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β-catenin and endothelial mesenchymal transformation play an important role in the formation of pulmonary hypertension. To explore the role of β-catenin in chronic thromboembolic pulmonary hypertension (CTEPH), we first established a rat model of CTEPH by repeated autologous thromboembolization and then treated these rats with a β-catenin specific inhibitor, XAV939, for two or four weeks. We further examined the expression of β-catenin, α-SMA and CD31, mean pulmonary artery pressure (mPAP), and histopathology in the pulmonary artery, and analyzed their correlation. In the thrombus group without treatment of the inhibitor, the expression of β-catenin and α-SMA in pulmonary artery was increased with time; mPAP, the thickness of pulmonary artery wall, and the area/total area of pulmonary artery (WA/TA) were also increased; however, the expression of CD31 was decreased. Interestingly, these symptoms could be improved by treatment with XAV939. In this study, in CTEPH rat model, the expression of β-catenin signal affects pulmonary vascular remodeling and pulmonary artery pressure, and positively correlated with pulmonary arterial endothelial mesenchymal transformation (EMT), indicating that β-catenin signal may play an important role in the occurrence and development of CTEPH. The inhibition of β-catenin signal and the improvement of pulmonary arterial EMT may provide therapeutic ideas for CTEPH. [ABSTRACT FROM AUTHOR]

Few reports have examined tissue factor (TF) and forkhead box transcription factor O-1 (FoxO1) expression in chronic thromboembolic pulmonary hypertension (CTEPH) animal models. To investigate the role of TF and FoxO1 and their interactions during CTEPH pathogenesis in a rat model. Autologous blood clots were repeatedly injected into the pulmonary arteries through right jugular vein to induce a rat model of CTEPH. Hemodynamic parameters, histopathology, and TF and FoxO1expression levels were detected. The mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance and vessel wall area/total area (WA/TA) ratio in the experiment group increased significantly than sham group ( P < 0.05). The cardiac output in the 1-, 2-, and 4-week groups decreased significantly ( P < 0.05) when compared to sham group. TF mRNA expression levels in the experiment group increased significantly than sham group ( P < 0.05). FoxO1 mRNA and protein expression levels were lower in the experiment group than sham group ( P < 0.05). The mPAP had a positive correlation with WA/TA ratio ( r = 0.45, P = 0.01). TF mRNA expression had a positive correlation with WA/TA ratio ( r = 0.374, P = 0.035) and a positive correlation with mPAP ( r = 0.48, P= 0.005). FoxO1 mRNA expression had a negative correlation trend with the WA/TA ratio ( r = −0.297, P = 0.099) and a negative correlation trend with mPAP ( r = −0.34, P = 0.057). TF mRNA expression had a negative correlation with FoxO1 mRNA expression ( r = −0.62, P < 0.001). A rat model of CTEPH can be successfully established by the injection of autologous blood clots into the pulmonary artery. TF and FoxO1 may play a key role in vascular remodeling during CTEPH pathogenesis. [ABSTRACT FROM AUTHOR]

Thrombosis and inflammation are two major factors underlying chronic thromboembolic pulmonary hypertension (CTEPH). Tissue factor (TF), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein 1 (MCP-1) may play critical roles in the process of CTEPH thrombosis and pulmonary vascular remodeling. Ten patients with a confirmed diagnosis of CTEPH, 20 patients with acute pulmonary thromboembolism and 15 patients with other types of pulmonary hypertension were enrolled in this study, along with 20 healthy subjects as the control group. The immunoturbidimetric method was used to determine the plasma content of CRP. The plasma levels of TNF-α, MCP-1, and TF antigen were measured by an enzyme-linked immunosorbent assay, and TF activity was measured by the chromogenic substrate method. Percoll density gradient centrifugation was used to separate peripheral blood mononuclear cells from plasma. The level of monocyte TF mRNA was examined by reverse transcriptase-polymerase chain reaction. The correlations between all indices described above were analyzed. In CTEPH patients, the expression of CRP, TNF-α, and MCP-1 was significantly higher than that in controls ( P < 0.05). The levels of TF activity, TF antigen, and TF mRNA in monocyte cells were increased in CTEPH patients when compared with control subjects, but only the TF antigen and TF mRNA levels were significantly different ( P < 0.05). In CTEPH patients, levels of CRP, MCP-1, and TNF-α significantly correlated with the level of TF antigen in plasma. TF gene expression was increased in patients with CTEPH, suggesting that blood-borne TF mainly comes from mononuclear cells. TF expression significantly correlated with levels of CRP, TNF-α and MCP-1. These factors may play an important role in the development of CTEPH via the inflammation-coagulation-thrombosis cycle. [ABSTRACT FROM AUTHOR]

To investigate the pulmonary angiography and pathology in a canine model with chronic pulmonary thromboembolism (PTE). The cylindrical blood clots were selectively introduced into the left (n = 10) or right (n = 20) lower pulmonary arteries of dogs. Pulmonary arteriography (PA) was performed before or after embolization. The values after embolization and baseline of mean pulmonary arterial pressure, pulmonary vascular resistance, cardiac output had changed. After 1 or 2 weeks' embolization, local PA demonstrated the abrupt cut-off perfusion defects or webs, bands, and abrupt vascular narrowing. 2 weeks after embolization, the pathology showed that the fibrin networks of the thrombi had multiple recanalization channels, and pulmonary artery had the concentric, lamellar (onion-like) intimal hyperplasia, multilayered, irregular arrangements of endothelial cells, and the infiltration of inflammatory cells. After embolectomy-mediated reperfusion, 2 weeks' subgroup showed destroyed and incomplete alveolar structures, and a large number of exudative cells, primarily neutrophils, and exudate. There close concordance between pulmonary angiography and pathology in a canine model with chronic PTE. The LIRI mechanisms after embolectomy-mediated reperfusion involve the destroyed, incomplete alveolar structures, and infiltration of inflammatory cells, primarily neutrophils. [ABSTRACT FROM AUTHOR]

Lung ischemia-reperfusion injury (LIRI) may occur in the region of the affected lung after reperfusion therapy. The inflammatory response mechanisms related to LIRI in pulmonary thromboembolism (PTE), especially in chronic PTE, need to be studied further. In a PTE model, inflammatory response and apoptosis may occur during LIRI and nitric oxide (NO) inhalation may alleviate the inflammatory response and apoptosis of pneumocytes during LIRI. A PTE canine model was established through blood clot embolism to the right lower lobar pulmonary artery. Two weeks later, we performed embolectomy with reperfusion to examine the LIRI changes among different groups. In particular, the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO/FiO), serum concentrations of tumor necrosis factor-α (TNF-α), myeloperoxidase concentrations in lung homogenates, alveolar polymorphonuclear neutrophils (PMNs), lobar lung wet to dry ratio (W/D ratio), apoptotic pneumocytes, and lung sample ultrastructure were assessed. The PaO/FiO in the NO inhalation group increased significantly when compared with the reperfusion group 4 and 6 h after reperfusion (368.83 ± 55.29 vs. 287.90 ± 54.84 mmHg, P < 0.05 and 380.63 ± 56.83 vs. 292.83 ± 6 0.34 mmHg, P < 0.05, respectively). In the NO inhalation group, TNF-α concentrations and alveolar PMN infiltration were significantly decreased as compared with those of the reperfusion group, 6 h after reperfusion (7.28 ± 1.49 vs. 8.90 ± 1.43 pg/mL, P < 0.05 and [(19 ± 6)/10 high power field (HPF) vs. (31 ± 11)/10 HPF, P < 0.05, respectively]. The amount of apoptotic pneumocytes in the lower lobar lung was negatively correlated with the arterial blood PaO/FiO, presented a positive correlation trend with the W/D ratio of the lower lobar lung, and a positive correlation with alveolar PMN in the reperfusion group and NO inhalation group. NO provided at 20 ppm for 6 h significantly alleviated LIRI in the PTE model. Our data indicate that, during LIRI, an obvious inflammatory response and apoptosis occur in our PTE model and NO inhalation may be useful in treating LIRI by alleviating the inflammatory response and pneumocyte apoptosis. This potential application warrants further investigation. [ABSTRACT FROM AUTHOR]