{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T13:22:44Z","timestamp":1787750564056,"version":"build-2784847793"},"reference-count":120,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004826","name":"Beijing Natural Science Foundation","doi-asserted-by":"publisher","award":["7264301"],"award-info":[{"award-number":["7264301"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Repair programs are pervasive in idiopathic pulmonary fibrosis (IPF), yet they fail to reach completion. While single-cell and spatial omics have identified cellular states associated with injury-repair programs, a central paradox remains: why do these programs persist without reconstituting functional lung architecture? This review integrates evidence from multiscale omics, spatial analyses, and translational studies to propose a lesion-centered \u201cnon-resolving repair\u201d framework that explains IPF progression. We argue that disease progression is driven by the persistence of cellular repair programs after the pathways required for maturation, state exit, and microenvironmental reset have become compromised. These compartment-specific failures converge within spatially organized lesion units, where aberrant cellular activity and matrix distortion reinforce one another, embedding failed repair within tissue architecture. This perspective shifts the focus from cataloging disease-associated cell states toward evaluating failed biological transitions and regional resolution capacity. Clinically, it reframes antifibrotic therapy around overcoming spatial barriers to repair and highlights the need for translational endpoints that distinguish marker suppression from structural stabilization and functional tissue reconstruction. Delineating which lesional niches retain resolution capacity will be essential for identifying where repair-oriented interventions may still re-engage organized tissue repair in IPF.<\/jats:p>","DOI":"10.3390\/ijms27177649","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T12:59:57Z","timestamp":1787749197000},"page":"7649","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Non-Resolving Repair in Idiopathic Pulmonary Fibrosis: From Failed Cellular Transitions to Architectural Lock-In"],"prefix":"10.3390","volume":"27","author":[{"given":"Chuang","family":"Ge","sequence":"first","affiliation":[{"name":"Center for Biological Science and Technology, Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Guangdong Zhuhai-Macao Joint Biotech Laboratory, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai 519087, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoyue","family":"Cui","sequence":"additional","affiliation":[{"name":"Center for Biological Science and Technology, Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Guangdong Zhuhai-Macao Joint Biotech Laboratory, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai 519087, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1016\/S0140-6736(17)30866-8","article-title":"Idiopathic pulmonary fibrosis","volume":"389","author":"Richeldi","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1056\/NEJMra1705751","article-title":"Idiopathic Pulmonary Fibrosis","volume":"378","author":"Lederer","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1038\/nm.2807","article-title":"Mechanisms of fibrosis: Therapeutic translation for fibrotic disease","volume":"18","author":"Wynn","year":"2012","journal-title":"Nat. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/s41586-020-2938-9","article-title":"Fibrosis: From mechanisms to medicines","volume":"587","author":"Henderson","year":"2020","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1146\/annurev-pathol-042320-030240","article-title":"Pathogenic Mechanisms Underlying Idiopathic Pulmonary Fibrosis","volume":"17","author":"Moss","year":"2022","journal-title":"Ann. Rev. Pathol. Mech. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1164\/rccm.201712-2410OC","article-title":"Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis","volume":"199","author":"Reyfman","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"eadl5473","DOI":"10.1126\/sciadv.adl5473","article-title":"Spatial transcriptomic characterization of pathologic niches in IPF","volume":"10","author":"Mayr","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"eaba1983","DOI":"10.1126\/sciadv.aba1983","article-title":"Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis","volume":"6","author":"Adams","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e90558","DOI":"10.1172\/jci.insight.90558","article-title":"Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis","volume":"1","author":"Xu","year":"2016","journal-title":"JCI Insight"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1038\/s41556-020-0542-8","article-title":"Persistence of a regeneration-associated, transitional alveolar epithelial cell state in pulmonary fibrosis","volume":"22","author":"Kobayashi","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3559","DOI":"10.1038\/s41467-020-17358-3","article-title":"Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis","volume":"11","author":"Strunz","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.stem.2020.06.020","article-title":"Inflammatory Signals Induce AT2 Cell-Derived Damage-Associated Transient Progenitors that Mediate Alveolar Regeneration","volume":"27","author":"Choi","year":"2020","journal-title":"Cell Stem Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1164\/rccm.201909-1726LE","article-title":"Ineffectual Type 2\u2013to\u2013Type 1 Alveolar Epithelial Cell Differentiation in Idiopathic Pulmonary Fibrosis: Persistence of the KRT8hi Transitional State","volume":"201","author":"Jiang","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"eaba1972","DOI":"10.1126\/sciadv.aba1972","article-title":"Single-cell RNA sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis","volume":"6","author":"Habermann","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e165612","DOI":"10.1172\/JCI165612","article-title":"Regulation of epithelial transitional states in murine and human pulmonary fibrosis","volume":"133","author":"Wang","year":"2023","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1038\/s41556-020-00591-9","article-title":"Gli1+ Mesenchymal Stromal Cells Form a Pathological Niche to Promote Airway Progenitor Metaplasia in the Fibrotic Lung","volume":"22","author":"Cassandras","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2102373","DOI":"10.1183\/13993003.02373-2021","article-title":"Single-cell RNA sequencing identifies G-protein coupled receptor 87 as a basal cell marker expressed in distal honeycomb cysts in idiopathic pulmonary fibrosis","volume":"59","author":"Heinzelmann","year":"2022","journal-title":"Eur. Respir. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5637","DOI":"10.1038\/s41467-022-33193-0","article-title":"Airway basal cells show a dedifferentiated KRT17highPhenotype and promote fibrosis in idiopathic pulmonary fibrosis","volume":"13","author":"Jaeger","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4148","DOI":"10.1038\/s41467-024-48632-3","article-title":"CEBPA restricts alveolar type 2 cell plasticity during development and injury-repair","volume":"15","author":"Hassan","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e175290","DOI":"10.1172\/jci.insight.175290","article-title":"Targeting CEBPA to restore cellular identity and tissue homeostasis in pulmonary fibrosis","volume":"9","author":"Tan","year":"2024","journal-title":"JCI Insight"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e173374","DOI":"10.1172\/jci.insight.173374","article-title":"Epithelial Yap\/Taz are required for functional alveolar regeneration following acute lung injury","volume":"8","author":"DiGiovanni","year":"2023","journal-title":"JCI Insight"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e198113","DOI":"10.1172\/jci.insight.198113","article-title":"Sustained Yap\/Taz activation promotes aberrant alveolar epithelial cell differentiation and drives persistent fibrotic remodeling","volume":"11","author":"Gaona","year":"2026","journal-title":"JCI Insight"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"L1119","DOI":"10.1152\/ajplung.00382.2007","article-title":"Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: Association with altered surfactant protein processing and herpesvirus infection","volume":"294","author":"Lawson","year":"2008","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e86704","DOI":"10.1172\/jci.insight.86704","article-title":"Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis","volume":"1","author":"Naikawadi","year":"2016","journal-title":"JCI Insight"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14532","DOI":"10.1038\/ncomms14532","article-title":"Cellular senescence mediates fibrotic pulmonary disease","volume":"8","author":"Schafer","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1038\/s41588-024-01819-2","article-title":"Mapping spatially resolved transcriptomes in human and mouse pulmonary fibrosis","volume":"56","author":"Ptasinski","year":"2024","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/s41588-025-02080-x","article-title":"Spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis","volume":"57","author":"Vannan","year":"2025","journal-title":"Nat. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8710","DOI":"10.1038\/s41467-025-63735-1","article-title":"Aberrant intermediate alveolar epithelial cells promote pathogenic activation of lung fibroblasts in preclinical fibrosis models","volume":"16","author":"Hoffman","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1038\/s41467-026-68354-y","article-title":"Transcriptomic signature-guided depletion of intermediate alveolar epithelial cells ameliorates pulmonary fibrosis in mice","volume":"17","author":"Peng","year":"2026","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3625","DOI":"10.1016\/j.celrep.2018.03.010","article-title":"Single-Cell Deconvolution of Fibroblast Heterogeneity in Mouse Pulmonary Fibrosis","volume":"22","author":"Xie","year":"2018","journal-title":"Cell Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1038\/s41467-020-15647-5","article-title":"Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis","volume":"11","author":"Tsukui","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1165\/rcmb.2022-0292OC","article-title":"Multiple Fibroblast Subtypes Contribute to Matrix Deposition in Pulmonary Fibrosis","volume":"69","author":"Liu","year":"2023","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/s41586-024-07660-1","article-title":"Alveolar fibroblast lineage orchestrates lung inflammation and fibrosis","volume":"631","author":"Tsukui","year":"2024","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e141618","DOI":"10.1172\/jci.insight.141618","article-title":"Loss of Fas signaling in fibroblasts impairs homeostatic fibrosis resolution and promotes persistent pulmonary fibrosis","volume":"6","author":"Redente","year":"2020","journal-title":"JCI Insight"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1165\/rcmb.2010-0284RC","article-title":"Cellular FLICE-like Inhibitory Protein Deviates Myofibroblast Fas-Induced Apoptosis Toward Proliferation during Lung Fibrosis","volume":"47","author":"Zisman","year":"2012","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1164\/rccm.201707-1497OC","article-title":"Protein Tyrosine Phosphatase-N13 Promotes Myofibroblast Resistance to Apoptosis in Idiopathic Pulmonary Fibrosis","volume":"198","author":"Bamberg","year":"2018","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/labinvest.2016.145","article-title":"Thy-1 interaction with Fas in lipid rafts regulates fibroblast apoptosis and lung injury resolution","volume":"97","author":"Liu","year":"2017","journal-title":"Lab. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e163762","DOI":"10.1172\/jci.insight.163762","article-title":"Inhibition of antiapoptotic BCL-2 proteins with ABT-263 induces fibroblast apoptosis, reversing persistent pulmonary fibrosis","volume":"8","author":"Cooley","year":"2023","journal-title":"JCI Insight"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3317","DOI":"10.1038\/s41467-026-69865-4","article-title":"Conditional BCL-2 Expression in Fibroblasts Promotes Persistent Pulmonary Fibrosis which is Reversible by Therapeutic BCL-2 Inhibition","volume":"17","author":"Redente","year":"2026","journal-title":"Nat. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.stem.2016.10.004","article-title":"Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis","volume":"20","author":"Moiseenko","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2987","DOI":"10.1038\/s41467-019-10839-0","article-title":"Metformin induces lipogenic differentiation in myofibroblasts to reverse lung fibrosis","volume":"10","author":"Kheirollahi","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2300482","DOI":"10.1183\/13993003.00482-2023","article-title":"Evidence for a lipofibroblast-to-Cthrc1+ myofibroblast reversible switch during the development and resolution of lung fibrosis in young mice","volume":"65","author":"Lingampally","year":"2025","journal-title":"Eur. Respir. J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"L344","DOI":"10.1152\/ajplung.00300.2014","article-title":"Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis","volume":"308","author":"Liu","year":"2015","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2200474","DOI":"10.1183\/13993003.00474-2022","article-title":"Single-nucleus chromatin accessibility identifies a critical role for TWIST1 in idiopathic pulmonary fibrosis myofibroblast activity","volume":"62","author":"Valenzi","year":"2023","journal-title":"Eur. Respir. J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1093\/ajrcmb\/aanag022","article-title":"RUNX1 is a mediator of fibrotic activation and epigenetic memory in lung fibroblasts","volume":"74","author":"Gilbert","year":"2026","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1016\/j.ard.2025.12.003","article-title":"Altered AP-1, RUNX, and EGR chromatin dynamics drive human fibrotic lung disease","volume":"85","author":"Valenzi","year":"2026","journal-title":"Ann. Rheum. Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2500022","DOI":"10.1183\/13993003.00022-2025","article-title":"Integrated spatial and single-cell transcriptomics reveal PAK kinase as a therapeutic target in fibroblastic foci and dense fibrosis of idiopathic pulmonary fibrosis","volume":"66","author":"Watanabe","year":"2025","journal-title":"Eur. Respir. J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2501549","DOI":"10.1183\/13993003.01549-2025","article-title":"From fibroblast foci to dense scars: PAK2-activated fibroblasts drive fibrosis progression in idiopathic pulmonary fibrosis","volume":"66","author":"Zhang","year":"2025","journal-title":"Eur. Respir. J."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"The Idiopathic Pulmonary Fibrosis Clinical Research Network, Raghu, G., Anstrom, K.J., King, T.E., Lasky, J.A., and Martinez, F.J. (2012). Prednisone, Azathioprine, and N-Acetylcysteine for Pulmonary Fibrosis. N. Engl. J. Med., 366, 1968\u20131977.","DOI":"10.1056\/NEJMoa1113354"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/nri.2015.4","article-title":"Specialized pro-resolving mediators: Endogenous regulators of infection and inflammation","volume":"16","author":"Basil","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1802441","DOI":"10.1183\/13993003.02441-2018","article-title":"Proliferating SPP1\/MERTK-expressing macrophages in idiopathic pulmonary fibrosis","volume":"54","author":"Morse","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.1016\/j.rmed.2012.08.020","article-title":"Defective efferocytosis by alveolar macrophages in IPF patients","volume":"106","author":"Morimoto","year":"2012","journal-title":"Respir. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1038\/s41419-018-1074-z","article-title":"Efferocytosis of apoptotic alveolar epithelial cells is sufficient to initiate lung fibrosis","volume":"9","author":"Kim","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e134539","DOI":"10.1172\/jci.insight.134539","article-title":"Monocyte-derived alveolar macrophage apolipoprotein E participates in pulmonary fibrosis resolution","volume":"5","author":"Cui","year":"2020","journal-title":"JCI Insight"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.1084\/jem.20162152","article-title":"Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span","volume":"214","author":"Misharin","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1900646","DOI":"10.1183\/13993003.00646-2019","article-title":"A spatially restricted fibrotic niche in pulmonary fibrosis is sustained by M-CSF\/M-CSFR signalling in monocyte-derived alveolar macrophages","volume":"55","author":"Joshi","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1038\/s41590-024-01975-x","article-title":"Profibrotic monocyte-derived alveolar macrophages are expanded in patients with persistent respiratory symptoms and radiographic abnormalities after COVID-19","volume":"25","author":"Bailey","year":"2024","journal-title":"Nat. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e182700","DOI":"10.1172\/jci.insight.182700","article-title":"Gpnmb and Spp1 mark a conserved macrophage injury response masking fibrosis-specific programming in the lung","volume":"9","author":"King","year":"2024","journal-title":"JCI Insight"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e12628","DOI":"10.14814\/phy2.12628","article-title":"17(R)-resolvin D1 ameliorates bleomycin-induced pulmonary fibrosis in mice","volume":"3","author":"Yatomi","year":"2015","journal-title":"Physiol. Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"15354","DOI":"10.1021\/acsnano.2c10388","article-title":"Pulmonary Delivery of Specialized Pro-Resolving Mediators-Based Nanotherapeutics Attenuates Pulmonary Fibrosis in Preclinical Animal Models","volume":"17","author":"Li","year":"2023","journal-title":"ACS Nano"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/s41586-020-2822-7","article-title":"Capillary cell-type specialization in the alveolus","volume":"586","author":"Gillich","year":"2020","journal-title":"Nature"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/s41586-020-2922-4","article-title":"A molecular cell atlas of the human lung from single-cell RNA sequencing","volume":"587","author":"Travaglini","year":"2020","journal-title":"Nature"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1161\/CIRCULATIONAHA.120.052318","article-title":"Integrated Single-Cell Atlas of Endothelial Cells of the Human Lung","volume":"144","author":"Schupp","year":"2021","journal-title":"Circulation"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e70102","DOI":"10.1002\/pul2.70102","article-title":"Ectopic Expansion of Pulmonary Vasculature in Fibrotic Lung Disease and Lung Adenocarcinoma Marked by Proangiogenic COL15A1+ Endothelial Cells","volume":"15","author":"Engelbrecht","year":"2025","journal-title":"Pulm. Circ."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1164\/rccm.202303-0544LE","article-title":"Alveolar Vascular Remodeling in Nonspecific Interstitial Pneumonia: Replacement of Normal Lung Capillaries with COL15A1-Positive Endothelial Cells","volume":"208","author":"Schupp","year":"2023","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"5449","DOI":"10.1038\/s41467-024-49545-x","article-title":"Lung injury-induced activated endothelial cell states persist in aging-associated progressive fibrosis","volume":"15","author":"Raslan","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1165\/rcmb.2024-0046OC","article-title":"Lung Fibrosis Is Linked to Increased Endothelial Cell Activation and Dysfunctional Vascular Barrier Integrity","volume":"71","author":"Jandl","year":"2024","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.cell.2011.10.003","article-title":"Endothelial-Derived Angiocrine Signals Induce and Sustain Regenerative Lung Alveolarization","volume":"147","author":"Ding","year":"2011","journal-title":"Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"107828","DOI":"10.1016\/j.celrep.2020.107828","article-title":"Angiocrine Sphingosine-1-Phosphate Activation of S1PR2-YAP Signaling Axis in Alveolar Type II Cells Is Essential for Lung Repair","volume":"31","author":"Chen","year":"2020","journal-title":"Cell Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/nm.4035","article-title":"Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis","volume":"22","author":"Cao","year":"2016","journal-title":"Nat. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"7234","DOI":"10.1038\/s41467-025-62431-4","article-title":"Aging affects reprogramming of pulmonary capillary endothelial cells after lung injury in male mice","volume":"16","author":"Truchi","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"4170","DOI":"10.1038\/s41467-022-31890-4","article-title":"Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis","volume":"13","author":"Caporarello","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e13196","DOI":"10.1111\/acel.13196","article-title":"Vascular dysfunction in aged mice contributes to persistent lung fibrosis","volume":"19","author":"Caporarello","year":"2020","journal-title":"Aging Cell"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e80900","DOI":"10.7554\/eLife.80900","article-title":"Single-cell transcriptomic atlas of lung microvascular regeneration after targeted endothelial cell ablation","volume":"12","author":"Godoy","year":"2023","journal-title":"eLife"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e125185","DOI":"10.1172\/jci.insight.125185","article-title":"Registration of the extracellular matrix components constituting the fibroblastic focus in idiopathic pulmonary fibrosis","volume":"4","author":"Herrera","year":"2019","journal-title":"JCI Insight"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1164\/rccm.200602-205OC","article-title":"Fibroblast Foci Are Not Discrete Sites of Lung Injury or Repair: The Fibroblast Reticulum","volume":"174","author":"Cool","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e86375","DOI":"10.1172\/jci.insight.86375","article-title":"Three-dimensional characterization of fibroblast foci in idiopathic pulmonary fibrosis","volume":"1","author":"Jones","year":"2016","journal-title":"JCI Insight"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e156115","DOI":"10.1172\/jci.insight.156115","article-title":"The UIP\/IPF fibroblastic focus is a collagen biosynthesis factory embedded in a distinct extracellular matrix","volume":"7","author":"Herrera","year":"2022","journal-title":"JCI Insight"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/labinvest.2016.135","article-title":"Fibroblastic foci, covered with alveolar epithelia exhibiting epithelial\u2013mesenchymal transition, destroy alveolar septa by disrupting blood flow in idiopathic pulmonary fibrosis","volume":"97","author":"Yamaguchi","year":"2017","journal-title":"Lab. Investig."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Calabrese, F., Lunardi, F., Tauro, V., Pezzuto, F., Fortarezza, F., Vedovelli, L., Faccioli, E., Balestro, E., Schiavon, M., and Esposito, G. (2022). RNA Sequencing of Epithelial Cell\/Fibroblastic Foci Sandwich in Idiopathic Pulmonary Fibrosis: New Insights on the Signaling Pathway. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23063323"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1172\/JCI71386","article-title":"Fibrotic extracellular matrix activates a profibrotic positive feedback loop","volume":"124","author":"Parker","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"6039","DOI":"10.1038\/s41467-023-41621-y","article-title":"Lung extracellular matrix modulates KRT5+ basal cell activity in pulmonary fibrosis","volume":"14","author":"Hewitt","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Seibold, M.A., Smith, R.W., Urbanek, C., Groshong, S.D., Cosgrove, G.P., Brown, K.K., Schwarz, M.I., Schwartz, D.A., and Reynolds, S.D. (2013). The Idiopathic Pulmonary Fibrosis Honeycomb Cyst Contains A Mucocilary Pseudostratified Epithelium. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0058658"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"231ra47","DOI":"10.1126\/scitranslmed.3008182","article-title":"Reversal of Persistent Fibrosis in Aging by Targeting Nox4-Nrf2 Redox Imbalance","volume":"6","author":"Hecker","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1165\/rcmb.2019-0092OC","article-title":"Impaired Myofibroblast Dedifferentiation Contributes to Nonresolving Fibrosis in Aging","volume":"62","author":"Kato","year":"2020","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"eadk5041","DOI":"10.1126\/sciimmunol.adk5041","article-title":"An aging bone marrow exacerbates lung fibrosis by fueling profibrotic macrophage persistence","volume":"10","author":"Farhat","year":"2025","journal-title":"Sci. Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/labinvest.2017.110","article-title":"Molecular similarities and differences from human pulmonary fibrosis and corresponding mouse model: MALDI imaging mass spectrometry in comparative medicine","volume":"98","author":"Aichler","year":"2018","journal-title":"Lab. Investig."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s12014-019-9226-4","article-title":"Quantitative proteomic characterization of lung tissue in idiopathic pulmonary fibrosis","volume":"16","author":"Tian","year":"2019","journal-title":"Clin. Proteom."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2759","DOI":"10.1038\/s41467-023-38437-1","article-title":"Spatial metabolomics reveals glycogen as an actionable target for pulmonary fibrosis","volume":"14","author":"Conroy","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Walsh, S.L.F., Wells, A.U., Sverzellati, N., Devaraj, A., von der Th\u00fcsen, J., Yousem, S.A., Colby, T.V., Nicholson, A.G., and Hansell, D.M. (2015). Relationship between fibroblastic foci profusion and high resolution CT morphology in fibrotic lung disease. BMC Med., 13.","DOI":"10.1186\/s12916-015-0479-0"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1183\/09031936.00141010","article-title":"Parenchymal trafficking of pleural mesothelial cells in idiopathic pulmonary fibrosis","volume":"39","author":"Mubarak","year":"2012","journal-title":"Eur. Respir. J."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/j.ajpath.2012.12.030","article-title":"Pleural Mesothelial Cell Differentiation and Invasion in Fibrogenic Lung Injury","volume":"182","author":"Zolak","year":"2013","journal-title":"Am. J. Pathol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"118806","DOI":"10.1016\/j.bbamcr.2020.118806","article-title":"Crosstalk between pleural mesothelial cell and lung fibroblast contributes to pulmonary fibrosis","volume":"1867","author":"Liu","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1801384","DOI":"10.1183\/13993003.01384-2018","article-title":"Quantitative high-resolution computed tomography fibrosis score: Performance characteristics in idiopathic pulmonary fibrosis","volume":"52","author":"Humphries","year":"2018","journal-title":"Eur. Respir. J."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1007\/s00330-019-06402-6","article-title":"Prediction of idiopathic pulmonary fibrosis progression using early quantitative changes on CT imaging for a short term of clinical 18\u201324-month follow-ups","volume":"30","author":"Kim","year":"2020","journal-title":"Eur. Radiol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1186\/s12931-018-0918-5","article-title":"Quantitative CT analysis using functional imaging is superior in describing disease progression in idiopathic pulmonary fibrosis compared to forced vital capacity","volume":"19","author":"Clukers","year":"2018","journal-title":"Respir. Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1164\/rccm.202311-2185OC","article-title":"Deep Learning\u2013based Segmentation of Computed Tomography Scans Predicts Disease Progression and Mortality in Idiopathic Pulmonary Fibrosis","volume":"210","author":"Thillai","year":"2024","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1513\/AnnalsATS.202301-084OC","article-title":"Deep Learning\u2013Based Fibrosis Extent on Computed Tomography Predicts Outcome of Fibrosing Interstitial Lung Disease Independent of Visually Assessed Computed Tomography Pattern","volume":"21","author":"Oh","year":"2024","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1056\/NEJMoa1402582","article-title":"A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis","volume":"370","author":"King","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1056\/NEJMoa1402584","article-title":"Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis","volume":"370","author":"Richeldi","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1056\/NEJMoa2414108","article-title":"Nerandomilast in Patients with Idiopathic Pulmonary Fibrosis","volume":"392","author":"Richeldi","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1165\/rcmb.2019-0328TR","article-title":"Pirfenidone: Molecular Mechanisms and Potential Clinical Applications in Lung Disease","volume":"62","author":"Ruwanpura","year":"2020","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1183\/09031936.00174914","article-title":"Mode of Action of Nintedanib in the Treatment of Idiopathic Pulmonary Fibrosis","volume":"45","author":"Wollin","year":"2015","journal-title":"Eur. Respir. J."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1165\/rcmb.2016-0217OC","article-title":"A Novel Antifibrotic Mechanism of Nintedanib and Pirfenidone. Inhibition of Collagen Fibril Assembly","volume":"57","author":"Ishikawa","year":"2017","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1165\/rcmb.2024-0614OC","article-title":"Insights into the Cellular and Molecular Mechanisms behind the Antifibrotic Effects of Nerandomilast","volume":"73","author":"Reininger","year":"2025","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"8672","DOI":"10.1038\/s41467-024-52827-z","article-title":"TR\u03b2 activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA","volume":"15","author":"Pan","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"3974","DOI":"10.1016\/j.ymthe.2024.09.008","article-title":"CasRx-based Wnt activation promotes alveolar regeneration while ameliorating pulmonary fibrosis in a mouse model of lung injury","volume":"32","author":"Shen","year":"2024","journal-title":"Mol. Ther."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"eabg6005","DOI":"10.1126\/sciadv.abg6005","article-title":"Mesenchymal Growth Hormone Receptor Deficiency Leads to Failure of Alveolar Progenitor Cell Function and Severe Pulmonary Fibrosis","volume":"7","author":"Xie","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1038\/s41467-020-14344-7","article-title":"Inhalation of Lung Spheroid Cell Secretome and Exosomes Promotes Lung Repair in Pulmonary Fibrosis","volume":"11","author":"Dinh","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/S2213-2600(16)30421-0","article-title":"Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: A randomised, double-blind, controlled, phase 2 trial","volume":"5","author":"Raghu","year":"2017","journal-title":"Lancet Respir. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1164\/rccm.202403-0636OC","article-title":"Bexotegrast in Patients with Idiopathic Pulmonary Fibrosis: The INTEGRIS-IPF Clinical Trial","volume":"210","author":"Lancaster","year":"2024","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1001\/jama.2024.8693","article-title":"Pamrevlumab for Idiopathic Pulmonary Fibrosis: The ZEPHYRUS-1 Randomized Clinical Trial","volume":"332","author":"Raghu","year":"2024","journal-title":"JAMA"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1001\/jama.2023.5355","article-title":"Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis: The ISABELA 1 and 2 Randomized Clinical Trials","volume":"329","author":"Maher","year":"2023","journal-title":"JAMA"},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Piciucchi, S., Tomassetti, S., Ravaglia, C., Gurioli, C., Gurioli, C., Dubini, A., Carloni, A., Chilosi, M., Colby, T.V., and Poletti, V. (2016). From \u201ctraction bronchiectasis\u201d to honeycombing in idiopathic pulmonary fibrosis: A spectrum of bronchiolar remodeling also in radiology?. BMC Pulm. Med., 16.","DOI":"10.1186\/s12890-016-0245-x"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1097\/MCP.0000000000001099","article-title":"The future of clinical trials in idiopathic pulmonary fibrosis","volume":"30","author":"Spagnolo","year":"2024","journal-title":"Curr. Opin. Pulm. Med."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1164\/rccm.202312-2213SO","article-title":"Meaningful Endpoints for Idiopathic Pulmonary Fibrosis (IPF) Clinical Trials: Emphasis on \u2018Feels, Functions, Survives\u2019. Report of a Collaborative Discussion in a Symposium with Direct Engagement from Representatives of Patients, Investigators, the National Institutes of Health, a Patient Advocacy Organization, and a Regulatory Agency","volume":"209","author":"Raghu","year":"2024","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"17534666211004238","DOI":"10.1177\/17534666211004238","article-title":"The value of imaging and clinical outcomes in a phase II clinical trial of a lysophosphatidic acid receptor antagonist in idiopathic pulmonary fibrosis","volume":"15","author":"Kim","year":"2021","journal-title":"Ther. Adv. Respir. Dis."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"e094559","DOI":"10.1136\/bmjopen-2024-094559","article-title":"Minimum clinically important difference in Quantitative Lung Fibrosis score associated with all-cause mortality in idiopathic pulmonary fibrosis: Subanalysis from two phase II trials of pamrevlumab","volume":"15","author":"Kim","year":"2025","journal-title":"BMJ Open"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1900283","DOI":"10.1183\/13993003.00283-2019","article-title":"Molecular endpoints for establishing target engagement by novel idiopathic pulmonary fibrosis therapies","volume":"53","author":"Wolters","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1164\/rccm.202303-0372LE","article-title":"Spatial Decoding of Immune Cell Contribution to Fibroblastic Foci in Idiopathic Pulmonary Fibrosis","volume":"208","author":"Yang","year":"2023","journal-title":"Am. J. 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