Endothelial to mesenchymal transition (EndoMT) in the pathogenesis of Systemic Sclerosis-associated pulmonary fibrosis and pulmonary arterial hypertension. Myth or reality?

Systemic Sclerosis (SSc) is a systemic autoimmune disease characterized by progressive fibrosis of skin and multiple internal organs and severe functional and structural microvascular alterations. SSc is considered to be the prototypic systemic fibrotic disorder. Despite currently available therapeutic approaches SSc has a high mortality rate owing to the development of SSc-associated interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH), complications that have emerged as the most frequent causes of disability and mortality in SSc. The pathogenesis of the fibrotic process in SSc is complex and despite extensive investigation the exact mechanisms have remained elusive. Myofibroblasts are the cells ultimately responsible for tissue fibrosis and fibroproliferative vasculopathy in SSc. Tissue myofibroblasts in SSc originate from several sources including expansion of quiescent tissue fibroblasts and tissue accumulation of CD34+ fibrocytes. Besides these sources, myofibroblasts in SSc may result from the phenotypic conversion of endothelial cells into activated myofibroblasts, a process known as endothelial to mesenchymal transition (EndoMT). Recently, it has been postulated that EndoMT may play a role in the development of SSc-associated ILD and PAH. However, although several studies have described the occurrence of EndoMT in experimentally induced cardiac, renal, and pulmonary fibrosis and in several human disorders, the contribution of EndoMT to SSc-associated ILD and PAH has not been generally accepted. Here, the experimental evidence supporting the concept that EndoMT plays a role in the pathogenesis of SSc-associated ILD and PAH will be reviewed

Role of growth factors in the pathogenesis of tissue fibrosis in systemic sclerosis.

The most severe clinical and pathologic manifestations of systemic sclerosis (SSc) are the result of a fibrotic process characterized by the excessive and often progressive deposition of collagen and other connective tissue macromolecules in skin and numerous internal organs. The mechanisms involved in the initiation and progression of the remarkable fibrotic process in SSc remain largely unknown. Extensive recent studies have indicated that a variety of polypeptide growth factors play a crucial role in this process. The most commonly implicated growth factors include transforming growth factor beta (TGF-β), connective tissue growth factor (CTGF), platelet derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Here, the experimental evidence supporting the participation of various growth factors in the pathogenesis of the fibrotic process in SSc and the molecular mechanisms involved will be reviewed

Molecular mechanisms of endothelial to mesenchymal cell transition (EndoMT) in experimentally induced fibrotic diseases.

Several recent studies have demonstrated that endothelial to mesenchymal transition (EndoMT), a newly recognized type of cellular transdifferentiation may be an important source of myofibroblasts during the development of experimentally induced pulmonary, cardiac and kidney fibrosis. EndoMT is a complex biological process induced by members of the transforming growth factor (TGF-β) family of regulatory polypeptides in which endothelial cells adopt a mesenchymal or myofibroblastic phenotype acquiring motile and contractile properties and initiating expression of mesenchymal cell products such as α smooth muscle actin (α-SMA) and type I collagen. Although these experimental studies provide compelling evidence for the participation of EndoMT in the development of experimentally-induced fibrotic processes the precise role of EndoMT in the pathogenesis of human fibrotic disorders requires confirmation and validation from studies of human clinical pathologic conditions. Such confirmation should lead to a change in the paradigm of the origin of profibrogenic myofibroblasts involved in human fibrotic diseases. Further understanding of the molecular mechanisms and the regulatory pathways involved in EndoMT may lead to the development of novel therapeutic approaches for the incurable and often devastating fibrotic disorders

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

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

Description of twelve cases of nephrogenic fibrosing dermopathy and review of the literature

ABSTRACT Objectives: To review the clinical and laboratory features of twelve cases of nephrogenic fibrosing dermopathy (NFD) studied at our institution and of 70 previously described cases in the literature. Methods: Clinical evaluation and laboratory studies of twelve patients with NFD associated with chronic hemodialysis or peritoneal dialysis for end-stage renal disease and a review of 23 previous publications describing 70 patients with this disease. Results: Eleven patients undergoing chronic hemodialysis and one patient undergoing chronic peritoneal dialysis for end-stage renal failure developed a severe and progressive cutaneous fibrotic process with woody induration of legs, thighs, hands and forearms, and severe loss of motion and flexion contractures in multiple joints. Several patients displayed systemic involvement including fibrosis of muscles, myocardium and lungs and marked elevations of the erythrocyte sedimentation rate and/or C reactive protein. Three patients died within two years of onset of symptoms. A review of previously published reports of this disorder confirmed the presence of systemic involvement and a poor prognosis with a high rate of mortality. Conclusions: The analysis of twelve cases and a review of 70 previously described cases indicate that NFD is a severe and usually progressive systemic fibrotic disease affecting the dermis, subcutaneous fascia and striated muscles. It also appears that the disease can cause fibrosis of lungs, myocardium and other organs

PTP4A1 promotes TGFβ signaling and fibrosis in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and internal organs. Protein tyrosine phosphatases have received little attention in the study of SSc or fibrosis. Here, we show that the tyrosine phosphatase PTP4A1 is highly expressed in fibroblasts from patients with SSc. PTP4A1 and its close homolog PTP4A2 are critical promoters of TGFβ signaling in primary dermal fibroblasts and of bleomycin-induced fibrosis in vivo. PTP4A1 promotes TGFβ signaling in human fibroblasts through enhancement of ERK activity, which stimulates SMAD3 expression and nuclear translocation. Upstream from ERK, we show that PTP4A1 directly interacts with SRC and inhibits SRC basal activation independently of its phosphatase activity. Unexpectedly, PTP4A2 minimally interacts with SRC and does not promote the SRC-ERK-SMAD3 pathway. Thus, in addition to defining PTP4A1 as a molecule of interest for TGFβ-dependent fibrosis, our study provides information regarding the functional specificity of different members of the PTP4A subclass of phosphatases

Aptamer Proteomics of Serum Exosomes From Patients With Primary Raynaud\u27s and Patients With Raynaud\u27s at Risk of Evolving into Systemic Sclerosis

BACKGROUND: A major unmet need for Systemic Sclerosis (SSc) clinical management is the lack of biomarkers for the early diagnosis of patients with Raynaud\u27s Phenomenon at high risk of evolving into SSc. OBJECTIVE: To identify proteins contained within serum exosomes employing an aptamer proteomic analysis that may serve to reveal patients with Raynaud\u27s Phenomenon at risk of developing SSc. METHODS: Exosomes were isolated from serum samples from patients with Primary Raynaud\u27s Phenomenon and from patients with Raynaud\u27s Phenomenon harbouring serum antinuclear antibodies (ANA) who may be at high risk of evolving into SSc. The expression of 1,305 proteins was quantified using SOMAscan aptamer proteomics, and associations of the differentially elevated or reduced proteins with the clinical subsets of Raynaud\u27s Phenomenon were assessed. RESULTS: Twenty one differentially elevated and one differentially reduced (absolute fold change \u3e|1.3|) proteins were identified. Principal component analysis using these 22 most differentially expressed proteins resulted in excellent separation of the two Raynaud\u27s Phenomenon clinical subsets. Remarkably, the most differentially elevated proteins are involved in enhanced inflammatory responses, immune cell activation and cell migration, and abnormal vascular functions. CONCLUSION: Aptamer proteomic analysis of circulating exosomes identified differentially elevated or reduced proteins between Raynaud\u27s Phenomenon at high risk of evolving into SSc and Primary Raynaud\u27s Phenomenon patients. Some of these proteins are involved in relevant biological pathways that may play a role in SSc pathogenesis including enhanced inflammatory responses, immune cell activation, and endothelial cell and vascular abnormalities

Repercusión del cambio del programa de Informática Médica en la Facultad de Ciencias Médicas "General Calixto García"

Introducción: la asignatura Informática Médica proporciona herramientas al futuro profesional de la salud, que le permiten aplicar las tecnologías de la información y comunicación y brinda métodos científicos para desarrollar sus labores docentes, asistenciales e investigativas. Objetivo: analizar el programa vigente de dicha asignatura en cuanto a contenido y describir el nivel de desempeño de los educandos por la formación recibida a través de los resultados de evaluación, obtenidos en los dos cursos académicos. Material y Métodos: se realizó un estudio cualitativo de tipo exploratorio_descriptivo, sobre la población de los estudiantes de 1er año matriculados en la carrera de Medicina de los cursos 2010-2011 y 2011-2012. Se utilizó el análisis documental y la técnica del Positivo/Negativo/Interesante para la obtención de los datos, aplicando el método fenomenológico y se categorizaron mediante el análisis de contenido. Resultados: se plantea que el programa actual se adapta a las condiciones económicas del país. La aplicación del P.N.I. mostró que el proceso de enseñanza fue bueno, ya que los aspectos negativos no fueron imputables a este proceso. Los resultados de las evaluaciones de los dos cursos analizados, fueron satisfactorios. Conclusiones: valorando a través del test P.N.I. aplicado, pudimos constatar que los educandos nuestros han aceptado el reto que supone la migración al software Libre a pesar de los aspectos negativos detallados, ya que estos no dependen de nuestra Institución. Los resultados de las evaluaciones realizadas así lo confirman.  Palabras Clave: Software Libre, Informática Médica, migración. </p

The significance of macrophage polarization subtypes for animal models of tissue fibrosis and human fibrotic diseases.

The systemic and organ-specific human fibrotic disorders collectively represent one of the most serious health problems world-wide causing a large proportion of the total world population mortality. The molecular pathways involved in their pathogenesis are complex and despite intensive investigations have not been fully elucidated. Whereas chronic inflammatory cell infiltration is universally present in fibrotic lesions, the central role of monocytes and macrophages as regulators of inflammation and fibrosis has only recently become apparent. However, the precise mechanisms involved in the contribution of monocytes/macrophages to the initiation, establishment, or progression of the fibrotic process remain largely unknown. Several monocyte and macrophage subpopulations have been identified, with certain phenotypes promoting inflammation whereas others display profibrotic effects. Given the unmet need for effective treatments for fibroproliferative diseases and the crucial regulatory role of monocyte/macrophage subpopulations in fibrogenesis, the development of therapeutic strategies that target specific monocyte/macrophage subpopulations has become increasingly attractive. We will provide here an overview of the current understanding of the role of monocyte/macrophage phenotype subpopulations in animal models of tissue fibrosis and in various systemic and organ-specific human fibrotic diseases. Furthermore, we will discuss recent approaches to the design of effective anti-fibrotic therapeutic interventions by targeting the phenotypic differences identified between the various monocyte and macrophage subpopulations