Abstract
BackgroundThis study aimed to explore whether the mechanical stretching-induced expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in pulmonary veins occurred through the stretch-activated channel (SAC)/ mitogen-activated protein kinases (MAPKs) pathway.MethodsSixty male Sprague-Dawley rats were divided into three sham groups and seven model groups. A metal clip was placed on the ascending aorta in the model group to establish PH-LHD rat model. The sham group received a similar operation without ascending aorta clamped. On day 25, pulmonary vein was given mechanical stretching with 0 g, 2.0 g tension in two model groups and two sham groups. Another four model groups were given 2.0 g tension after MAPKs pathway inhibitors soaked. The last sham group and model group rats’ pulmonary veins, pulmonary artery and lung tissues were obtained on day 35. Pulmonary vein, pulmonary artery and lung tissue were evaluated by echocardiography, HE staining, immunohistochemistry and western blotting respectively.ResultsOn day 25, left heart weight, right ventricular pressure (35.339 cmH2O) and left atrial pressure (13.657 cmH2O) were increased in model group than those in sham group. Echocardiography showed left heart failure in the PH-LHD group (Interventrieular septum dimension 1.716 mm, left ventricular internal end diastolic dimension 4.888 mm, left ventricular posterior wall thickness in diastole 1.749 mm, ejection fraction 76.917%). But there was no difference in lung tissue between the sham group and PH-LHD group as showed by HE staining. Our results showed that the expression of IL-6 and TNF-α was highly expressed in PH-LHD rats’ serum and pulmonary vein, which were further increased after 2.0 g tension was given and were decreased after SAC/MAPKs inhibitors treatment. Meanwhile, on day 25, immunohistochemistry analysis showed the expression of IL-6 and TNF-α was higher in the PH-LHD rats’ pulmonary vein than that in pulmonary artery and lung tissue, and these expressions in pulmonary vein of PH-LHD group were also higher than that in sham group. However, on day 35, IL-6 and TNF-α were all increased in the pulmonary veins, arteries and lung tissues. Besides, our results uncovered that SAC/MAPKs pathway were upregulating in PH-LHD rats’ pulmonary vein.ConclusionIn conclusion, pulmonary vein mechanical stretching exacerbated PH-LHD possibly through the SAC/MAPKs pathway and upregulating expression of IL-6 and TNF-α.
Highlights
This study aimed to explore whether the mechanical stretching-induced expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in pulmonary veins occurred through the stretch-activated channel (SAC)/ mitogen-activated protein kinases (MAPKs) pathway
Our results showed that the expression of IL-6 and TNF-α was highly expressed in pulmonary hypertension (PH)-LHD rats’ serum and pulmonary vein, which were further increased after 2.0 g tension was given and were decreased after SAC/MAPKs inhibitors treatment
On day 25, immunohistochemistry analysis showed the expression of IL-6 and TNF-α was higher in the PH-LHD rats’ pulmonary vein than that in pulmonary artery and lung tissue, and these expressions in pulmonary vein of PH-LHD group were higher than that in sham group
Summary
This study aimed to explore whether the mechanical stretching-induced expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in pulmonary veins occurred through the stretch-activated channel (SAC)/ mitogen-activated protein kinases (MAPKs) pathway. The pressure of the left atrium first increases, followed by increased pulmonary vein pressure and pulmonary vascular smooth muscle cell proliferation, leading to pulmonary hypertension (PH). It is of great importance to study the mechanism of pulmonary vascular remodeling. Mechanical stretching caused by blood flow is an important factor maintaining the structure and function of the pulmonary vasculature in animals. Excessive blood pressure can promote thickening of the middle-level smooth muscle of pulmonary vascular and lead to pulmonary vascular remodeling. Current studies on PH-LHD have mostly focused on pulmonary artery, but Ahmed UF found that the severity of pulmonary hypertension was related to pulmonary vein remodeling, and pulmonary vein remodeling occurred earlier than pulmonary artery remodelin g[2]. Ping YX showed that pulmonary veins first underwent arterialized changes during the progression of P H[3]
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