Lung Microenvironments and Disease Progression in Fibrotic Hypersensitivity Pneumonitis

Sadeleer, Laurens J. De; McDonough, John E.; Schupp, Jonas C.; Yan, Xiting; Vanstapel, Arno; Herck, Anke Van; Everaerts, Stephanie; Geudens, Vincent; Sacreas, Annelore; Goos, Tinne; Aelbrecht, Celine; Nawrot, Tim S.; Martens, Dries S.; Schols, Dominique; Claes, Sandra; Verschakelen, Johny; Verbeken, Eric; Ackermann, Maximilian; Decottignies, Anabelle; Mahieu, Manon; Hackett, Tillie-Louise; Hogg, James C.; Vanaudenaerde, Bart M.; Verleden, Stijn E.; Kaminski, Naftali; Wuyts, Wim

doi:10.1164/rccm.202103-0569oc

Cited by 26 publications

(20 citation statements)

References 38 publications

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“…It is very important to emphasize that this process of freezing the lung in toto and using microCT also has limited negative impact on further downstream molecular analysis illustrated by e.g., similar gene expression signatures in scanned vs. non-scanned specimens ( 8 ). Also bulk RNA-sequencing ( 9 , 10 ), immunohistochemistry ( 11 ), and microbiome sequencing (Einarsson et al accepted for publication) have already been performed, making ours a valid tool for more molecular-based research.…”

Section: Methodology Of Lung Processingmentioning

confidence: 99%

“…This is valuable given the temporal heterogeneity in non-neoplastic lung diseases, since genuine specimens with early disease features for research purposes are difficult to obtain. There is certainly some ground truth in such a hypothesis as distinct morphological and molecular processes have been demonstrated in minimally affected vs. severely affected regions ( 9 , 10 ).…”

Section: Ct and Microct Of Explant Lungsmentioning

confidence: 99%

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From Macroscopy to Ultrastructure: An Integrative Approach to Pulmonary Pathology

et al. 2022

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Pathology and radiology are complimentary tools, and their joint application is often crucial in obtaining an accurate diagnosis in non-neoplastic pulmonary diseases. However, both come with significant limitations of their own: Computed Tomography (CT) can only visualize larger structures due to its inherent–relatively–poor resolution, while (histo) pathology is often limited due to small sample size and sampling error and only allows for a 2D investigation. An innovative approach of inflating whole lung specimens and subjecting these subsequently to CT and whole lung microCT allows for an accurate matching of CT-imaging and histopathology data of exactly the same areas. Systematic application of this approach allows for a more targeted assessment of localized disease extent and more specifically can be used to investigate early mechanisms of lung diseases on a morphological and molecular level. Therefore, this technique is suitable to selectively investigate changes in the large and small airways, as well as the pulmonary arteries, veins and capillaries in relation to the disease extent in the same lung specimen. In this perspective we provide an overview of the different strategies that are currently being used, as well as how this growing field could further evolve.

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Section: Methodology Of Lung Processingmentioning

confidence: 99%

Section: Ct and Microct Of Explant Lungsmentioning

confidence: 99%

From Macroscopy to Ultrastructure: An Integrative Approach to Pulmonary Pathology

et al. 2022

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“…The lung processing protocol is described extensively elsewhere 35,94 . Lungs were air-inflated upon total lung capacity after explantation and immediately frozen in the fumes of liquid After conventional scanning using computed tomography, the lungs were processed into cores (2cm height, 1.5 cm diameter).…”

Section: Microct Based Staging Of Human Ipf Patient Tissuementioning

confidence: 99%

Ex vivotissue perturbations coupled to single cell RNA-seq reveal multi-lineage cell circuit dynamics in human lung fibrogenesis

Lang

Gote-Schniering

Porras-Gonzalez

et al. 2023

Preprint

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Pulmonary fibrosis develops as a consequence of failed regeneration after injury. Analyzing mechanisms of regeneration and fibrogenesis directly in human tissue has been hampered by the lack of organotypic models and analytical techniques. In this work, we coupledex vivocytokine and drug perturbations of human precision-cut lung slices (hPCLS) with scRNAseq and induced a multi-lineage circuit of fibrogenic cell states in hPCLS, which we show to be highly similar to thein vivocell circuit in a multi-cohort lung cell atlas from pulmonary fibrosis patients. Using micro-CT staged patient tissues, we characterized the appearance and interaction of myofibroblasts, an ectopic endothelial cell state and basaloid epithelial cells in the thickened alveolar septum of early-stage lung fibrosis. Induction of these states in theex vivohPCLS model provides evidence that the basaloid cell state was derived from alveolar type-2 cells, whereas the ectopic endothelial cell state emerged from capillary cell plasticity. Cell-cell communication routes in patients were largely conserved in the hPCLS model and anti-fibrotic drug treatments showed highly cell type specific effects. Our work provides an experimental framework for perturbational single cell genomics directly in human lung tissue that enables analysis of tissue homeostasis, regeneration and pathology. We further demonstrate that hPCLS offers novel avenues for scalable, high-resolution drug testing to accelerate anti-fibrotic drug development and translation.

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“… 13 , 14 Moreover, the weighted gene co‐expression network analysis (WGCNA) and RNA‐seq are also widely used to identify core targets of human diseases. 15 , 16 Hence, three strategies (RNA‐seq analysis, WGCNA, 17 and database search) were conducted in this study to obtain genes associated with the pathogenesis of sepsis (Figure 1a ). Then, pharmacological targets for MEL were predicted according to the Drugbank database.…”

Section: Introductionmentioning

confidence: 99%

Identification of PIK3CG as a hub in septic myocardial injury using network pharmacology and weighted gene co‐expression network analysis

Liu

Dong

Escames

et al. 2022

Bioengineering & Transla Med

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Sepsis causes multiple organ injuries, among which the heart is one most severely damaged organ. Melatonin (MEL) alleviates septic myocardial injury, although a systematic and comprehensive approach is still lacking to understand the precise protective machinery of MEL. This study aimed to examine the underlying mechanisms of MEL on improvement of septic myocardial injury at a systematic level. This study integrated three analytic modalities including database investigations, RNA‐seq analysis, and weighted gene co‐expression network analysis (WCGNA), in order to acquire a set of genes associated with the pathogenesis of sepsis. The Drugbank database was employed to predict genes that may serve as pharmacological targets for MEL‐elicited benefits, if any. A pharmacological protein–protein interaction network was subsequently constructed, and 66 hub genes were captured which were enriched in a variety of immune response pathways. Notably, PIK3CG, one of the hub genes, displayed high topological characteristic values, strongly suggesting its promise as a novel target for MEL‐evoked treatment of septic myocardial injury. Importantly, molecular docking simulation experiments as well as in vitro and in vivo studies supported an essential role for PIK3CG in MEL‐elicited effect on septic myocardial injury. This study systematically clarified the mechanisms of MEL intervention in septic myocardial injury involved multiple targets and multiple pathways. Moreover, PIK3CG‐governed signaling cascade plays an important role in the etiology of sepsis and septic myocardial injury. Findings from our study provide valuable information on novel intervention targets for the management of septic myocardial injury. More importantly, this study has indicated the utility of combining a series of techniques for disease target discovery and exploration of possible drug targets, which should shed some light on elucidation of experimental and clinical drug action mechanisms systematically.

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Lung Microenvironments and Disease Progression in Fibrotic Hypersensitivity Pneumonitis

Cited by 26 publications

References 38 publications

From Macroscopy to Ultrastructure: An Integrative Approach to Pulmonary Pathology

From Macroscopy to Ultrastructure: An Integrative Approach to Pulmonary Pathology

Ex vivotissue perturbations coupled to single cell RNA-seq reveal multi-lineage cell circuit dynamics in human lung fibrogenesis

Identification of PIK3CG as a hub in septic myocardial injury using network pharmacology and weighted gene co‐expression network analysis

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