Mechanical stretching of the pulmonary vein mediates pulmonary hypertension due to left heart disease by regulating SAC/MAPK pathway and the expression of IL-6 and TNF-α

Abstract

Background 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. Methods Sixty 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. Results On 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. Conclusion In conclusion, pulmonary vein mechanical stretching exacerbated PH-LHD possibly through the SAC/MAPKs pathway and upregulating expression of IL-6 and TNF-α.

Animal models of pulmonary hypertension due to left heart disease

“…32 In 2009, this research team used this rat model to study PH-LHD and found that inhaled nitric oxide improved pulmonary hemodynamics and pulmonary edema in group 2 PH. 33 This animal model was further promoted, and aortic banding in rats is at present the most commonly used animal model to study PH-LHD, [34][35][36][37][38][39][40][41][42] although the timing of the banding varies depending on the operator's experience. 1.…”

Pulmonary hypertension: Linking inflammation and pulmonary arterial stiffening

“…Among these, IL-6 and TNF were found to be increased in plasma, lung, pulmonary arteries and veins, as well as in PA ECs in both patients and animal models of various PH groups ( Table 1 ). In PAH patients ( 60 ) and in PH-LHD rat models ( 61 , 81 ), IL-6 contributes to PA remodeling by inducing medial wall thickening via SMC proliferation and muscularization of the distal pulmonary arterial tree due to migration of SMCs into precapillary arterioles ( 60 , 61 , 81 ) ( Table 2 ; Figure 2 ), potentially affecting arterial compliance by increased wall thickening. In the pulmonary adventitia, fibroblasts activate recruited macrophages through paracrine IL-6 signaling, initiating a pro-inflammatory and pro-fibrotic phenotype that is associated with an increased inflammatory response and vascular remodeling in PH ( 7 ).…”

“…Of relevance, these alterations in biomechanical forces acting upon the lung vascular wall can induce pro-inflammatory responses in ECs of distal PAs ( 58 , 59 ) and promote the aggregation of immune cells ( 58 ). This includes inflammatory cell recruitment and release of immune-cell-derived cytokines, such as IL-6 ( 60 , 61 ) and TNF ( 62 ) and bioactive enzymes, including MMPs ( 46 ), which may, in turn, promote vascular remodeling and stiffening processes, thus establishing a progressive vicious cycle. Such interplay between inflammation-triggered signaling events that, in turn, initiate wound healing processes and ECM remodeling, ultimately culminating in tissue fibrosis and scar formation, is well established in cardiac and systemic vascular diseases ( 63 – 65 ).…”

Update in approaches to pulmonary hypertension because of left heart disease

“…Furthermore, animal models of left-sided pressure overload lead to an increase in lung inflammation and right heart hypertrophy, which can be attenuated by the administration of antibodies against interleukin-1β [12]. In similar models where the pulmonary vein is mechanically stretched, there is a demonstrable upregulation of pro-inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α [13].…”