BackgroundAlveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) is a lethal disorder of lung development. ACDMPV is associated with haploinsufficiency of the transcription factor FOXF1, which plays an important role in the development of the lung and intestine. CNVs upstream of the FOXF1 gene have also been associated with an ACDMPV phenotype, but mechanism(s) by which these deletions disrupt lung development are not well understood. The objective of our study is to gain insights into the mechanisms by which CNVs contribute to an ACDMPV phenotype.MethodsWe analysed primary lung tissue from an infant with classic clinical and histological findings of ACDMPV and harboured a 340 kb deletion on chromosome 16q24.1 located 250 kb upstream of FOXF1.ResultsIn RNA generated from paraffin-fixed lung sections, our patient had lower expression of FOXF1 than age-matched controls. He also had an abnormal pattern of FOXF1 protein expression, with a dramatic loss of FOXF1 expression in the lung. To gain insights into the mechanisms underlying these changes, we assessed the epigenetic landscape using chromatin immunoprecipitation, which demonstrated loss of histone H3 lysine 27 acetylation (H3K27Ac), an epigenetic mark of active enhancers, in the region of the deletion.ConclusionsTogether, these data suggest that the deletion disrupts an enhancer responsible for directing FOXF1 expression in the developing lung and provide novel insights into the mechanisms underlying a fatal developmental lung disorder.
Exogenous electric fields are currently used in human therapy in a number of contexts. Interestingly, electric fields have also been shown to alter migration and function of immune cells, suggesting the potential for electric field-based immune therapy. Little is known as to the effect of electric field treatment (EFT) on the lung. To determine if EFT associates with changes in lung immune cell infiltration, we used a mouse model with varying methods of EFT application and measured cells and soluble mediators using flow cytometry and cytokine/chemokine multiplex. EFT was associated with a transient increase in lung neutrophils and decrease in eosinophils in naïve mice within 2 h of treatment, accompanied by an increase in IL-6 levels. In order to test whether EFT could alter eosinophil/neutrophil recruitment in a relevant disease model, a mouse model of allergic airway inflammation was used. Four EFT doses in allergen-sensitized mice resulted in increased neutrophil and reduced eosinophil infiltrates following allergen challenge, suggesting a durable change in inflammation by EFT. Mice with allergic inflammation were analyzed by flexiVent for measures of lung function. EFT-treated mice had increased inspiratory capacity and other measures of lung function were not diminished. These data suggest EFT may be used to manipulate immune cell infiltration in the lung without affecting lung function.
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