scholarly journals uPA and uPAR are Critical Mediators of Mesothelial Mesenchymal Transition and Pleural Fibrosis

2021 ◽  
Author(s):  
T.A. Tucker ◽  
R. Logan ◽  
A. Jeffers ◽  
W. Qin ◽  
S. Owens ◽  
...  
Keyword(s):  
Mesenchymal Transition ◽  
Pleural Fibrosis

Calponin 1 contributes to myofibroblast differentiation of human pleural mesothelial cells

2022 ◽  
Author(s):  
Young-yeon Choo ◽  
Tsuyoshi Sakai ◽  
Satoshi Komatsu ◽  
Reiko Ikebe ◽  
Ann Jeffers ◽  
...  
Keyword(s):  
Contractile Activity ◽  
Focal Adhesions ◽  
Scar Tissue ◽  
Mesothelial Cells ◽  
Fiber Formation ◽  
Stress Fibers ◽  
Myofibroblast Differentiation ◽  
Mesenchymal Transition ◽  
Pleural Mesothelial Cells ◽  
Pleural Fibrosis

Pleural mesothelial cells (PMCs) can become myofibroblasts via mesothelial-mesenchymal transition (MesoMT) and contribute to pleural organization, fibrosis, and rind formation. However, how these transformed mesothelial cells contribute to lung fibrosis remains unclear. Here, we investigated the mechanism of contractile myofibroblast differentiation of PMCs. TGF-b induced marked upregulation of calponin 1 expression, which was correlated with notable cytoskeletal rearrangement in human PMCs (HPMCs) to produce stress fibers. Downregulation of calponin 1 expression reduced stress fiber formation. Interestingly, induced stress fibers predominantly contain αSMA associated with calponin 1 but not b-actin. Calponin 1 associated stress fibers also contained myosin II and α-actinin. Further, focal adhesions were aligned with the produced stress fibers. These results suggest that calponin 1 facilitates formation of stress fibers that resemble contractile myofibrils. Supporting this notion, TGF-b significantly increased the contractile activity of HPMCs, an effect that was abolished by downregulation of calponin 1 expression. We infer that differentiation of HPMCs to contractile myofibroblasts facilitates stiffness of scar tissue in pleura to promote pleural fibrosis and that upregulation of calponin 1 plays a central role in this process.

DOCK2 Promotes Pleural Fibrosis by Modulating Mesothelial to Mesenchymal Transition

2021 ◽  
Author(s):  
Guoqing Qian ◽  
Oluwaseun Adeyanju ◽  
Saptarshi Roy ◽  
Christudas Sunil ◽  
Ann Jeffers ◽  
...  
Keyword(s):  
Mesenchymal Transition ◽  
Pleural Fibrosis

scholarly journals Thrombin Upregulates PAI-1 and Mesothelial–Mesenchymal Transition Through PAR-1 and Contributes to Tuberculous Pleural Fibrosis

2019 ◽  
Vol 20 (20) ◽  
pp. 5076
Author(s):  
Cheng-Ying Hsieh ◽  
Joen-Rong Sheu ◽  
Chih-Hao Yang ◽  
Wei-Lin Chen ◽  
Jie-Heng Tsai ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Smooth Muscle Actin ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Mesenchymal Transition ◽  
Pleural Thickening ◽  
Pleural Fibrosis ◽  
Pai 1

Thrombin is an essential procoagulant and profibrotic mediator. However, its implication in tuberculous pleural effusion (TBPE) remains unknown. The effusion thrombin and plasminogen activator inhibitor-1 (PAI-1) levels were measured among transudative pleural effusion (TPE, n = 22) and TBPE (n = 24) patients. Pleural fibrosis, identified as radiological residual pleural thickening (RPT) and shadowing, was measured at 12-month follow-up. Moreover, in vivo and in vitro effects of thrombin on PAI-1 expression and mesothelial–mesenchymal transition (MMT) were assessed. We demonstrated the effusion thrombin levels were significantly higher in TBPE than TPE, especially greater in TBPE patients with RPT > 10mm than those without, and correlated positively with PAI-1 and pleural fibrosis area. In carbon black/bleomycin-treated mice, knockdown of protease-activated receptor-1 (PAR-1) markedly downregulated α-smooth muscle actin (α-SMA) and fibronectin, and attenuated pleural fibrosis. In pleural mesothelial cells (PMCs), thrombin concentration-dependently increased PAI-1, α-SMA, and collagen I expression. Specifically, Mycobacterium tuberculosis H37Ra (MTBRa) induced thrombin production by PMCs via upregulating tissue factor and prothrombin, and PAR-1 silencing considerably abrogated MTBRa−stimulated PAI-1 expression and MMT. Consistently, prothrombin/PAR-1 expression was evident in the pleural mesothelium of TBPE patients. Conclusively, thrombin upregulates PAI-1 and MMT and may contribute to tuberculous pleural fibrosis. Thrombin/PAR-1 inhibition may confer potential therapy for pleural fibrosis.

scholarly journals Mesomesenchymal transition of pleural mesothelial cells is PI3K and NF-κB dependent

2015 ◽  
Vol 308 (12) ◽  
pp. L1265-L1273 ◽  
Author(s):  
Shuzi Owens ◽  
Ann Jeffers ◽  
Jake Boren ◽  
Yoshikazu Tsukasaki ◽  
Kathleen Koenig ◽  
...  
Keyword(s):  
Smooth Muscle Actin ◽  
Akt Signaling ◽  
Mesothelial Cells ◽  
Acute Injury ◽  
Phosphatidylinositol 3 Kinase ◽  
Mesenchymal Transition ◽  
Pleural Diseases ◽  
Pleural Mesothelial Cells ◽  
Pleural Fibrosis

Pleural organization follows acute injury and is characterized by pleural fibrosis, which may involve the visceral and parietal pleural surfaces. This process affects patients with complicated parapneumonic pleural effusions, empyema, and other pleural diseases prone to pleural fibrosis and loculation. Pleural mesothelial cells (PMCs) undergo a process called mesothelial mesenchymal transition (MesoMT), by which PMCs acquire a profibrotic phenotype characterized by cellular enlargement and elongation, increased expression of α-smooth muscle actin (α-SMA), and matrix proteins including collagen-1. Although MesoMT contributes to pleural fibrosis and lung restriction in mice with carbon black/bleomycin-induced pleural injury and procoagulants and fibrinolytic proteases strongly induce MesoMT in vitro, the mechanism by which this transition occurs remains unclear. We found that thrombin and plasmin potently induce MesoMT in vitro as does TGF-β. Furthermore, these mediators of MesoMT activate phosphatidylinositol-3-kinase (PI3K)/Akt and NF-κB signaling pathways. Inhibition of PI3K/Akt signaling prevented TGF-β-, thrombin-, and plasmin-mediated induction of the MesoMT phenotype exhibited by primary human PMCs. Similar effects were demonstrated through blockade of the NF-κB signaling cascade using two distinctly different NF-κB inhibitors, SN50 and Bay-11 7085. Conversely, expression of constitutively active Akt-induced mesenchymal transition in human PMCs whereas the process was blocked by PX866 and AKT8. Furthermore, thrombin-mediated MesoMT is dependent on PAR-1 expression, which is linked to PI3K/Akt signaling downstream. These are the first studies to demonstrate that PI3K/Akt and/or NF-κB signaling is critical for induction of MesoMT.

scholarly journals Inhibition of NADPH Oxidase 4 (NOX4) Signaling Attenuates Tuberculous Pleural Fibrosis

2019 ◽  
Vol 8 (1) ◽  
pp. 116 ◽  
Author(s):  
Youngmi Kim ◽  
So Park ◽  
Harry Jung ◽  
You Noh ◽  
Jae Lee ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Epithelial Mesenchymal Transition ◽  
Mesothelial Cell ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Ros Production ◽  
Angiotensin Ii Receptor ◽  
Mesenchymal Transition ◽  
Nadph Oxidase 4 ◽  
Pleural Fibrosis

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [NOX] enzymes serve several hemostatic and host defense functions in various lung diseases, but the role of NOX4 signaling in tuberculous pleurisy is not well understood. The role of NOX4 signaling in tuberculous pleural fibrosis was studied using invitro pleural mesothelial cell (PMC) experiments and a murine model of Mycobacterium bovis bacillus Calmette–Guérin (BCG) pleural infection. The production of NOX4 reactive oxygen species (NOX4–ROS) and the epithelial mesenchymal transition (EMT) in PMCs were both induced by heat-killed mycobacterium tuberculosis (HKMT). In cultured PMCs, HKMT-induced collagen-1 synthesis and EMT were blocked by pretreatment with small interfering RNA (siRNA) NOX4. Moreover, NOX4–ROS production and subsequent fibrosis were reduced by treatment with losartan and the toll-like receptor 4 (TLR4) inhibitor TAK-242. The HKMT-induced EMT and intracellular ROS production were mediated by NOX4 via the activation of extracellular signal-regulated kinase (ERK) signaling. Finally, in a BCG-induced pleurisy model, recruitment of inflammatory pleural cells, release of inflammatory cytokines, and thickened mesothelial fibrosis were attenuated by SiNOX4 compared to SiCon. Our study identified that HKMT-induced pleural fibrosis is mediated by NOX4–ERK–ROS via TLR4 and Angiotensin II receptor type1 (AT1R). There results suggest that NOX4 may be a novel therapeutic target for intervention in tuberculous pleural fibrosis.

scholarly journals Endothelin-1 Induces Mesothelial Mesenchymal Transition and Correlates with Pleural Fibrosis in Tuberculous Pleural Effusions

2019 ◽  
Vol 8 (4) ◽  
pp. 426 ◽  
Author(s):  
Zhung-Han Wu ◽  
Jie-Heng Tsai ◽  
Cheng-Ying Hsieh ◽  
Wei-Lin Chen ◽  
Chi-Li Chung
Keyword(s):  
Pleural Effusion ◽  
Smooth Muscle Actin ◽  
Mesenchymal Transition ◽  
Pleural Diseases ◽  
Pleural Thickening ◽  
Pleural Fibrosis ◽  
Parapneumonic Pleural Effusion ◽  
Insight Into

Endothelin (ET)-1 is involved in various fibrotic diseases. However, its implication in pleural fibrosis remains unknown. We aimed to study the profibrotic role of ET-1 in tuberculous pleural effusion (TBPE). The pleural effusion ET-1 levels were measured among 68 patients including transudative pleural effusion (TPE, n = 12), parapneumonic pleural effusion (PPE, n = 20), and TBPE (n = 36) groups. Pleural fibrosis, defined as radiological residual pleural thickening (RPT) and shadowing, was measured at 12-month follow-up. Additionally, the effect of ET-1 on mesothelial mesenchymal transition (MMT) and extracellular matrix (ECM) producion in human pleural mesothelial cells (PMCs) was assessed. Our findings revealed that effusion ET-1 levels were significantly higher in TBPE than in TPE and PPE, and were markedly higher in TBPE patients with RPT >10 mm than those with RPT ≤10 mm. ET-1 levels correlated substantially with residual pleural shadowing and independently predicted RPT >10 mm in TBPE. In PMCs, ET-1 time-dependently induced MMT with upregulation of α-smooth muscle actin and downregulation of E-cadherin, and stimulated ECM production; furthermore, ET receptor antagonists effectively abrogated these effects. In conclusion, ET-1 induces MMT and ECM synthesis in human PMCs and correlates with pleural fibrosis in TBPE. This study confers a novel insight into the pathogenesis and potential therapies for fibrotic pleural diseases.

TMEM88 inhibits TGF-β1-induced-extracellular matrix (ECM) accumulation and epithelial-mesenchymal transition (EMT) program in human pleural mesothelial cells through modulating TGF-β1/Smad pathway

2020 ◽  
Author(s):  
Zhongmin Sun ◽  
Ning Qian ◽  
Hong Li ◽  
Tinghua Hu ◽  
Ling Tang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Epithelial Mesenchymal Transition ◽  
Mesothelial Cell ◽  
Pathological Process ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Pleural Fibrosis ◽  
Tgf Β1

Abstract Pleural fibrosis is an irreversible pathological process occurred in the development of several lung diseases. TMEM88 is a member of transmembrane (TMEM) family and has been found to be involved in the regulation of fibrogenesis. However, the role of TMEM88 in pleural fibrosis remains unknown. In this study, we aimed to explore the role of TMEM88 in pleural fibrosis in vitro using TGF-β1-induced human pleural mesothelial cell line MeT-5A cells. Our results showed that the expression levels of TMEM88 were downregulated in pleural fibrosis tissues and TGF-β1-treated Met-5A cells. Overexpression of TMEM88 inhibited the proliferation of Met-5A cells under TGF-β1 stimulation. In addition, TMEM88 overexpression prevented TGF-β1-induced extracellular matrix (ECM) accumulation and epithelial-mesenchymal transition (EMT) in Met-5A cells with decreased expression levels of Col I and fibronectin, increased levels of cytokeratin-8 and E-cadherin, as well as decreased levels of vimentin and α-SMA. Furthermore, overexpression of TMEM88 inhibited the expression of TGF-β receptor I (TβRI) and TβRII and suppressed the phosphorylation of Smad2 and Smad3 in Met-5A cells. In conclusion, these results indicated that TMEM88 exhibited an anti-fibrotic activity in pleural fibrosis via inhibiting the activation of TGF-β1/Smad signaling pathway.

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