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Updated: May 10, 2026
The Left Pneumonectomy Combined with Monocrotaline or Sugen as a Model of Pulmonary Hypertension in Rats
Published on: March 8, 2019
Effect of thrombomodulin on the development of monocrotaline-induced pulmonary hypertension
Yasuharu Yamada1, Junko Maruyama, Erquan Zhang
1Anesthesiology and Critical Care Medicine, Mie University School of Medicine, Mie, Japan.
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.
Insights
Thrombomodulin (TM) showed limited benefits in preventing monocrotaline-induced pulmonary hypertension (PH) in rats. While TM temporarily reduced key PH markers, it did not improve survival rates, suggesting limited clinical significance.
Area of Science:
- Cardiovascular Research
- Pulmonary Medicine
- Pharmacology
Background:
- Pulmonary hypertension (PH) is a severe condition characterized by high blood pressure in the pulmonary arteries.
- Monocrotaline (MCT) is a toxin commonly used to induce PH in animal models for research purposes.
- Thrombomodulin (TM) is a protein involved in regulating coagulation and inflammation, with potential therapeutic applications.
Purpose of the Study:
- To investigate the potential of thrombomodulin (TM) in preventing or mitigating the development of monocrotaline (MCT)-induced pulmonary hypertension (PH) in a rat model.
- To assess the effects of TM administration on hemodynamic parameters, vascular remodeling, and inflammatory markers associated with PH.
Main Methods:
- Male Sprague-Dawley rats were injected with MCT to induce PH.
- Rats received human recombinant TM or saline for 19 or 29 days.
- Measurements included mean pulmonary artery pressure (mPAP), right ventricular hypertrophy (RVH), arterial muscularization (%muscularization), and medial wall thickness (%MWT).
- Broncho-alveolar lavage fluid (BALF) was analyzed for inflammatory and coagulation markers.
- Western blotting assessed endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (peNOS) expression.
- Survival rates were determined.
Main Results:
- MCT injection led to significant increases in mPAP, RVH, %muscularization, and %MWT.
- TM treatment reduced mPAP, %muscularization, and %MWT at 19 days post-MCT injection, but these effects diminished by 29 days.
- MCT increased pro-inflammatory cytokines and thrombin-antithrombin complex in BALF.
- TM administration modulated eNOS and peNOS levels.
- No significant difference in survival rates was observed between TM-treated and control groups.
Conclusions:
- Thrombomodulin (TM) administration may offer a temporary delay in the progression of MCT-induced pulmonary hypertension (PH).
- However, the observed physiological benefits of TM were limited and did not translate into improved survival rates.
- The findings suggest that the therapeutic significance of TM for treating established PH may be restricted.
