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 group of lung disorders in which repeated injury leads to abnormal repair, scar formation and progressive loss of gas-exchange capacity. Idiopathic pulmonary fibrosis (IPF) is the best-known form, although similar fibrotic patterns may occur after autoimmune disease, occupational exposure, infection, radiation or certain medicines.

  Macrophages are central to this process. These immune cells clear damaged material, coordinate inflammation and communicate with epithelial cells, fibroblasts and blood vessels. Their behaviour can influence whether injured lung tissue returns towards normal or enters a persistent cycle of inflammation and scarring.

  The term macrophage polarization describes the functional states macrophages adopt in response to local signals. It is useful for understanding disease biology, but the familiar M1 and M2 categories are a simplification. In fibrotic lung disease, macrophages often display mixed, changing profiles shaped by their origin, location and exposure to cytokines.

  For respiratory physicians and researchers in Australia, this subject has practical importance. Patients may present through metropolitan centres such as Sydney, Melbourne, Brisbane or Perth, while people in regional and remote communities can face longer journeys to specialist interstitial lung disease services. Understanding immune mechanisms may eventually support more precise diagnosis and treatment across this varied healthcare landscape.

  Macrophage state or feature	Common signals	Possible effect in fibrotic lung disease
  Inflammatory activation	Interferons, microbial products, tissue injury	Cytokine release and recruitment of additional immune cells
  Reparative activation	Interleukin-4, interleukin-13, damaged tissue signals	Wound healing, matrix turnover and potential profibrotic activity
  Monocyte-derived macrophages	CCL2 and inflammatory recruitment	Accumulation in injured areas and interaction with fibroblasts
  Alveolar macrophage dysfunction	Altered surfactant and epithelial signals	Poor clearance, persistent injury and impaired resolution
  Scar-associated macrophages	TGF-β, lipid signals and local matrix cues	Support for fibroblast activation and collagen deposition

  Macrophages In The Healthy Lung

  Healthy alveolar macrophages patrol the air spaces and remove particles, dying cells and microorganisms. They help maintain a relatively quiet immune environment because the lungs are continuously exposed to inhaled material. Their ability to clear debris without triggering excessive inflammation is essential for normal breathing.

  These cells also communicate with alveolar epithelial cells and influence surfactant recycling. When the lung is injured, resident macrophages can rapidly change their activity. Blood monocytes may enter the tissue and develop into macrophages with different properties, creating a diverse population rather than a single uniform cell type.

  Why The M1 And M2 Model Is Limited

  M1 macrophages are commonly associated with inflammatory activity, antimicrobial defence and the release of mediators such as tumour necrosis factor and interleukin-1. M2 macrophages are often linked with repair, immune regulation and responses to interleukin-4 or interleukin-13. This framework is helpful for teaching, but it does not fully represent human pulmonary fibrosis.

  In real tissue, macrophages can express markers from several functional programmes at the same time. Their behaviour may change as an injury develops, and nearby cells can alter their response. Single-cell RNA sequencing and spatial profiling have shown distinct macrophage populations located around fibrotic niches, blood vessels and damaged alveoli.

  From Inflammation To Scar Formation

  After epithelial injury, macrophages release chemokines that recruit circulating monocytes. CCL2 and its receptor CCR2 are important in this process. Recruited cells can accumulate in areas of damage and interact with fibroblasts, epithelial cells and extracellular matrix components.

  Some macrophages produce or activate transforming growth factor beta (TGF-β), a major driver of fibroblast activation and myofibroblast differentiation. Myofibroblasts produce excess collagen and other matrix proteins, gradually reducing the flexibility of the lung. Platelet-derived growth factor, osteopontin and other mediators may further support this profibrotic environment.

  The Role Of Alveolar Epithelial Injury

  Macrophage activity cannot be separated from epithelial damage. In IPF, abnormal alveolar epithelial cells may release signals that attract and reprogramme macrophages. In turn, activated macrophages can intensify epithelial stress through inflammatory mediators, oxidative products and altered matrix interactions.

  The result is a self-reinforcing wound-healing response. Instead of resolving after the initial insult, the tissue remains biologically active. This helps explain why fibrosis can progress even when there is little overt inflammation on clinical examination or high-resolution computed tomography.

  Efferocytosis And Failed Resolution

  Efferocytosis is the process by which macrophages remove dead or dying cells. Effective efferocytosis normally helps end inflammation and supports tissue repair. If this clearance system becomes inefficient, apoptotic cells and cellular debris can remain in the lung, providing ongoing danger signals.

  Lipid handling is another important factor. Macrophages exposed to altered surfactant, oxidised lipids or damaged cell membranes may develop a dysfunctional phenotype. Research into lipid-associated macrophages suggests that metabolic state can influence inflammatory signalling, matrix deposition and the persistence of fibrotic lesions.

  Therapeutic Implications

  Current antifibrotic medicines, including nintedanib and pirfenidone for appropriate patients with IPF, slow functional decline but do not specifically eliminate every profibrotic macrophage population. Macrophage biology may offer additional targets, including CCR2-dependent recruitment, TGF-β signalling, inflammasome activity and pathways involved in efferocytosis.

  A major challenge is avoiding broad immune suppression. Macrophages also protect against infection and help repair tissue, so removing all activated cells could create harm. Future treatments may need to redirect macrophage behaviour, reduce damaging communication with fibroblasts or target a disease-associated population within a particular fibrotic niche.

  Research And Clinical Relevance In Australia

  Australia has strong expertise in respiratory research, with specialist services and clinical trials concentrated in major cities including Sydney, Melbourne, Brisbane and Adelaide. National registries, biobanks and multidisciplinary interstitial lung disease clinics can help connect biological findings with lung function, imaging and patient-reported outcomes.

  Access remains uneven for people in rural, regional and remote areas, including communities across Western Australia, the Northern Territory and Queensland. Telehealth, coordinated referrals and local pulmonary rehabilitation can reduce some barriers, although specialist assessment may still require travel. Australian studies must also account for occupational exposures, smoking history, environmental dust and the different healthcare needs of Aboriginal and Torres Strait Islander communities.

  Connecting Cell Biology With Patient Care

  Macrophage polarization is best understood as a dynamic spectrum rather than a fixed switch between two cell types. The most important questions concern which macrophages are present, where they are located, what signals they receive and whether their actions help resolution or sustain scar formation.

  For clinicians, this biology reinforces the value of early referral, high-quality imaging, multidisciplinary review and regular assessment of lung function and symptoms. For researchers, it points towards therapies that are selective, spatially informed and responsive to disease stage. The key point to remember is that macrophages can influence whether lung injury resolves or becomes fibrosis, making their signals, origins and interactions important targets in the search for more precise 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)