52 research outputs found

    Aberrant TGFβ/BMP signalling in connective tissue disease associated pulmonary hypertension

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    Up to 10 percent of systemic sclerosis (SSc) patients develop pulmonary arterial hypertension (PAH). This risk persists throughout the disease and is time dependent, suggesting that SSc operates as a susceptibility factor. Outcomes for SSc-PAH patients remain poor compared with heritable (HPAH) or idiopathic (HPAH) forms, despite clinical and pathological similarities. Whereas susceptibility in HPAH and HPAH is strongly associated with gene mutations that lead to reduced expression of functional bone morphogenetic protein type II receptor (BMPRII), these mutations have not been observed in SSc-PAH. My initial aim was to investigate BMPRII expression and downstream signalling pathways in whole lung tissue and explant cultured fibroblasts derived from a murine model of SSc (TβRIIΔk-fib) that is susceptible to developing PAH Complementary studies examined SSc or control lung tissue and fibroblasts. My results suggest reduced BMPRII levels, impaired signalling and altered receptor turnover could be due to increased TGFβ activity in a model of SSc-PAH. Similarly a significant reduction in BMPRII expression is observed in SSc lung tissue and fibroblasts. Increased proteasomal degradation of BMPRII appears to underlie this and may result from heightened TGFβ activity. Proteasomal inhibition restored BMPRII expression and cellular responses. Collectively suggesting that impaired TGFβ/BMP signalling leading to increased receptor degradation, may promote PAH susceptibility in SSc and provide a unifying mechanism across different forms of PAH. Since more than one cell type contribute to the development of PAH and the pathophysiology of the disease BMPRII expression and TGFβ responses in pulmonary arterial smooth muscle cells (PASMCs) were also investigated. Initial studies generated a synthetic “disease” like PASMC that also displayed a reduction in BMPRII expression and increased response to TGFβ, which was similar to IPAH cells Finally, the role of epigenetic inhibition in the TβRIIΔk-fib model was investigated. The epigenetic inhibitor JQ1 was able to attenuate the spontaneous development of PAH in the TβRIIΔk-fib model of PAH. Taken together, work described in this thesis strongly suggests that a reduction in BMPRII is a susceptibility factor to the development of PAH in a pre-clinical model of SSc and in SSc patients

    Endothelial Cells Expressing Endothelial and Mesenchymal Cell Gene Products in Lung Tissue From Patients With Systemic Sclerosis-Associated Interstitial Lung Disease.

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    OBJECTIVE: To examine whether lung endothelial cells (ECs) from patients with systemic sclerosis (SSc)-associated interstitial lung disease (ILD) express mesenchymal cell-specific proteins and gene transcripts, indicative of the occurrence of endothelial-to-mesenchymal phenotypic transition (EndoMT). METHODS: Lung tissue from 6 patients with SSc-associated pulmonary fibrosis was examined by histopathology and immunohistochemistry. Confocal laser microscopy was utilized to assess the simultaneous expression of EC and myofibroblast molecular markers. CD31+CD102+ ECs were isolated from the lung tissue of 2 patients with SSc-associated ILD and 2 normal control subjects, and the expression of EC and mesenchymal cell markers and other relevant genes was analyzed by quantitative polymerase chain reaction, immunofluorescence microscopy, and Western blotting. RESULTS: Immunohistochemical staining revealed cells expressing the EC-specific marker CD31 in the subendothelial, perivascular, and parenchymal regions of the lungs from all SSc patients. Confocal microscopy identified cells displaying simultaneous expression of von Willebrand factor and α-smooth muscle actin in small and medium-sized arterioles in the SSc lung tissue but not in normal control lungs. CD31+CD102+ ECs isolated from SSc lungs expressed high levels of mesenchymal cell-specific genes (type I collagen, type III collagen, and fibronectin), EC-specific genes (type IV collagen and VE-cadherin), profibrotic genes (transforming growth factor β1 and connective tissue growth factor), and genes encoding EndoMT-related transcription factors (TWIST1 and SNAI2). CONCLUSION: Cells coexpressing EC- and mesenchymal cell-specific molecules are present in the lungs of patients with SSc-associated ILD. CD31+CD102+ ECs isolated from SSc lungs simultaneously expressed mesenchymal cell- and EC-specific transcripts and proteins. Collectively, these observations demonstrate the occurrence of EndoMT in the lungs of patients with SSc-associated ILD

    Pension Lawsuit Documents

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    Documents from state and federal court cases regarding pension refor

    Advances in pathogenesis and treatment of systemic sclerosis

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    Systemic sclerosis is the most severe disease within the scleroderma spectrum and is a major medical challenge with high mortality and morbidity. There have been advances in understanding of pathogenesis that reflect the interplay between immune-inflammatory processes and vasculopathy and fibrosis. It can be regarded as a disease of connective tissue repair and this leads to organ-based complications. However the aetiology and triggering events remain to be elucidated. Treatment is available for many aspects of the disease although the available therapies are not curative and some complications remain very challenging, especially non-lethal manifestations such as fatigue, calcinosis and anorectal dysfunction. Immunosuppression is now established as a beneficial approach but balancing risk and benefit is vital, especially for powerful approaches such as autologous stem cell transplantation

    Vietnam Veterans Memorial Wall

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    The wall seen in this photo is a memorial to those who served in the Vietnam War. The memorial is located in the Constitution Gardens near the Lincoln Memorial in Washington, D.C. The land was acquired through legislation passed by President Carter. Construction began on the Vietnam Veterans Memorial on March 16, 1982 and was completed in late October of the same year. The project was originally conceived by Vietnam Veterans and supported by the Vietnam Veterans Memorial Fund, Inc. Maya Ying Lin, a Yale University undergraduate, designed the memorial wall. The Gilbane Building Company was responsible for the construction of the site under the direction of architecture firm Cooper-Lecky Partnership.https://digitalcommons.ric.edu/smolski_images/1209/thumbnail.jp
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