Effect of thrombomodulin on the development of monocrotaline-induced pulmonary hypertension

Purpose

The purpose of the present study was to investigate whether thrombomodulin (TM) prevents the development of pulmonary hypertension (PH) in monocrotaline (MCT)-injected rats.

Methods

Human recombinant TM (3 mg/kg/2 days) or saline were given to MCT-injected male Sprague–Dawley rats for 19 (n = 14) or 29 (n = 11) days. Control rats (n = 6) were run for 19 days. The mean pulmonary artery pressure (mPAP), right ventricular hypertrophy (RVH), percentages of muscularized peripheral arteries (%muscularization), and medial wall thickness of small muscular arteries (%MWT) were measured. To determine inflammatory and coagulation responses, broncho-alveolar lavage fluid (BALF) was analyzed in another set of rats (n = 29). Western blotting for endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (peNOS) in the lung tissue was performed in separate rats (n = 13). Survival was determined in 60 rats.

Results

MCT increased mPAP, RVH, %muscularization, and %MWT. TM treatment significantly reduced mPAP, %muscularization, and %MWT in peripheral arteries with an external diameter of 50–100 μm in 19 days after MCT injection, but the effect was lost after 29 days. MCT increased the levels of tumor necrosis factor alpha, monocyte chemoattractant protein-1, and thrombin-antithrombin complex in BALF. Expression of eNOS increased in MCT rats, while peNOS decreased. The relative amount of peNOS to total eNOS increased in MCT/TM rats compared to MCT/Vehicle rats. A Kaplan–Meier survival curve showed no difference with and without TM.

Conclusion

Although the administration of TM might slightly delay the progression of MCT-induced PH, the physiological significance for treatment is limited, since the survival rate was not improved.