scholarly journals Cytokines trigger disruption of endothelium barrier function and p38 MAP kinase activation in BMPR2-silenced human lung microvascular endothelial cells

2019 ◽  
Vol 9 (4) ◽  
pp. 204589401988360 ◽  
Author(s):  
Birger Tielemans ◽  
Leanda Stoian ◽  
Rik Gijsbers ◽  
Annelies Michiels ◽  
Allard Wagenaar ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Barrier Function ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Endothelial Barrier ◽  
Endothelial Barrier Function ◽  
Pulmonary Arterial ◽  
Factor Α ◽  
Necrosis Factor

The bone morphogenetic protein receptor II (BMPRII) signaling pathway is impaired in pulmonary arterial hypertension and mutations in the BMPR2 gene have been observed in both heritable and idiopathic pulmonary arterial hypertension. However, all BMPR2 mutation carriers do not develop pulmonary arterial hypertension, and inflammation could trigger the development of the disease in BMPR2 mutation carriers. Circulating levels and/or lung tissue expression of cytokines such as tumor necrosis factor-α or interleukin-18 are elevated in patients with pulmonary arterial hypertension and could be involved in the pathogenesis of pulmonary arterial hypertension. We consequently hypothesized that cytokines could trigger endothelial dysfunction in addition to impaired BMPRII signaling. Our aim was to determine whether impairment of BMPRII signaling might affect endothelium barrier function and adhesiveness to monocytes, in response to cytokines. BMPR2 was silenced in human lung microvascular endothelial cells (HLMVECs) using lentiviral vectors encoding microRNA-based hairpins. Effects of tumor necrosis factor-α and interleukin-18 on HLMVEC adhesiveness to the human monocyte cell line THP-1, adhesion molecule expression, endothelial barrier function and activation of P38MAPK were investigated in vitro. Stable BMPR2 silencing in HLMVECs resulted in impaired endothelial barrier function and constitutive activation of P38MAPK. Adhesiveness of BMPR2-silenced HLMVECs to THP-1 cells was enhanced by tumor necrosis factor-α and interleukin-18 through ICAM-1 adhesion molecule. Interestingly, tumor necrosis factor-α induced activation of P38MAPK and disrupted endothelial barrier function in BMPR2-silenced HLMVECs. Altogether, our findings showed that stable BMPR2 silencing resulted in impaired endothelial barrier function and activation of P38MAPK in HLMVECs. In BMPR2-silenced HLMVECs, cytokines enhanced adhesiveness capacities, activation of P38MAPK and impaired endothelial barrier function suggesting that cytokines could trigger the development of pulmonary arterial hypertension in a context of impaired BMPRII signaling pathway.

MicroRNA‐140‐5p targeting tumor necrosis factor‐α prevents pulmonary arterial hypertension

2018 ◽  
Vol 234 (6) ◽  
pp. 9535-9550 ◽  
Author(s):  
Tian‐Tian Zhu ◽  
Wei‐Fang Zhang ◽  
Ya‐Ling Yin ◽  
Yu‐Hao Liu ◽  
Ping Song ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Tumor Necrosis Factor ◽  
Arterial Hypertension ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Pulmonary Arterial ◽  
Factor Α ◽  
Necrosis Factor

Tumor necrosis factor-α–dependent expression of phosphodiesterase 2: role in endothelial hyperpermeability

Blood ◽  
2005 ◽  
Vol 105 (9) ◽  
pp. 3569-3576 ◽  
Author(s):  
Joachim Seybold ◽  
Dirk Thomas ◽  
Martin Witzenrath ◽  
Şengül Boral ◽  
Andreas C. Hocke ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Barrier Function ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Endothelial Barrier ◽  
Endothelial Barrier Function ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

AbstractThe pleiotropic cytokine tumor necrosis factor-α (TNF-α) and thrombin lead to increased endothelial permeability in sepsis. Numerous studies demonstrated the significance of intracellular cyclic nucleotides for the maintenance of endothelial barrier function. Actions of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are terminated by distinct cyclic nucleotide phosphodiesterases (PDEs). We hypothesized that TNF-α could regulate PDE activity in endothelial cells, thereby impairing endothelial barrier function. In cultured human umbilical vein endothelial cells (HUVECs), we found a dramatic increase of PDE2 activity following TNF-α stimulation, while PDE3 and PDE4 activities remained unchanged. Significant PDE activities other than PDE2, PDE3, and PDE4 were not detected. TNF-α increased PDE2 expression in a p38 mitogen-activated protein kinase (MAPK)–dependent manner. Endothelial barrier function was investigated in HUVECs and in isolated mice lungs. Selective PDE2 up-regulation sensitized HUVECs toward the permeability-increasing agent thrombin. In isolated mice lungs, we demonstrated that PDE2 inhibition was effective in preventing thrombin-induced lung edema, as shown with a reduction in both lung wet-to-dry ratio and albumin flux from the vascular to bronchoalveolar compartment. Our findings suggest that TNF-α–mediated up-regulation of PDE2 may destabilize endothelial barrier function in sepsis. Inhibition of PDE2 is therefore of potential therapeutic interest in sepsis and acute respiratory distress syndrome (ARDS).

scholarly journals Immunological aspects of pathogenesis of metabolic syndrome-related arterial hypertension

2014 ◽  
Vol 95 (3) ◽  
pp. 322-325 ◽  
Author(s):  
A F Salikhova
Keyword(s):  
Metabolic Syndrome ◽  
Tumor Necrosis Factor ◽  
Arterial Hypertension ◽  
Immunoglobulin G ◽  
Interleukin 6 ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Serum Leptin ◽  
Factor Α ◽  
Necrosis Factor

Aim. To analyze the link between levels of adipocytokines (leptine), non-specific cytokines (interleukin-6, tumor necrosis factor-α) and arterial hypertension. Methods. 123 subjects, including 100 patients with metabolic syndrome (according to 2005 Criteria of International Diabetes Federation) and 23 healthy subjects, were examined. General examination was performed, body weight, height and waist circumference were measured, body mass index was calculated. Following laboratory test were performed: serum leptin, interleukin-6, tumor necrosis factor-α, main classes of immunoglobulin, C-reactive protein levels were measured. Results. In patients with metabolic syndrome, increased body weight was associated with increased risk of arterial hypertension. A 10-fold increase of serum leptin level (44.69±8.96 ng/ml) compared to healthy controls (4.72±1.33 ng/ml, p 0.01), was revealed. Leptin level elevation was strongly associated with increased body mass index (r=0.77; p 0.001). Tumor necrosis factor-α concentration in patients with metabolic syndrome exceeded 2 pg/ml, while in healthy controls it didn’t reach this level. Interleukin-6 level was elevated in patients with metabolic syndrome (7.32 [3.25; 7.17] pg/ml) compared to controls (1.53 [1.19; 2.49] pg/ml, Fisher’s exact test, p 0.001). Examination of immunoglobulin levels in patients with metabolic syndrome revealed decreased serum level of immunoglobulin E (97.12±66.24 IU/ml) compared to controls (60.47±19.04 IU/ml, p=0.01). Concentration of immunoglobulin G in patients with metabolic syndrome was also higher (14.61±3.50 g/l) compared to controls (12.57±2.07 g/l, p=0.009). Increased interleukin-6 and immunoglobulin G levels were associated with presence of arterial hypertension. Conclusion. Increased interleukin-6 and immunoglobulin G might be an important factor for arterial hypertension onset and progression.

scholarly journals TIFA protein expression is associated with pulmonary arterial hypertension

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hao-Chih Chang ◽  
Tong-You Wade Wei ◽  
Pei-Yu Wu ◽  
Ming-Daw Tsai ◽  
Wen-Chung Yu ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Tumor Necrosis Factor ◽  
Protein Expression ◽  
Arterial Hypertension ◽  
Tumor Necrosis ◽  
Heart Catheterization ◽  
Cellular Expression ◽  
Tnf Α ◽  
Pulmonary Arterial ◽  
Necrosis Factor

AbstractTumor necrosis factor receptor-associated factor-interacting protein with a forkhead-associated domain (TIFA), a key regulator of inflammation, may be involved in the pathogenesis of pulmonary arterial hypertension (PAH). A total of 48 PAH patients (age 50.1 ± 13.1 years, 22.9% men), 25 hypertensive subjects, and 26 healthy controls were enrolled. TIFA protein expression in peripheral blood mononuclear cells (PBMCs) and plasma interleukin (IL)-1β and tumor necrosis factor (TNF)-α were measured. Pulmonary arterial hemodynamics were derived from right heart catheterization. PAH patients had the highest expression of TIFA, TNF-α, and IL-1β. TIFA protein expression was significantly associated with IL-1β (r = 0.94; P < 0.001), TNF-α (r = 0.93; P < 0.001), mean pulmonary artery pressure (r = 0.41; P = 0.006), and pulmonary vascular resistance (r = 0.41; P = 0.007). TIFA protein expression could independently predict the presence of PAH (odds ratio [95% confidence interval per-0.1 standard deviation]: 1.72 [1.37–2.16]; P < 0.001) and outperformed echocardiographic estimation. Ex vivo silencing of TIFA protein expression in PBMCs led to the suppression of the cellular expression of IL-1β and TNF-α. IL-1β and TNF-α mediated 80.4% and 56.6% of the causal relationship between TIFA and PAH, respectively, supporting the idea that TIFA protein is involved in the pathogenesis of PAH.

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