Genetic predisposition and Pediatric Acute Respiratory Distress Syndrome: New tools for genetic study

Indexación: Web of Science; Scielo.El síndrome de distrés respiratorio agudo (SDRA) es la forma más grave de falla respiratoria. Teóricamente, cualquier noxa pulmonar aguda puede resultar en un SDRA, pero solo un pequeño porcentaje de individuos desarrolla la enfermedad. Sobre este fundamento, factores genéticos han sido implicados en el riesgo de desarrollar SDRA. Basado en la fisiopatología de esta enfermedad, múltiples genes candidatos han sido evaluados como potenciales modificadores, tanto en pacientes como en modelos animales de SDRA. Datos experimentales y estudios clínicos recientes sugieren que variantes de genes implicados en procesos clave de daño tisular, celular y molecular pulmonar pueden influir en la predisposición y el pronóstico del SDRA. Sin embargo, la patogénesis del SDRA pediátrico es compleja y, en consecuencia, es posible anticipar que muchos genes pueden contribuir a ella. Variantes genéticas, tales como polimorfismos de nucleótido simple y variantes del número de copias, están probablemente asociadas con la predisposición al SDRA en niños con lesión pulmonar primaria. El estudio de asociación del genoma completo (GWAS, del inglés Genome-Wide Association Study) puede examinar estas variantes sin sesgos y ayudar a identificar nuevos genes fundamentales y vías patogénicas clave para futuros análisis. Esta aproximación también puede tener implicancias clínicas diagnósticas y terapéuticas, como predecir el riesgo del paciente o desarrollar un enfoque terapéutico personalizado para este grave síndrome.Acute respiratory distress syndrome (ARDS) is the most severe form of respiratory failure. Theoretically, any acute lung condition can lead to ARDS, but only a small percentage of individuals actually develop the disease. On this basis, genetic factors have been implicated in the risk of developing ARDS. Based on the pathophysiology of this disease, many candidate genes have been evaluated as potential modifiers in patient, as well as in animal models, of ARDS. Recent experimental data and clinical studies suggest that variations of genes involved in key processes of tissue, cellular and molecular lung damage may influence susceptibility and prognosis of ARDS. However, the pathogenesis of pediatric ARDS is complex, and therefore, it can be expected that many genes might contribute. Genetic variations such as single nucleotide polymorphisms and copy-number variations are likely associated with susceptibility to ARDS in children with primary lung injury. Genome-wide association (GWA) studies can objectively examine these variations, and help identify important new genes and pathogenetic pathways for future analysis. This approach might also have diagnostic and therapeutic implications, such as predicting patient risk or developing a personalized therapeutic approach to this serious syndrome.http://ref.scielo.org/kqgf3

Progression of regional lung strain and heterogeneity in lung injury: assessing the evolution under spontaneous breathing and mechanical ventilation

Indexación ScopusBackground: Protective mechanical ventilation (MV) aims at limiting global lung deformation and has been associated with better clinical outcomes in acute respiratory distress syndrome (ARDS) patients. In ARDS lungs without MV support, the mechanisms and evolution of lung tissue deformation remain understudied. In this work, we quantify the progression and heterogeneity of regional strain in injured lungs under spontaneous breathing and under MV. Methods: Lung injury was induced by lung lavage in murine subjects, followed by 3 h of spontaneous breathing (SB-group) or 3 h of low Vt mechanical ventilation (MV-group). Micro-CT images were acquired in all subjects at the beginning and at the end of the ventilation stage following induction of lung injury. Regional strain, strain progression and strain heterogeneity were computed from image-based biomechanical analysis. Three-dimensional regional strain maps were constructed, from which a region-of-interest (ROI) analysis was performed for the regional strain, the strain progression, and the strain heterogeneity. Results: After 3 h of ventilation, regional strain levels were significantly higher in 43.7% of the ROIs in the SB-group. Significant increase in regional strain was found in 1.2% of the ROIs in the MV-group. Progression of regional strain was found in 100% of the ROIs in the SB-group, whereas the MV-group displayed strain progression in 1.2% of the ROIs. Progression in regional strain heterogeneity was found in 23.4% of the ROIs in the SB-group, while the MV-group resulted in 4.7% of the ROIs showing significant changes. Deformation progression is concurrent with an increase of non-aerated compartment in SB-group (from 13.3% ± 1.6% to 37.5% ± 3.1%), being higher in ventral regions of the lung. Conclusions: Spontaneous breathing in lung injury promotes regional strain and strain heterogeneity progression. In contrast, low Vt MV prevents regional strain and heterogeneity progression in injured lungs. © 2020, The Author(s).https://annalsofintensivecare.springeropen.com/articles/10.1186/s13613-020-00725-

Megalin/LRP2 Expression Is Induced by Peroxisome Proliferator-Activated Receptor -Alpha and -Gamma: Implications for PPARs' Roles in Renal Function

BACKGROUND: Megalin is a large endocytic receptor with relevant functions during development and adult life. It is expressed at the apical surface of several epithelial cell types, including proximal tubule cells (PTCs) in the kidney, where it internalizes apolipoproteins, vitamins and hormones with their corresponding carrier proteins and signaling molecules. Despite the important physiological roles of megalin little is known about the regulation of its expression. By analyzing the human megalin promoter, we found three response elements for the peroxisomal proliferator-activated receptor (PPAR). The objective of this study was to test whether megalin expression is regulated by the PPARs. METHODOLOGY/PRINCIPAL FINDINGS: Treatment of epithelial cell lines with PPARα or PPARγ ligands increased megalin mRNA and protein expression. The stimulation of megalin mRNA expression was blocked by the addition of specific PPARα or PPARγ antagonists. Furthermore, PPAR bound to three PPAR response elements located in the megalin promoter, as shown by EMSA, and PPARα and its agonist activated a luciferase construct containing a portion of the megalin promoter and the first response element. Accordingly, the activation of PPARα and PPARγ enhanced megalin expression in mouse kidney. As previously observed, high concentrations of bovine serum albumin (BSA) decreased megalin in PTCs in vitro; however, PTCs pretreated with PPARα and PPARγ agonists avoided this BSA-mediated reduction of megalin expression. Finally, we found that megalin expression was significantly inhibited in the PTCs of rats that were injected with BSA to induce tubulointerstitial damage and proteinuria. Treatment of these rats with PPARγ agonists counteracted the reduction in megalin expression and the proteinuria induced by BSA. CONCLUSIONS: PPARα/γ and their agonists positively control megalin expression. This regulation could have an important impact on several megalin-mediated physiological processes and on pathophysiologies such as chronic kidney disease associated with diabetes and hypertension, in which megalin expression is impaired