Mir-155-5p targets TP53INP1 to promote proliferative phenotype in hypersensitivity pneumonitis lung fibroblasts.

Background: Hypersensitivity pneumonitis (HP) is an inflammatory disorder affecting lung parenchyma and often evolves into fibrosis (fHP). The altered regulation of genes involved in the pathogenesis of the disease is not well comprehended, while the role of microRNAs in lung fibroblasts remains unexplored. Methods: We used integrated bulk RNA-Seq and enrichment pathway bioinformatic analyses to identify differentially expressed (DE)-miRNAs and genes (DEGs) associated with HP lungs. In vitro, we evaluated the expression and potential role of miR-155-5p in the phenotype of fHP lung fibroblasts. Loss and gain assays were used to demonstrate the impact of miR-155-5p on fibroblast functions. In addition, mir-155-5p and its target TP53INP1 were analyzed after treatment with TGF-ß, IL-4, and IL-17A. Results: We found around 50 DEGs shared by several databases that differentiate HP from control and IPF lungs, constituting a unique HP lung transcriptional signature. Additionally, we reveal 18 DE-miRNAs that may regulate these DEGs. Among the candidates likely associated with HP pathogenesis was miR-155-5p. Our findings indicate that increased miR-155-5p in fHP fibroblasts coincides with reduced TP53INP1 expression, high proliferative capacity, and a lack of senescence markers compared to IPF fibroblasts. Induced overexpression of miR-155-5p in normal fibroblasts remarkably increases the proliferation rate and decreases TP53INP1 expression. Conversely, miR-155-5p inhibition reduces proliferation and increases senescence markers. TGF-ß, IL-4, and IL-17A stimulated miR-155-5p overexpression in HP lung fibroblasts. Conclusion: Our findings suggest a distinctive signature of 53 DEGs in HP, including CLDN18, EEF2, CXCL9, PLA2G2D, and ZNF683, as potential targets for future studies. Likewise, 18 miRNAs, including miR-155-5p, could be helpful to establish differences between these two pathologies. The overexpression of miR-155-5p and downregulation of TP53INP1 in fHP lung fibroblasts may be involved in his proliferative and profibrotic phenotype. These findings may help differentiate and characterize their pathogenic features and understand their role in the disease.

Absence of HDAC3 by Matrix Stiffness Promotes Chromatin Remodeling and Fibroblast Activation in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease characterized by progressive and irreversible lung scarring associated with persistent activation of fibroblasts. Epigenetics could integrate diverse microenvironmental signals, such as stiffness, to direct persistent fibroblast activation. Histone modifications by deacetylases (HDAC) may play an essential role in the gene expression changes involved in the pathological remodeling of the lung. Particularly, HDAC3 is crucial for maintaining chromatin and regulating gene expression, but little is known about its role in IPF. In the study, control and IPF-derived fibroblasts were used to determine the influence of HDAC3 on chromatin remodeling and gene expression associated with IPF signature. Additionally, the cells were grown on hydrogels to mimic the stiffness of a fibrotic lung. Our results showed a decreased HDAC3 in the nucleus of IPF fibroblasts, which correlates with changes in nucleus size and heterochromatin loss. The inhibition of HDAC3 with a pharmacological inhibitor causes hyperacetylation of H3K9 and provokes an increased expression of Col1A1, ACTA2, and p21. Comparable results were found in hydrogels, where matrix stiffness promotes the loss of nuclear HDAC3 and increases the profibrotic signature. Finally, latrunculin b was used to confirm that changes by stiffness depend on the mechanotransduction signals. Together, these results suggest that HDAC3 could be a link between epigenetic mechanisms and the fibrotic microenvironment.

Lack of ZNF365 Drives Senescence and Exacerbates Experimental Lung Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant activation of the alveolar epithelium, the expansion of the fibroblast population, and the accumulation of extracellular matrix. Global gene expression of human lung fibroblasts stimulated with TGFß-1, a strong fibrotic mediator revealed the overexpression of ZNF365, a zinc finger protein implicated in cell cycle control and telomere stabilization. We evaluated the expression and localization of ZNF365 in IPF lungs and in the fibrotic response induced by bleomycin in WT and deficient mice of the orthologous gene Zfp365. In IPF, ZNF365 was overexpressed and localized in fibroblasts/myofibroblasts and alveolar epithelium. Bleomycin-induced lung fibrosis showed an upregulation of Zfp365 localized in lung epithelium and stromal cell populations. Zfp365 KO mice developed a significantly higher fibrotic response compared with WT mice by morphology and hydroxyproline content. Silencing ZNF365 in human lung fibroblasts and alveolar epithelial cells induced a significant reduction of growth rate and increased senescence markers, including Senescence Associated ß Galactosidase activity, p53, p21, and the histone variant γH2AX. Our findings demonstrate that ZNF365 is upregulated in IPF and experimental lung fibrosis and suggest a protective role since its absence increases experimental lung fibrosis mechanistically associated with the induction of cell senescence.

Efecto de las Técnicas Instrumentales KineticXer® en la Modificación de Parámetros Séricos y Mecánicos en Usuarios Sedentarios con Dolor Lumbar Inespecífico / Effect of KineticXer® Instrumental Techniques in the Modification of Serum and Mechanical Parameters in Sedentary Users with Nonspecific Low Back Pain

Introducción. El dolor lumbar es una de las causas mas comunes de discapacidad en el mundo, existen diferentes tratamientos conservadores dentro de la kinesiología para el manejo de este. La presente investigación describe los efectos de la aplicación de técnicas de liberación miofascial instrumental y, cómo éstas modifican parámetros mecánicos y la expresión de parámetros séricos, tales como: Leucocitos, Bilirrubina y Fierro en estudiantes sedentarios que presenten dolor lumbar inespecífico de la Universidad de las Américas. Objetivo. Describir el efecto de la técnica de liberación miofascial instrumental en la modificación de parámetros mecánicos y séricos en usuarios sedentarios con dolor lumbar inespecífico. Métodos. Analítico experimental. Resultado. Fueron intervenidos 14 participantes sedentarios con dolor lumbar inespecífico, los resultados no fueron significativos en los cambios serios, por el contrario, fueron significativo en los cambios mecánicos. Conclusión. Las técnicas de liberación miofascial instrumental pueden ser una herramienta eficaz para el manejo del dolor lumbar inespecífico, pero faltan mas estudios para demostrar sus efectos a nivel sérico.

Introduction. Low back pain is one of the most common causes of disability in the world, there are different conservative treatments within kinesiology for its management. The present research describes the effects of the application of instrumental myofascial release techniques and how they modify mechanical parameters and the expression of serum parameters, such as: Leukocytes, Biliverdin and Iron in sedentary students with non-specific lumbar pain from the University of Las Américas. Objective. To describe the effect of the instrumental myofascial release technique in the modification of mechanical and serum parameters in sedentary users with nonspecific low back pain. Methods. Case series Results. 14 sedentary participants with non-specific lumbar pain were operated on, the results were not significant in the serious changes, on the contrary, they were significant in the mechanical changes. Conclusion. Instrumental myofascial release techniques can be an effective tool for the management of nonspecific low back pain, but more studies are needed to demonstrate their effects at the serum level.

Melanoma primario de mucosa nasal: Presentación de caso y revisión de la literatura / Primary melanoma of the nasal mucosa: Case presentation and systematic review of the literature

Introducción: Los melanomas de mucosa nasosinusales, representa una de las patologías de menor proporción en las tumoraciones de nariz y senos paranasales y como consecuencia diagnósticos tardíos. Reporte de caso: paciente masculino de la sexta década de la vida, que inicio con cuadro de obstrucción nasal y epistaxis leve, fue enviado para su valoración nuestro hospital de tercer nivel, donde se sometió a biopsia, presentando el resultado histopatológico de melanoma de mucosa nasal. Conclusión: las lesiones se presentaron principalmente como epistaxis y obstrucción nasal, involucraron a la cavidad nasal y senos paranasales y el lado izquierdo fue el más común involucrado. Los estadios de la enfermedad avanzada y metástasis a distancia se presentaron con gran frecuencia y en general con una pobre supervivencia a 5 años.

Background:Mucosalmelanomarepresentsoneofthe pathologies with a lower proportion among tumors of the nose and paranasal sinuses and as a consequence late diagnoses. Objective:To present the case of a male patient in the sixth decade of life with nasal mucosal melanoma and a systematic review of studies reported from 2016 to 2021. The Results:systematic search was carried out from January 2016 to December 2021 in PubMed, Google Scholar and Elsevier; 147 articles that meet the 19 criteria were located.Conclusion:The injury was prevalent in women, there was a higher prevalence in the seventh and eighth decades. The main lesions were epistaxis and nasal obstruction, involved the nasal cavity and paranasal sinuses and the left side was the most common involved. There was high frequency of advanced disease stages and distant metastases and generally with poor 5-year survival.

Loss of MT1-MMP in Alveolar Epithelial Cells Exacerbates Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a lethal age-related lung disease whose pathogenesis involves an aberrant response of alveolar epithelial cells (AEC). Activated epithelial cells secrete mediators that participate in the activation of fibroblasts and the excessive deposition of extracellular matrix proteins. Previous studies indicate that matrix metalloproteinase 14 (MMP14) is increased in the lung epithelium in patients with IPF, however, the role of this membrane-type matrix metalloproteinase has not been elucidated. In this study, the role of Mmp14 was explored in experimental lung fibrosis induced with bleomycin in a conditional mouse model of lung epithelial MMP14-specific genetic deletion. Our results show that epithelial Mmp14 deficiency in mice increases the severity and extension of fibrotic injury and affects the resolution of the lesions. Gain-and loss-of-function experiments with human epithelial cell line A549 demonstrated that cells with a deficiency of MMP14 exhibited increased senescence-associated markers. Moreover, conditioned medium from these cells increased fibroblast expression of fibrotic molecules. These findings suggest a new anti-fibrotic mechanism of MMP14 associated with anti-senescent activity, and consequently, its absence results in impaired lung repair. Increased MMP14 in IPF may represent an anti-fibrotic mechanism that is overwhelmed by the strong profibrotic microenvironment that characterizes this disease.

Nariz bífida: Presentación de caso / Bifid Nose: Case presentation

Objetivo:Una nariz bífida es una anomalía congénita poco común que ocurre durante el desarrollo embriológico de la nariz. En 1939, Esser publicó una serie de 11 casos. Acontinuación, presentamos el caso de Reporte de Caso:una niña que nació con una nariz bifurcada que fue manejada con una traqueotomía para asegurar la vía aérea. Posteriormente, a los 6 meses de edad, se sometió a una primera intervención para mejorar el aspecto externo de la nariz.

Objetive:Abifid nose is a rare congenital anomaly that occurs during embryological development of the nose. In 1939, Esser published a series of 11 cases.Here we present the case of a girl who was born with a Case Report:forked nose that was managed with a tracheostomy to secure the airway. Later, at 6 months of age, she underwent a first intervention to improve the external appearance of the nose.

Nariz bífida: Presentación de caso / Bifid Nose: Case presentation

RESUMEN Objetivo: Una nariz bífida es una anomalía congénita poco común que ocurre durante el desarrollo embriológico de la nariz. En 1939, Esser publicó una serie de 11 casos. Reporte de Caso: A continuación, presentamos el caso de una niña que nació con una nariz bifurcada que fue manejada con una traqueotomía para asegurar la vía aérea. Posteriormente, a los 6 meses de edad, se sometió a una primera intervención para mejorar el aspecto externo de la nariz.

ABSTRACT Objetive: A bifid nose is a rare congenital anomaly that occurs during embryological development of the nose. In 1939, Esser published a series of 11 cases. Case Report: Here we present the case of a girl who was born with a forked nose that was managed with a tracheostomy to secure the airway. Later, at 6 months of age, she underwent a first intervention to improve the external appearance of the nose.

Quiste dermoide nasofrontal: presentación de un caso y revisión narrativa / Nasofrontal dermoid cyst: case presentation

Las lesiones de la región nasofrontal en los niños son un reto diagnóstico debido a su rareza, y su potencial comunicación con el sistema nervioso central también aumenta su complicaciones. Dentro de las principales entidades de esta región se encuentran los quistes dermoides, los gliomas nasales y los encefaloceles. Un abordaje diagnóstico y terapéutico inapropiado podría generar desde simples recurrencias hasta fistulas e infecciones en el sistema nervioso central, que podrían contribuir a mayores complicaciones o incluso, poner en riesgo la vida de los pacientes.

Injuries to the naso-frontal region in children are a diagnostic challenge, associated with their rarity, their complexity also implies their potential communication with the central nervous system. Dermoid cysts, nasal gliomas, and encephaloceles are among the main entities in this region. An inappropriate diagnostic and therapeutic approach could generate from simple recurrences (as in our case), to fistulas and infections of the central nervous system that could contribute to greater complications or even put the lives of patients at risk.

Dysregulated expression of hypoxia-inducible factors augments myofibroblasts differentiation in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an age-related, progressive and lethal disease, whose pathogenesis is associated with fibroblasts/myofibroblasts foci that produce excessive extracellular matrix accumulation in lung parenchyma. Hypoxia has been described as a determinant factor in its development and progression. However, the role of distinct members of this pathway is not completely described. METHODS: By western blot, quantitative PCR, Immunohistochemistry and Immunocitochemistry were evaluated, the expression HIF alpha subunit isoforms 1, 2 & 3 as well, as their role in myofibroblast differentiation in lung tissue and fibroblast cell lines derived from IPF patients. RESULTS: Hypoxia signaling pathway was found very active in lungs and fibroblasts from IPF patients, as demonstrated by the abundance of alpha subunits 1 and 2, which further correlated with the increased expression of myofibroblast marker αSMA. In contrast, HIF-3α showed reduced expression associated with its promoter hypermethylation. CONCLUSIONS: This study lends further support to the involvement of hypoxia in the pathogenesis of IPF, and poses HIF-3α expression as a potential negative regulator of these phenomena.