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)

• Macrophage polarization and pulmonary fibrosis

  Pulmonary fibrosis is a broad term for scarring that stiffens lung tissue and interferes with oxygen transfer. It can develop after repeated injury, autoimmune disease, environmental exposure or without a clear cause, as in idiopathic pulmonary fibrosis (IPF). Although the disease is often discussed through fibroblasts and collagen, immune cells help determine whether injury resolves or becomes permanent.

  Macrophages are abundant in healthy and damaged lungs. They remove debris, communicate with epithelial cells and regulate inflammation, repair and tissue remodelling. Their behaviour is flexible rather than fixed, which is why researchers increasingly describe macrophage states as a spectrum shaped by local signals.

  This biology has practical relevance in Australia, where respiratory teams manage IPF alongside dust-related disease, connective tissue disorders and the effects of bushfire smoke. A patient referred from regional New South Wales may face very different exposure histories and access issues from someone treated in a tertiary centre in Melbourne or Perth.

  How macrophages respond to lung injury

  After an insult, resident alveolar macrophages and monocyte-derived macrophages detect damaged cells, altered proteins and inflammatory mediators. Early responses can be protective: macrophages clear dead material, recruit other immune cells and help restore the alveolar barrier. If this phase is controlled, inflammation may settle without extensive scarring.

  The older M1/M2 model remains useful as a teaching shorthand, but it does not fully represent human disease. “M1” often describes inflammatory, antimicrobial activity, while “M2” refers to repair-associated functions. In fibrotic lungs, macrophages can express mixed or changing features, responding to transforming growth factor beta (TGF-β), interleukins, lipids, hypoxia and signals from damaged epithelium.

  When repair becomes fibrotic

  Persistent epithelial injury can keep macrophages activated long after the initial trigger has disappeared. They release TGF-β, platelet-derived growth factor, connective tissue growth factor and other mediators that stimulate fibroblast migration and myofibroblast differentiation. These myofibroblasts produce excess extracellular matrix, including collagen, gradually disrupting the normal architecture of the lung.

  Macrophages may also influence fibrosis by changing how matrix is broken down. Altered metalloproteinase activity, abnormal lipid handling and poor clearance of cellular debris can create a feedback loop: stiff tissue changes cell behaviour, and the changed cells promote still more stiffness. This helps explain why established pulmonary fibrosis can continue even when the original injury is difficult to identify.

  Evidence from tissue and experimental models

  Single-cell RNA sequencing has shown that fibrotic lungs contain several macrophage populations rather than one uniform group. Some express markers associated with recruited monocytes, while others occupy niches near scarred regions and show profibrotic signatures. The presence of receptors such as MerTK, osteopontin-related pathways and TREM2 in particular macrophage subsets is being studied for clues about disease progression.

  Animal models have clarified mechanisms but do not perfectly reproduce human IPF. Bleomycin-induced fibrosis, for example, is useful for examining inflammation and repair, yet it may resolve differently from chronic human disease. Results therefore need to be compared with bronchoalveolar lavage, surgical or cryobiopsy material, imaging and clinical outcomes before they can guide treatment.

  When reviewing research or congress material online, source checking is sensible because medical pages can appear beside unrelated external items, including this conference news item. For Australian clinicians, the key questions are whether a finding comes from human tissue, whether the macrophage state is stable over time and whether it correlates with lung function or survival.

  Therapeutic opportunities and limits

  Targeting macrophage polarisation could involve blocking profibrotic signals, altering macrophage recruitment, improving efferocytosis or changing cellular metabolism. Potential approaches include inhibition of TGF-β pathways, modulation of colony-stimulating factor signalling and therapies aimed at specific chemokine or lipid pathways. The goal is unlikely to be simply “switching off” macrophages, since these cells remain important for infection control and tissue maintenance.

  Current antifibrotic medicines, including nintedanib and pirfenidone, can slow functional decline in appropriate patients but do not remove established scar tissue. Their effects may partly reflect broader control of injury and remodelling rather than selective macrophage reprogramming. Any future immune-directed treatment will need to avoid increasing susceptibility to infection, a particularly important consideration for older people and those with coexisting bronchiectasis.

  Relevance to Australian respiratory care

  Australia’s geography makes early assessment and ongoing monitoring a practical concern. Patients in the Northern Territory, western Queensland or remote Western Australia may travel long distances for high-resolution CT, pulmonary function testing and multidisciplinary review. Telehealth can support follow-up, but it cannot replace local access to oxygen assessment, rehabilitation and culturally safe care.

  Environmental context also matters. Smoke from summer bushfires can worsen respiratory symptoms and increase particulate exposure, while occupational inhalation of silica, coal dust, metal dust or agricultural particles may contribute to chronic lung injury. A careful history should include work, home heating, mining or construction exposure and time spent outdoors during poor air-quality events.

  Health services should also recognise the distinct needs of Aboriginal and Torres Strait Islander communities, including the effects of remoteness, housing conditions and unequal access to specialist care. A macrophage-focused research agenda will be most useful when it connects molecular findings with earlier diagnosis, practical exposure reduction and treatment pathways that work across metropolitan and regional settings.

  A useful clinical framework is to view macrophages as active participants in a changing ecosystem rather than as a single disease switch. Their signals interact with epithelial cells, fibroblasts, endothelial cells, extracellular matrix and the patient’s broader immune state. This perspective may help identify biomarkers that distinguish active inflammation from relatively established scar.

  For now, clinicians should continue evidence-based antifibrotic care, pulmonary rehabilitation, vaccination, smoking cessation support and referral for transplant assessment when appropriate. Researchers can strengthen the field by pairing macrophage profiling with longitudinal clinical data, including forced vital capacity, imaging progression, exacerbations and patient-reported breathlessness.

  The next concrete step is to add a structured exposure and infection history to the assessment of every patient with suspected fibrotic interstitial lung disease, then discuss the case through a multidisciplinary respiratory meeting.

  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)