[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [General pathology](https://durgical.com/en/general-pathology/) › [Lung](https://durgical.com/en/general-pathology/areas/lung/) › Smoking-related and rare diffuse lung diseases

# 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).

Updated Nov 12, 2026

## Key points

- RB-ILD: pigmented ('smoker's') macrophages in respiratory bronchioles; mild symptoms; improves on quitting.
- DIP: alveoli diffusely filled with pigmented macrophages (not desquamated cells, despite the name); good prognosis with smoking cessation.
- Pulmonary Langerhans cell histiocytosis: young adult smokers; stellate nodules and cysts in upper zones; CD1a and langerin positive, Birbeck granules; BRAF V600E in many.
- Alveolar proteinosis: PAS-positive, granular pink material in alveoli; most are autoimmune (anti-GM-CSF antibodies); treated by whole-lung lavage.
- Surfactant gene disorders: ABCA3 (commonest, recessive), SFTPC (dominant), SFTPB (recessive); neonatal failure to adult ILD.

On this page

- The basics Key points
- What it is
- Structure
- Step by step
- Markers
- Memory aid
- Elsewhere in DurgiPedia

- Clinical Rare diffuse lung diseases compared
- Clinical notes

- Study Test yourself

- Connections Connections

## 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](https://durgical.com/en/conditions/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](https://durgical.com/en/conditions/neonatal-respiratory-distress-syndrome/) | 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.

## Memory aid

Smokers' lungs collect brown macrophages; proteinosis lungs collect pink surfactant.

## 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.

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## Elsewhere in DurgiPedia

- [Surface tension, surfactant and Laplace's law](https://durgical.com/en/physiology/surface-tension-surfactant-and-laplace-s-law/)

## Connections

## Related 5

- [Tobacco: how smoking injures tissue](https://durgical.com/en/general-pathology/tobacco-how-smoking-injures-tissue/)
- [Neonatal respiratory distress syndrome: surfactant and hyaline membranes](https://durgical.com/en/general-pathology/neonatal-respiratory-distress-syndrome-surfactant-and-hyaline-membranes/)
- [Emphysema](https://durgical.com/en/general-pathology/emphysema/)
- [Coal workers' pneumoconiosis and silicosis](https://durgical.com/en/general-pathology/coal-workers-pneumoconiosis-and-silicosis/)
- [Idiopathic pulmonary fibrosis (UIP pattern)](https://durgical.com/en/general-pathology/idiopathic-pulmonary-fibrosis/)

## Related conditions 3

- [Langerhans cell histiocytosis](https://durgical.com/en/conditions/langerhans-cell-histiocytosis/)
- [Interstitial lung disease](https://durgical.com/en/conditions/interstitial-lung-disease/)
- [Neonatal respiratory distress syndrome (hyaline membrane disease)](https://durgical.com/en/conditions/neonatal-respiratory-distress-syndrome/)

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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](https://medlineplus.gov/genetics/condition/langerhans-cell-histiocytosis/) (MedlinePlus, US National Library of Medicine, 2025); [Interstitial Lung Disease](https://www.ncbi.nlm.nih.gov/books/NBK541084/) (StatPearls (NCBI Bookshelf), 2025).

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License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/general-pathology/smoking-related-and-rare-diffuse-lung-diseases/