Lung Microenvironments and Disease Progression in Fibrotic Hypersensitivity Pneumonitis
Year: 2021
Type: article
Study design: Observational Study
Abstract: Rationale Fibrotic hypersensitivity pneumonitis (fHP) is an interstitial lung disease caused by sensitization to an inhaled allergen. Objectives To identify the molecular determinants associated with progression of fibrosis. Methods Nine fHP explant lungs and six unused donor lungs (as controls) were systematically sampled (4 samples/lung). According to microcomputed tomography measures, fHP cores were clustered into mild, moderate, and severe fibrosis groups. Gene expression profiles were assessed using weighted gene co-expression network analysis, xCell, gene ontology, and structure enrichment analysis. Gene expression of the prevailing molecular traits was also compared with idiopathic pulmonary fibrosis (IPF). The explant lung findings were evaluated in separate clinical fHP cohorts using tissue, BAL samples, and computed tomography scans. Measurements and Main Results We found six molecular traits that associated with differential lung involvement. In fHP, extracellular matrix and antigen presentation/sensitization transcriptomic signatures characterized lung zones with only mild structural and histological changes, whereas signatures involved in honeycombing and B cells dominated the transcriptome in the most severely affected lung zones. With increasing disease severity, endothelial function was progressively lost, and progressive disruption in normal cellular homeostatic processes emerged. All six were also found in IPF, with largely similar associations with disease microenvironments. The molecular traits correlated with in vivodisease behavior in a separate clinical fHP cohort. Conclusions We identified six molecular traits that characterize the morphological progression of fHP and associate with in vivoclinical behavior. Comparing IPF with fHP, the transcriptome landscape was determined considerably by local disease extent rather than by diagnosis alone.
Authors: Laurens J. De Sadeleer, John E. McDonough, Jonas C. Schupp, Xiting Yan, Arno Vanstapel, Anke Van Herck, Stephanie Everaerts, Vincent Geudens, Annelore Sacreas, Tinne Goos, Celine Aelbrecht, Tim S. Nawrot, Dries S. Martens, Dominique Schols, Sandra Claes, Johny A. Verschakelen, Eric K. Verbeken, Maximilian Ackermann, Anabelle Decottignies, Manon Mahieu, Tillie-Louise Hackett, James C. Hogg, Bart M. Vanaudenaerde, Stijn E. Verleden, Naftali Kaminski, Wim A. Wuyts
Institutions: Yale University, Medizinische Hochschule Hannover, Hasselt University, KU Leuven, Universitair Ziekenhuis Leuven, Witten/Herdecke University, University Medical Center of the Johannes Gutenberg University Mainz, Helios Universitätsklinikum Wuppertal, de Duve Institute, UCLouvain, University of British Columbia, Centre for Heart Lung Innovation, University of Antwerp
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: U.S. Department of Defense, AstraZeneca, Francis Family Foundation, Providence Health Care, Veracyte, Michael Smith Health Research BC, Fonds De La Recherche Scientifique - FNRS, Fonds Wetenschappelijk Onderzoek, KU Leuven, Stichting Tegen Kanker, National Institutes of Health, Canadian Institutes of Health Research, National Heart, Lung, and Blood Institute, U.S. National Library of Medicine, National Center for Advancing Translational Sciences
Awards: G2083595557, IDENTIFYING REVERSIBLE MOLECULAR NETWORKS IN HUMAN PULMONARY FIBROSIS USING SINGLE NUCLEAR TRANSCRIPTOMICS AND SYSTEMS BIOLOGY, Early detection of familial idiopathic pulmonary fibrosis: lessons for the whole spectrum of interstitial lung diseases, Epithelial Protective Effects of Thyroid Hormone Signaling in Fibrosis, G411088585, G4119534169, Deep and Integrative Analysis of RNA Sequencing Data to Identify Pathogenesis Heterogeneity of Chronic Lung Disease, Lung-on-a-chip as a dynamic tool to capture interplay between airway and vascular cells in their microenvironment: a focus on the course of chronic obstructive pulmonary disease, Tissue is the issue: unravelling histopathologic changes in chronic lung allograft dysfunction after lung transplantation, G5850682332, G6619541416, G7376162541, Mir-29 mimicry as a therapy for pulmonary fibrosis, Normal Aging Lung Cell Atlas (NALCA), The prenatal exposome and cardiovascular fetal programming: the role of telomere ageing dynamics., Genomic Analysis of Tissue and Cellular Heterogeneity in IPF, Yale Clinical and Translational Science Award
OpenAlex ID: W3209302925