Lymphangioleiomyomatosis

2020 ◽  
pp. 4257-4259
Author(s):  
S. J. Bourke
Keyword(s):  
Smooth Muscle ◽  
Lung Function ◽  
Lung Transplantation ◽  
Hormonal Therapy ◽  
Muscle Cells ◽  
Gas Diffusion ◽  
Hormonal Replacement ◽  
Increased Risk ◽  
Genes Encoding ◽  
Thin Walled

Lymphangioleiomyomatosis is characterized by cystic destruction of the lungs due to abnormal proliferation of smooth muscle cells. It is caused by mutations of the genes encoding hamartin and tuberin, sometimes in association with tuberous sclerosis. CT imaging shows characteristic multiple thin-walled cysts. There is usually progressive airways obstruction and impaired gas diffusion, and two-thirds of patients suffer pneumothoraces. Sirolimus can stabilize lung function and improve symptoms. Patients should avoid exogenous oestrogens, including oestrogen contraceptives or hormonal replacement therapy. Pregnancy may be associated with an increased risk of pneumothorax and loss of lung function. Hormonal therapy with progesterone or tamoxifen appears to be ineffective: other antioestrogen therapies, such as letrozole, are being studied. Lung transplantation is the main option for advanced disease.

scholarly journals Mesenchymal Stem Cells Attenuate Lipopolysaccharide-Induced Inflammatory Response in Human Uterine Smooth Muscle Cells

2020 ◽  
Vol 10 (03) ◽  
pp. e335-e341
Author(s):  
Arunmani Mani ◽  
John W. Hotra ◽  
Sean C. Blackwell ◽  
Laura Goetzl ◽  
Jerrie S. Refuerzo
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Smooth Muscle ◽  
Preterm Birth ◽  
Inflammatory Response ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Uterine Smooth Muscle ◽  
Cell Based Therapy ◽  
Increased Risk

Abstract Objective The aim of this study was to determine if mesenchymal stem cells (MSCs) would suppress the inflammatory response in human uterine cells in an in vitro lipopolysaccharide (LPS)-based preterm birth (PTB) model. Study Design Cocultures of human uterine smooth muscle cells (HUtSMCs) and MSCs were exposed to 5 μg/mL LPS for 4 hours and further challenged with 1 μg/mL LPS for a subsequent 24 hours. Key elements of the parturition cascade regulated by toll-like receptors (TLRs) through activation of mitogen-activated protein kinases (MAPKs) were quantified in culture supernatant as biomarkers of MSC modulation. Results Coculture with MSCs significantly attenuated TLR-4, p-JNK, and p- extracellular signal-regulated kinase 1/2 (ERK1/2) protein levels compared with HUtSMCs monoculture (p = 0.05). In addition, coculture was associated with significant inhibition of proinflammatory cytokines interleukin (IL)-6 and IL-8 (p = 0.0001) and increased production of anti-inflammatory cytokines IL-10 and transforming growth factor (TGF)-β1 (p = 0.0001). Conclusion MSCs appear to play a role in significantly attenuating LPS-mediated inflammation via alteration of down-stream MAPKs. MSCs may represent a novel, cell-based therapy in women with increased risk of inflammatory-mediated preterm birth.

scholarly journals From genetics to response to injury: vascular smooth muscle cells in aneurysms and dissections of the ascending aorta

2018 ◽  
Vol 114 (4) ◽  
pp. 578-589 ◽  
Author(s):  
Jean-Baptiste Michel ◽  
Guillaume Jondeau ◽  
Dianna M Milewicz
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Protein Transport ◽  
Nuclear Translocation ◽  
Muscle Cells ◽  
Genes Encoding ◽  
Inflammatory Processes ◽  
Adhesive Proteins

Abstract Vascular smooth muscle cells (vSMCs) play a crucial role in both the pathogenesis of Aneurysms and Dissections of the ascending thoracic aorta (TAAD) in humans and in the associated adaptive compensatory responses, since thrombosis and inflammatory processes are absent in the majority of cases. Aneurysms and dissections share numerous characteristics, including aetiologies and histopathological alterations: vSMC disappearance, medial areas of mucoid degeneration, and extracellular matrix (ECM) breakdown. Three aetiologies predominate in TAAD in humans: (i) genetic causes in heritable familial forms, (ii) an association with bicuspid aortic valves, and (iii) a sporadic degenerative form linked to the aortic aging process. Genetic forms include mutations in vSMC genes encoding for molecules of the ECM or the TGF-β pathways, or participating in vSMC tone. On the other hand, aneurysms and dissections, whatever their aetiologies, are characterized by an increase in wall permeability leading to transmural advection of plasma proteins which could interact with vSMCs and ECM components. In this context, blood-borne plasminogen appears to play an important role, because its outward convection through the wall is increased in TAAD, and it could be converted to active plasmin at the vSMC membrane. Active plasmin can induce vSMC disappearance, proteolysis of adhesive proteins, activation of MMPs and release of TGF-β from its ECM storage sites. Conversely, vSMCs could respond to aneurysmal biomechanical and proteolytic injury by an epigenetic phenotypic switch, including constitutional overexpression and nuclear translocation of Smad2 and an increase in antiprotease and ECM protein synthesis. In contrast, such an epigenetic phenomenon is not observed in dissections. In this context, dysfunction of proteins involved in vSMC tone are interesting to study, particularly in interaction with plasma protein transport through the wall and TGF-β activation, to establish the relationship between these dysfunctions and ECM proteolysis.

Homocysteine rapidly increases matrix metalloproteinase-2 expression and activity in cultured human vascular smooth muscle cells

2005 ◽  
Vol 94 (12) ◽  
pp. 1285-1293 ◽  
Author(s):  
Gabriella Doronzo ◽  
Isabella Russo ◽  
Luigi Mattiello ◽  
Mariella Trovati ◽  
Giovanni Anfossi
Keyword(s):  
Smooth Muscle ◽  
Matrix Metalloproteinase ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Conditioned Media ◽  
Matrix Metalloproteinase 2 ◽  
Cell Lysates ◽  
Increased Risk

SummaryIn this study we aimed to test the hypothesis that in human vascular smooth muscle cells (VSMC) homocysteine influences synthesis and release of matrix metalloproteinase-2 (MMP-2), which is deeply involved in vascular remodeling and atherosclerotic plaque instabilization. Experiments were carried out in cultured human VSMC exposed to 50–500 μmol/l homocysteine after a 24-hour culture with MEM containing 0.1% BSA. Both in supernatants and cell lysates we evaluated MMP-2 activity (gelatin zimography), MMP-2 and TIMP-2 protein synthesis (Western immunoblotting). Homocysteine effects were investigated also after cell exposure to i) specific MEK inhibitor PD98059 (30 μmol/l) to evaluate the involvement of Mitogen-Activated Protein Kinase (MAPK) and ii) specific phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002 (100 μmol/l) to evaluate the involvement of PI3-K pathway. Gelatin zimography evidenced that MMP-2 activity is increased both in conditioned media and in cell lysates starting from 8-hour incubation with 100 μmol/l homocysteine. Western blot analysis evidenced increased MMP-2 levels in both conditioned media and cell lysates. Cell exposure to PD98059 and LY294002 prevented homocysteine effects on MMP-2 synthesis. Homocysteine, at concentrations associated with increased risk of cardiovascular events, increases MMP-2 activity, synthesis and secretion in VSMC through a mechanism involving the activation of MAPK and PI3-K pathways. These data suggest that homocysteine is directly involved in mechanisms leading to remodelling and instabilization of atherosclerotic plaques.

Upregulation of thrombospondin-1 expression by leptin in vascular smooth muscle cells via JAK2- and MAPK-dependent pathways

2012 ◽  
Vol 303 (2) ◽  
pp. C179-C191 ◽  
Author(s):  
Ronaldo J. Chavez ◽  
Rebecca M. Haney ◽  
Rene H. Cuadra ◽  
Rituparna Ganguly ◽  
Ravi K. Adapala ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Muscle Cells ◽  
Matricellular Protein ◽  
Vascular Cells ◽  
Increased Risk ◽  
Thrombospondin 1

Hyperleptinemia, characteristic of diabetes and a hallmark feature of human obesity, contributes to the increased risk of atherosclerotic complications. However, molecular mechanisms mediating leptin-induced atherogenesis and gene expression in vascular cells remain incompletely understood. Accumulating evidence documents a critical role of a potent antiangiogenic and proatherogenic matricellular protein, thrombospondin-1 (TSP-1), in atherosclerosis. Although previous studies reported elevated TSP-1 levels in both diabetic and obese patients and rodent models, there is no direct information on TSP-1 expression in vascular cells in response to leptin. In the present study, we show that leptin upregulates TSP-1 expression in cultured human aortic smooth muscle cells (HASMC) in vitro, and this increase occurs at the level of transcription, revealed by mRNA stability and TSP-1 promoter-reporter assays. Utilizing specific pharmacological inhibitors and siRNA approaches, we demonstrate that upregulation of TSP-1 expression by leptin is mediated by JAK2/ERK/JNK-dependent mechanisms. Furthermore, we report that while ERK and JNK are required for both the constitutive and leptin-induced expression of TSP-1, JAK-2 appears to be specifically involved in leptin-mediated TSP-1 upregulation. Finally, we found that increased HASMC migration and proliferation in response to leptin is significantly inhibited by a TSP-1 blocking antibody, thereby revealing the physiological significance of leptin-TSP-1 crosstalk. Taken together, these findings demonstrate, for the first time, that leptin has a direct regulatory effect on TSP-1 expression in HASMCs, underscoring a novel role of TSP-1 in hyperleptinemia-induced atherosclerotic complications.

Cerebral Aneurysms

2002 ◽  
Vol 15 (5) ◽  
pp. 495-499
Author(s):  
D. Schiffer ◽  
V. Fiano ◽  
C. Ghimenti
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Cerebral Aneurysms ◽  
Muscle Cells ◽  
Internal Elastic Lamina ◽  
Experimental Conditions ◽  
Genetic Studies ◽  
Genetic Components ◽  
Genes Encoding

This is an overview on the pathology and pathogenesis of aneurysms, focused on the weakness of the tunica muscularis and the existence of a locus minoris resistentiae. In this regard emphasis is brought to alterations of the internal elastic lamina (IEL) and consequently to the decrease of smooth muscle cells. Tears of IEL, endothelial disruption and formation of thrombi are discussed also in relation to the occurrence of apoptosis of smooth muscle cells. In the remodelling of the vessel walls a major role is played by the constituents of extracellular matrix which have been studied especially in experimental conditions. Many examples of the illustrated pathology have been provided from the personal collection of aneurysm surgical material. Since there is little doubt that the susceptibility to develop aneurysms has genetic components, a special attention is paid to genetic studies dealing with genes encoding for proteins of the extracellular matrix.

scholarly journals Novel Voltage-Gated Potassium Channel Signaling Pathway and Asthma utilizing Bronchoscopy Data

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Allison Higgs ◽  
Taylor Stewart ◽  
Jennifer Douyere ◽  
Yi Zhao ◽  
Joe Zein ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Lung Function ◽  
Potassium Channels ◽  
Smooth Muscle Cells ◽  
Gene Family ◽  
Signaling Pathway ◽  
Receptor Gene ◽  
Muscle Cells ◽  
Asthma Severity ◽  
Airway Smooth Muscle Cells

Asthma is a disease characterized by an excess of free-radical nitric oxide, NO, which leads to airway inflammation and obstruction. S-nitrosothiols (SNO’s) are an important regulator in NO signaling, helping to relieve oxidative stress as well as bronchodilate and relax airway smooth muscle cells. SNO’s exert most of their effects through the NO-cysteine interactions found particularly in S-nitrosocysteine (CSNO). The particular S-nitrosocysteine of interest in this paper is L-CSNO due to its ability to inhibit potassium channels associated with poor lung function, thereby improving ventilation in asthmatic patients. Potassium channels, amongst other ion channels as well, are a new target for therapeutic asthma treatment due to their ability to regulate vascular smooth muscle cells. KCN genes from bronchoscopy data from asthma and control patients were sequenced and analyzed against several measures for asthma and general lung function: asthma severity, FeNO, FEV1%, and androgen receptor gene expression. The goal of this study was to determine which KCN genes, and subsequent Kv channels, are associated with better lung function and which are associated with worse lung function/more severe asthma. The most beneficial KCN genes were found to be KCNA1 and KCNA4, whereas the KCN gene associated with the worst lung function was the KCNK6 gene family. Thus, a potential novel signaling pathway for asthma regulation may involve the binding of L-CSNO to the Kv channels encoded by the KCNK6 gene family in order to inactivate them and improve ventilation and overall lung function.

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