 5148507 Japan ; Department of Medical Engineering, Suzuka University of Medical Science, 1001-1 Kishiokacho, Suzuka, Mie 510-0226 Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Maruyama
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie 5148507 Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Yokochi
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie 5148507 Japan ; Department of Medical Engineering, Suzuka University of Medical Science, 1001-1 Kishiokacho, Suzuka, Mie 510-0226 Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie 5148507 Japan ; Department of Pediatrics, School of Medicine, Mie University, Tsu, Mie Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sawada
authors.affiliation: Department of Pediatrics, School of Medicine, Mie University, Tsu, Mie Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Mitani
authors.affiliation: Department of Emergency Critical Care Center, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507 Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Imai
authors.affiliation: Department of Pharmacological Science, Suzuka University of Medical Science, 1001-1 Kishiokacho, Suzuka, Mie 510-0226 Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie 5148507 Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Maruyama
keywords: Nitric oxide; Pulmonary hypertension; Thrombomodulin; Ventilator-induced lung injury