Abstract
Fibrosis is a complex disorder characterized by the excessive deposition of extracellular matrix, which disrupts normal tissue architecture and compromises organ function. Fibrosis can affect any organ, with pulmonary fibrosis being one of the most common and life-threatening forms. Despite marked research efforts, effective antifibrotic therapies remain limited, largely due to an incomplete understanding of the underlying disease mechanisms. At the centre of fibrotic processes are fibroblasts, which are tissue-resident mesenchymal cells responsible for extracellular matrix production, tissue remodelling, wound healing and fibrosis. For decades, the biology of fibroblasts remained poorly understood, but advances in single-cell sequencing have recently provided deeper insights into their heterogeneity, plasticity and functional diversity. These insights have prompted renewed efforts to identify the core regulatory programmes that govern fibroblast states in health and disease. In this Review, we examine how immunological, mechanical and metabolic regulators influence fibroblast function in fibrosing interstitial lung diseases. We show how loss of stromal regulation through chronic inflammation, immune dysfunction, altered tissue biomechanics and metabolic stress can tip the balance from successful tissue repair to progressive fibrosis.
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Acknowledgements
The authors gratefully acknowledge J. Hudson, M. Z. Chaudhry and C. Armitage for insightful discussions and valuable contributions to the conceptual development of this Review.
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Glossary
- Airway basal epithelial cell
-
A multipotent progenitor cell found in the basal layer of the airway epithelium that serves as a source of regeneration after lung injury.
- Alveolar differentiation intermediate cells
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(ADI). After mouse lung injury, type 2 alveolar epithelial (AT2) cells adopt a Krt8+ intermediate transitional state, which has been variably termed damage-associated transient progenitors, pre-alveolar type 1 transient state or ADI cells. This state emerges in response to damage signals and is characterized by loss of AT2 cell marker identity, upregulation of p53 signalling, cell cycle arrest and a shift towards squamous morphology.
- Dysplastic repair
-
After severe lung injury, airway basal epithelial cells expressing keratin 5 (Krt5) migrate to alveoli, where they form abnormal cystic structures that cannot participate in gas exchange.
- Euplastic regeneration
-
In response to mild-to-moderate lung injury, AT2 cells re-enter the cell cycle and differentiate into AT1 cells, repopulating the alveolus and restoring normal barrier morphology, integrity and function.
- Fibroblastic foci
-
Discrete aggregates of proliferating fibroblasts and myofibroblasts located beneath the alveolar epithelium, representing sites of active extracellular matrix deposition at the leading edge of active fibrosis.
- Fibroblast-to-myofibroblast transition
-
The process by which fibroblasts acquire specialized repair states characterized by upregulation of contractile features, enhanced extracellular matrix production and increased migratory properties.
- Group 2 innate lymphoid cells
-
(ILC2s). A class of tissue-resident sentinel cell at barrier sites such as the lungs, gut and skin. ILC2s bridge innate and adaptive type 2 immunity by orchestrating allergic inflammation, protective antiparasitic responses and tissue repair. They are major sources of type 2 cytokines such as IL-5, IL-13 and amphiregulin, which they secrete in response to the alarmins IL-33, IL-25 and thymic stromal lymphopoietin.
- Interstitial lung disease
-
(ILD). An umbrella term for a heterogeneous group of disorders resulting in inflammation and/or fibrosis of the alveolar interstitium. ILDs have a broad spectrum of outcomes, from fully reversible inflammation to severe and irreversible scarring.
- Progressive fibrosing phenotype
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A phenotype of ILD that displays progressive clinical behaviour defined by irreversible and progressive scarring, despite treatment of known or identifiable triggers.
- Senescence-associated secretory phenotype
-
(SASP). A secretory programme comprising the release of cytokines, growth factors and proteases by senescent cells. The SASP secretome has diverse effects on neighbouring cells and tissue microenvironments, including inflammation, fibrosis and tumour promotion or suppression.
- Tertiary lymphoid structures
-
(TLSs). Organized aggregates of immune cells that form in non-lymphoid tissues in pathological conditions such as chronic inflammation, infection or cancer. Mature TLSs drive antigen-specific adaptive immune responses and modulate local immunity. They differ from secondary lymphoid organs in that they are inducible, ectopic and non-encapsulated immune follicles lack an external capsule enabling direct sampling of antigens and danger signals.
- Trained immunity
-
A form of immune memory in which innate immune cells develop enhanced responses to later infections or stimuli after an initial exposure. This memory is encoded through epigenetic changes, such as histone modifications and DNA methylation, that alter chromatin accessibility and transcription factor binding.
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Bell, P.T., Belz, G.T. Fibroblasts as regulators of lung immunity, repair and fibrosis. Nat Rev Immunol (2026). https://doi.org/10.1038/s41577-026-01268-4
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DOI: https://doi.org/10.1038/s41577-026-01268-4
