Abstract
Idiopathic pulmonary fibrosis (IPF) is a lethal fibrotic lung disease characterized by aberrant remodeling of the lung parenchyma with extensive changes to the phenotypes of all lung resident cells. The introduction of transcriptomics, genome scale profiling of thousands of RNA transcripts, caused a significant inversion in IPF research. Instead of generating hypotheses based on animal models of disease, or biological plausibility, with limited validation in humans, investigators were able to generate hypotheses based on unbiased molecular analysis of human samples and then use animal models of disease to test their hypotheses. In this review, we describe the insights made from transcriptomic analysis of human IPF samples. We describe how transcriptomic studies led to identification of novel genes and pathways involved in the human IPF lung such as: matrix metalloproteinases, WNT pathway, epithelial genes, role of microRNAs among others, as well as conceptual insights such as the involvement of developmental pathways and deep shifts in epithelial and fibroblast phenotypes. The impact of lung and transcriptomic studies on disease classification, endotype discovery, and reproducible biomarkers is also described in detail. Despite these impressive achievements, the impact of transcriptomic studies has been limited because they analyzed bulk tissue and did not address the cellular and spatial heterogeneity of the IPF lung. We discuss new emerging technologies and applications, such as single-cell RNAseq and microenvironment analysis that may address cellular and spatial heterogeneity. We end by making the point that most current tissue collections and resources are not amenable to analysis using the novel technologies. To take advantage of the new opportunities, we need new efforts of sample collections, this time focused on access to all the microenvironments and cells in the IPF lung.
Highlights
Impact of Transcriptomics on Our Understanding of Pulmonary FibrosisSection of Pulmonary, Critical Care and Sleep Medicine, Precision Pulmonary Medicine Center (P2MED), Yale University School of Medicine, New Haven, CT, United States
Our understanding of idiopathic pulmonary fibrosis (IPF), a chronically progressive scarring lung disease, with a significant genetic component, has dramatically changed in the last two decades
The increased availability of well-characterized human tissues and the emergence of high throughput transcriptomic profiling technologies facilitated a new era in Idiopathic pulmonary fibrosis (IPF) research, one in which novel hypotheses are based on observations from human lungs
Summary
Section of Pulmonary, Critical Care and Sleep Medicine, Precision Pulmonary Medicine Center (P2MED), Yale University School of Medicine, New Haven, CT, United States. Edited by: Demosthenes Bouros, National and Kapodistrian University of Athens, Greece. Keren Sarah Borensztajn, INSERM UMRS933 Physiopathologie des maladies génétiques d’expression pédiatrique, France. Specialty section: This article was submitted to Pulmonary Medicine, a section of the journal
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