Abstract 14828: Recombinant Human Soluble Thrombomodulin Prevents Acute Lung Injury in a Rat Cardiopulmonary Bypass Model
Backgrounds: Cardiopulmonary bypass (CPB) may induce systemic inflammatory responses causing acute lung injury. Recombinant human soluble thrombomodulin (rTM) is reported to attenuate secretion of inflammatory cytokines and high-mobility group box 1 (HMGB1) protein which plays a critical role in controlling systemic inflammation and apoptosis. We investigated protective effects of rTM on CPB-induced lung injury in a rat model.
Methods: Eighteen male Sprague-Dawley rats were divided into three groups: control (C: CPB alone), rTM (T: CPB + rTM) and sham (S). CPB was conducted for 90 min in groups C and T, whereas no CPB conduction in group S. A bolus of rTM (3mg/kg) was administered to group T rats 30 minutes before establishment of CPB. We evaluated systemic and pulmonary responses at 4 hours after CPB.
Results: The PaO2/FiO2 ratio markedly dropped only in group C. Group C showed significantly higher lung wet-to-dry weight ratio compared to those in others (p = 0.02). These results indicate that rTM administration rescued pulmonary dysfunction mediated by overhydration after CPB. Serum TNF-α, IL-6 and HMGB1 levels were significantly higher in group C after CPB (p = 0.013, p < 0.001 and p = 0.0017, respectively). Pathological study revealed more severe congestion, alveolar hemorrhage, neutrophil accumulation and edema significantly in group C compared to those in others (p < 0.001). Immunohistochemical analysis revealed that the number of lung cells expressing HMGB1 increased in group C (p < 0.001). The mRNA expression levels of TNF-α, IL-6 and HMGB1 in group C were significantly higher than in others. According to western blot analysis, nuclear factor-kappa B p65 in lung tissue was significantly downregulated in group T. According to the TUNEL staining, the number of apoptotic cells was significantly reduced in group T compared to that in group C. In addition, the expression of the messenger RNA and the protein of cleaved Caspase-3 were reduced in group T. These results indicate that rTM administration attenuated lung apoptosis after CPB.
Conclusion: These results suggest that recombinant human soluble thrombomodulin prevents acute lung injury through attenuating inflammation and apoptosis during and after CPB in a rat model.
Author Disclosures: S. Hirao: None. K. Minakata: None. H. Masumoto: None. S. Setozaki: None. K. Yamazaki: None. T. Ikeda: None. R. Sakata: None.
- © 2016 by American Heart Association, Inc.