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Respiratory Research Nov 2023Idiopathic pulmonary fibrosis (IPF) is a heterogeneous disease that is pathologically characterized by areas of normal-appearing lung parenchyma, active fibrosis...
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a heterogeneous disease that is pathologically characterized by areas of normal-appearing lung parenchyma, active fibrosis (transition zones including fibroblastic foci) and dense fibrosis. Defining transcriptional differences between these pathologically heterogeneous regions of the IPF lung is critical to understanding the distribution and extent of fibrotic lung disease and identifying potential therapeutic targets. Application of a spatial transcriptomics platform would provide more detailed spatial resolution of transcriptional signals compared to previous single cell or bulk RNA-Seq studies.
METHODS
We performed spatial transcriptomics using GeoMx Nanostring Digital Spatial Profiling on formalin-fixed paraffin-embedded (FFPE) tissue from 32 IPF and 12 control subjects and identified 231 regions of interest (ROIs). We compared normal-appearing lung parenchyma and airways between IPF and controls with histologically normal lung tissue, as well as histologically distinct regions within IPF (normal-appearing lung parenchyma, transition zones containing fibroblastic foci, areas of dense fibrosis, and honeycomb epithelium metaplasia).
RESULTS
We identified 254 differentially expressed genes (DEGs) between IPF and controls in histologically normal-appearing regions of lung parenchyma; pathway analysis identified disease processes such as EIF2 signaling (important for cap-dependent mRNA translation), epithelial adherens junction signaling, HIF1α signaling, and integrin signaling. Within IPF, we identified 173 DEGs between transition and normal-appearing lung parenchyma and 198 DEGs between dense fibrosis and normal lung parenchyma; pathways dysregulated in both transition and dense fibrotic areas include EIF2 signaling pathway activation (upstream of endoplasmic reticulum (ER) stress proteins ATF4 and CHOP) and wound healing signaling pathway deactivation. Through cell deconvolution of transcriptome data and immunofluorescence staining, we confirmed loss of alveolar parenchymal signals (AGER, SFTPB, SFTPC), gain of secretory cell markers (SCGB3A2, MUC5B) as well as dysregulation of the upstream regulator ATF4, in histologically normal-appearing tissue in IPF.
CONCLUSIONS
Our findings demonstrate that histologically normal-appearing regions from the IPF lung are transcriptionally distinct when compared to similar lung tissue from controls with histologically normal lung tissue, and that transition zones and areas of dense fibrosis within the IPF lung demonstrate activation of ER stress and deactivation of wound healing pathways.
Topics: Humans; Eukaryotic Initiation Factor-2; Idiopathic Pulmonary Fibrosis; Lung; Transcriptome; Fibrosis
PubMed: 37978501
DOI: 10.1186/s12931-023-02572-6 -
Biology Aug 2023The central nervous system (CNS) plays a crucial role in regulating bodily functions by sensing and integrating environmental cues and maintaining proper physiological... (Review)
Review
The central nervous system (CNS) plays a crucial role in regulating bodily functions by sensing and integrating environmental cues and maintaining proper physiological conditions. Recent research has revealed that CNS functions are closely coordinated with the immune system. As even minor disturbances of the immune system in the CNS can lead to various dysfunctions, diseases, or even death, it is highly specialized and segregated from that in peripheral regions. Microglia in the parenchyma and macrophages at the interface between the CNS and peripheral regions are essential immune cells in the CNS that monitor environmental changes. Recent omics analyses have revealed that these cells exhibit highly heterogeneous populations. In this review, we summarize the functions and diversity of microglia in the brain parenchyma and those of macrophages in the border regions, such as the meninges, perivascular spaces, and choroid plexus.
PubMed: 37626977
DOI: 10.3390/biology12081091 -
Acta Neurobiologiae Experimentalis Dec 2023Over the past decade glymphatic concept has gained more and more interest. Despite some lacking data regarding structural and functional aspects, glymphatic system is... (Review)
Review
Over the past decade glymphatic concept has gained more and more interest. Despite some lacking data regarding structural and functional aspects, glymphatic system is widely considered the main mechanism of water and solutes transport in brain parenchyma, as well as waste clearance from the brain. Glymphatic system modulates the extracellular space volume and is involved in spatial K+ buffering (via influencing Kir4.1 channel functioning), two factors crucial for neuronal excitability and seizure susceptibility, and is itself strongly stimulated during sleep. This review summarizes information regarding the potential role of the glymphatic system in the development and progression of epilepsy, especially the role of the glial water channel aquaporin‑4 in modulation of brain excitability and in epilepsy. Data from animal models and human studies are presented.
Topics: Animals; Humans; Brain; Epilepsy; Glymphatic System; Neuroglia; Seizures; Aquaporin 4
PubMed: 38224279
DOI: 10.55782/ane-2023-2498