Speaker's Highlight

• Don Sin University of British Columbia, St. Paul Hospital (Canada)
  Kenneth R. Chapman Toronto General Hospital Research Institute (Canada)
• Parameswaran Nair McMaster University (Canada)
  Carolyn Calfee UCSF (U.S.A.)
• Gregory P. Downey University of Colorado School of Medicine (U.S.A.)
  David A. Schwartz University of Colorado School of Medicine (U.S.A.)
• Neil Schluger Tuberculosis Control Branch, California Department of Public Health (U.S.A.)
  Nick Kim Critical Care & Sleep Medicine, University of California San Diego (U.S.A.)
• Nicola Hananiah Baylor College of Medicine (U.S.A.)
  Jae-Joon Yim Seoul National University College of Medicine (Republic of Korea)
• Koichiro Asano Tokai University School of Medicine (Japan)
  Diahn-Warng Perng Taipei Veterans General Hospital (Taiwan)
• Konstantinos Kostikas University of Ioannina (Greece)
  Karin Klooster University Medical Center Groningen (Kingdom of the Netherlands)

• Targeting Epithelial–Mesenchymal Transition in Pulmonary Fibrosis

  Pulmonary fibrosis is a progressive scarring disorder in which repeated epithelial injury, abnormal repair and persistent inflammation can gradually replace healthy lung tissue with stiff, poorly functioning matrix. Idiopathic pulmonary fibrosis (IPF) is the best-known form, although connective-tissue disease, occupational exposure, hypersensitivity pneumonitis and other interstitial lung diseases may also develop a progressive fibrotic phenotype.

  Epithelial–mesenchymal transition (EMT) has become an important framework for understanding this process. During EMT, injured epithelial cells lose some features that maintain the air–airway barrier and acquire mesenchymal characteristics associated with migration, contractility and extracellular matrix production. In pulmonary fibrosis, the biology is rarely a complete conversion from one cell type to another. Partial EMT, epithelial plasticity and signalling between epithelial cells, fibroblasts and immune cells are more accurate descriptions.

  The therapeutic goal is therefore broader than simply blocking a single transition. Researchers are investigating ways to preserve alveolar epithelial integrity, interrupt profibrotic communication and prevent fibroblast activation before scar tissue becomes irreversible. These strategies may complement established antifibrotic treatment rather than replace it.

  For respiratory clinicians in Australia, this field is particularly relevant as diagnosis often involves multidisciplinary review across major centres such as Sydney, Melbourne, Brisbane and Perth. Patients may also live far from specialist interstitial lung disease services, making reliable biomarkers, telehealth and practical treatment pathways important parts of care.

  Why Epithelial Injury Matters

  The alveolar epithelium is exposed to inhaled particles, infection, cigarette smoke and environmental pollutants throughout life. When type 2 alveolar epithelial cells are repeatedly injured, they may fail to regenerate the delicate gas-exchange surface. Instead, they can release transforming growth factor beta (TGF-β), connective tissue growth factor and other mediators that alter nearby fibroblasts and recruit immune cells.

  TGF-β is a central driver of fibrogenesis. It can reduce epithelial markers such as E-cadherin while increasing proteins associated with a mesenchymal state, including vimentin and α-smooth muscle actin. Wnt/β-catenin, Notch, Hedgehog, platelet-derived growth factor and integrin pathways also influence epithelial plasticity, myofibroblast differentiation and matrix deposition.

  Current research places these signals within a wider cellular ecosystem. Senescent epithelial cells, macrophages, endothelial cells and fibroblast subpopulations communicate through cytokines, growth factors, extracellular vesicles and mechanical forces. This explains why a treatment aimed at a single molecule may have limited results once established fibrosis has become self-sustaining.

  Distinguishing Plasticity From Cell Conversion

  A major scientific question is whether epithelial cells become genuine collagen-producing fibroblasts in human pulmonary fibrosis. Animal studies have produced evidence for epithelial cells expressing mesenchymal markers, but lineage-tracing research has shown that complete epithelial-to-fibroblast conversion may be less common than initially proposed.

  The more clinically useful concept may be partial EMT. An epithelial cell can lose barrier function and gain migratory or inflammatory behaviour without becoming a fully differentiated myofibroblast. Even this incomplete transition can worsen alveolar damage by increasing permeability, reducing repair capacity and amplifying profibrotic signalling.

  This distinction matters for drug development. A therapy that restores epithelial differentiation, strengthens cell junctions or limits abnormal crosstalk may be valuable even if it does not eliminate every mesenchymal marker. It also encourages investigators to measure lung function, imaging and patient outcomes alongside molecular changes.

  Potential Therapeutic Targets

  TGF-β inhibition remains an attractive strategy, although systemic blockade carries risks because the pathway also regulates immune responses, wound healing and normal tissue maintenance. More selective approaches are examining integrins that activate latent TGF-β, downstream kinases, focal adhesion signalling and mechanotransduction pathways linked to a stiffening extracellular matrix.

  Other candidates include Wnt pathway modulators, tyrosine kinase inhibitors, lysyl oxidase-like proteins that cross-link collagen, and agents targeting cellular senescence. Therapies that protect mitochondrial function, reduce oxidative stress or improve autophagy may also help epithelial cells tolerate injury and recover their normal phenotype.

  Nintedanib and pirfenidone remain important antifibrotic medicines for appropriate patients with IPF, and nintedanib is also used in selected progressive fibrosing interstitial lung diseases. These medicines slow decline rather than reverse established scar. In Australia, access, prescribing criteria and reimbursement through the Pharmaceutical Benefits Scheme can influence how quickly treatment begins, so molecularly targeted therapies will need evidence of meaningful clinical benefit as well as promising laboratory results.

  Biomarkers And Personalised Care

  EMT-related biomarkers could help identify patients whose disease is biologically active before a major fall in forced vital capacity. Candidate measures include circulating epithelial and mesenchymal proteins, extracellular microRNAs, collagen fragments, blood gene-expression signatures and cell-free DNA. Bronchoalveolar lavage and single-cell sequencing may provide deeper information, but their cost and invasiveness limit routine use.

  High-resolution computed tomography remains central to assessing fibrotic pattern and progression, while pulmonary function testing, exercise tolerance and oxygen requirements show how disease affects the individual. Combining these clinical measures with molecular profiles may distinguish active remodelling from relatively stable residual scarring.

  Australia’s geography makes practical biomarker development especially valuable. A person in regional New South Wales or the Northern Territory may face long travel for serial specialist reviews. Remote monitoring, local spirometry and coordinated respiratory nursing could reduce that burden, provided results are integrated safely with specialist interpretation and Aboriginal and Torres Strait Islander health services.

  Translating Laboratory Findings Into Practice

  Successful translation will require treatments to be tested across the diverse causes of progressive pulmonary fibrosis, not only classic IPF. Trials should account for age, comorbid emphysema, autoimmune disease, occupational exposure and differences in disease trajectory. Combination treatment may be necessary because epithelial injury, inflammation, fibroblast activation and matrix stiffening reinforce each other.

  Environmental prevention also remains important. Australia’s bushfire seasons can produce prolonged exposure to fine particulate matter, which may aggravate respiratory disease and complicate recovery after lung injury. Smoking cessation, appropriate workplace controls and advice about smoke exposure support medical treatment, even though they cannot replace disease-modifying therapy.

  Future care is likely to combine early identification, antifibrotic medication, pulmonary rehabilitation, oxygen assessment and carefully selected molecular therapies. Research partnerships involving Australian universities, public hospitals and patient organisations such as Lung Foundation Australia can help ensure that trial outcomes reflect the needs of people living in both metropolitan and remote communities.

  Pulmonary fibrosis is best understood as a failure of coordinated repair rather than a single switch that turns epithelial cells into fibroblasts. EMT-related pathways remain promising because they connect epithelial vulnerability with fibroblast activation and scar formation. The most durable advances will come from protecting the alveolar barrier, interrupting harmful cell-to-cell signals and matching treatment to the biology of each patient. What readers should remember is that controlling epithelial plasticity may help slow the cycle of injury and scarring, but meaningful progress depends on combining molecular insight with early diagnosis and accessible, whole-person respiratory care.

  Richard Russell Nuffield Department of Clinical Medicine, University of Oxford (United Kingdom)
• Mona Bafadhel King’s College London (United Kingdom)
  David Jackson Guy’s and St Thomas’ Hospital, King’s College London (United Kingdom)
• James Chalmers University of Dundee (United Kingdom)
  David Price University of Aberdeen (United Kingdom)