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© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Idiopathic pulmonary fibrosis (IPF) is the most common and lethal form of the interstitial pneumonias. The cause of the disease is unknown, and new therapies that stop or reverse disease progression are desperately needed. Recent advances in next-generation sequencing have led to an abundance of freely available, clinically relevant, organ-and-disease-specific, single-cell transcriptomic data, including studies from patients with IPF. We mined data from published IPF data sets and identified gene signatures delineating pro-fibrotic or antifibrotic macrophages and then used the Enrichr platform to identify compounds with the potential to drive the macrophages toward the antifibrotic transcriptotype. We then began testing these compounds in a novel in vitro phenotypic drug screening assay utilising human lung macrophages recovered from whole-lung lavage of patients with silicosis. As predicted by the Enrichr tool, glitazones potently modulated macrophage gene expression towards the antifibrotic phenotype. Next, we assayed a subset of the NatureBank pure compound library and identified the cyclobutane lignan, endiandrin A, which was isolated from the roots of the endemic Australian rainforest plant, Endiandra anthropophagorum, with a similar antifibrotic potential to the glitazones. These methods open new avenues of exploration to find treatments for lung fibrosis.

Details

Title
A Methodological Approach to Identify Natural Compounds with Antifibrotic Activity and the Potential to Treat Pulmonary Fibrosis Using Single-Cell Sequencing and Primary Human Lung Macrophages
Author
Apte, Simon H 1   VIAFID ORCID Logo  ; Groves, Penny L 2 ; Tan, Maxine E 1 ; Lutzky, Viviana P 1 ; Tharushi de Silva 1   VIAFID ORCID Logo  ; Monteith, Joshua N 3 ; Yerkovich, Stephanie T 3 ; Brendan J O’Sullivan 1 ; Davis, Rohan A 4   VIAFID ORCID Logo  ; Chambers, Daniel C 1 

 Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, QLD 4032, Australia; [email protected] (P.L.G.); [email protected] (M.E.T.); [email protected] (V.P.L.); [email protected] (T.d.S.); [email protected] (B.J.O.); Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072, Australia; [email protected] (J.N.M.); [email protected] (S.T.Y.) 
 Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, QLD 4032, Australia; [email protected] (P.L.G.); [email protected] (M.E.T.); [email protected] (V.P.L.); [email protected] (T.d.S.); [email protected] (B.J.O.) 
 Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072, Australia; [email protected] (J.N.M.); [email protected] (S.T.Y.) 
 School of Environment and Science, Griffith University, Brisbane, QLD 4111, Australia; [email protected]; NatureBank, Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia 
First page
15104
Publication year
2023
Publication date
2023
Publisher
MDPI AG
ISSN
16616596
e-ISSN
14220067
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2882595440
Copyright
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.