Smoking-related and rare diffuse lung diseases
- Lesion
Rarer diffuse lung diseases: smokers' pigmented macrophages (DIP, RB-ILD), Langerhans cell nodules, and alveoli filled with surfactant (proteinosis).
What it is
Beyond COPD, smoking causes interstitial diseases marked by pigmented macrophages: respiratory bronchiolitis–associated ILD and desquamative interstitial pneumonia, which form a spectrum. Pulmonary Langerhans cell histiocytosis is a clonal, smoking-related neoplasm of Langerhans cells. Pulmonary alveolar proteinosis and surfactant dysfunction disorders fill the alveoli with surfactant because it is not cleared or not made correctly.
Structure
- RB-ILD and DIP: macrophages with finely granular golden-brown cytoplasm (iron, weakly Prussian blue positive) in bronchioles or filling alveoli; mild septal fibrosis.
- PLCH: nodules of Langerhans cells with grooved, folded nuclei, eosinophils and lymphocytes around bronchioles, becoming stellate scars and cysts.
- Alveolar proteinosis: alveoli packed with homogeneous, granular, PAS-positive precipitate with cholesterol clefts; walls normal.
- Surfactant disorders: type II pneumocyte hyperplasia, interstitial fibrosis, abnormal lamellar bodies on EM (small dense-core bodies in ABCA3).
Step by step
- Tobacco smoke particles are taken up by alveolar macrophages, which accumulate where smoke deposits.
- Mild bronchiolar inflammation with these macrophages is RB-ILD; diffuse alveolar filling is DIP.
- In PLCH, clonal Langerhans cells with MAPK pathway mutations (often BRAF) proliferate around bronchioles; smoking seems to promote them.
- In autoimmune proteinosis, antibodies block GM-CSF, so alveolar macrophages never mature and cannot break down surfactant.
- In surfactant gene disorders, misfolded or missing surfactant proteins injure type II cells and fail to lower surface tension.
Rare diffuse lung diseases compared
| Disease | Who | Key lesion | Marker |
|---|---|---|---|
| RB-ILD | Smokers | Pigmented macrophages in respiratory bronchioles | Smoker's macrophages |
| DIP | Smokers | Pigmented macrophages filling alveoli | Smoker's macrophages |
| Langerhans cell histiocytosis | Young adult smokers | Stellate nodules and cysts, upper zones | CD1a, langerin, Birbeck granules |
| Alveolar proteinosis | Adults (autoimmune) | Alveoli full of PAS-positive surfactant | Anti-GM-CSF antibodies |
| Surfactant gene disorder | Neonates to adults | Type II hyperplasia, fibrosis | ABCA3, SFTPC, SFTPB variants |
Markers
- CD1a
- Langerin (CD207)
- Birbeck granules
- PAS
- Anti-GM-CSF antibodies
Clinical notes
- RB-ILD, DIP and PLCH occur almost only in smokers; stopping smoking is the core treatment.
- PLCH can cause pneumothorax from cysts.
- Proteinosis: cough with gelatinous sputum, progressive dyspnoea, secondary infections (Nocardia); whole-lung lavage helps, inhaled GM-CSF in autoimmune cases.
- A term neonate with unexplained respiratory failure may have a surfactant gene mutation.
Test yourself
Think of the answer, then tap the question to see it.
What cells fill the alveoli in desquamative interstitial pneumonia?
Pigmented alveolar macrophages from smoking, despite the old belief that they were desquamated pneumocytes.
Which markers identify the cells of pulmonary Langerhans cell histiocytosis?
CD1a and langerin (CD207) by immunohistochemistry, and Birbeck granules by electron microscopy.
What causes most cases of pulmonary alveolar proteinosis?
Autoantibodies against GM-CSF that block maturation of alveolar macrophages, so surfactant is not cleared.
Elsewhere in DurgiPedia
Connections
Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.
Sources: Langerhans cell histiocytosis: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2025); Interstitial Lung Disease (StatPearls (NCBI Bookshelf), 2025).
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Representative model, for educational purposes only.