Restrictive lung diseases (interstitial lung diseases) Histological Structure of Alveoli The wall of the alveoli is formed by a thin sheet of tissue separating two neighbouring alveoli. This sheet is formed by epithelial cells and intervening connective tissue. Collagenous , reticular and elastic fibres are present. Between the connective tissue fibres we find a dense, anastomosing network of pulmonary capillaries. The wall of the capillaries are in direct contact with the epithelial lining of the alveoli. Neighbouring alveoli may be connected to each other by small alveolar pores (pores of Kohn). The epithelium of the alveoli is formed by two cell types: Alveolar type I cells (small alveolar cells or type I pneumocytes) are extremely flattened and form the bulk (95%) of the surface of the alveolar walls.   Alveolar type II cells (large alveolar cells or type II pneumocytes) are irregularly (sometimes cuboidal) shaped. They form small bulges on the alveolar walls. Type II alveolar cells contain are large number of granules called cytosomes (or multilamellar bodies), which consist of precursors to pulmonary surfactant (the mixture of phospholipids which keep surface tension in the alveoli low) . Cilia are absent from the alveolar epithelium and cannot help to remove particulate matter which continuously enters the alveoli with the inspired air. Alveolar macrophages take care of this job. They migrate freely over the alveolar epithelium and ingest particulate matter. FUNCTIONS OF PULMONARY CELLS Type I pneumocytes Permeable to Oxygen and CO2, do not divide Type II pneumocytes Reserve cells secrete pulmonary surfactant Serve as repair cells Alveolar macrophages Phagocytosis Pores of Kohn (allow passage of Macrophages)

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Restrictive lung diseases
(interstitial lung diseases)
(ILD)

2. Restrictive lung diseases (interstitial lung diseases)
 During inspiration: air expands
the alveolar sacs by
stretching the alveolar
septae.
 Normally alveolar septae are
very thin. Composed of:
 single layer of pneumocytes,
 capillary and
 small amount of connective
tissue (mainly elastic fibres)

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The alveolar wall= Alveolar septa

4.  Interstitial lung diseases (ILD's)
add cells and fibrous tissue to the
interstitium.
 This:
 Thickens and stiffens the
septae and
 Restricts stretching,
 Making it harder to breath in.
 Therefore, ILD associated with:
 Reduced lung compliance (
decreased filling of lungs on
inspiration)
 Increased elasticity (increased
recoil of lungs on expiration)

5. Restrictive lung diseases (interstitial lung diseases)
 The PFT reveal the following:
 Decreased FEV 1sec (3L vs 4L)
 Decreased FVC (3L vs 5L)
 Increased FEV 1sec / FVC ratio ~ 3/3 =
100%.
 Compare with
 obstructive lung diseases:
 FEV 1sec / FVC ratio = 33%.

6. Findings in all interstitial lung diseases
 Clinical:
 Stiff lung increased effort of breathing 
DYSPNEA
 DRY COUGH
 Ventilation perfusion abnormalities  Hypoxemia 
pulmonary hypertension  cor pulmonale 
Respiratory failure
 All lung volumes and capacities are decreased
 Increased FEV 1sec / FVC ratio
 Pathologic:
 Diffuse fibrosis of alveolar interstitium
 X-Ray:
 Diffuse infiltrate (ground glass shadows)

7. Interstitial fibrosis
Ground glass opacities

8. Causes of Restrictive lung diseases
1. Chest wall and other disorders in the presence
of normal lungs:
 Kyphoscoliosis, pleural disease (mesothelioma)
2. Acute or chronic interstitial lung disease:
1. Acute
 Acute respiratory distress syndrome
(ARDS)
2. Chronic
 Based on etiology: Classified in to two
major groups:
 ILD with known cause
 ILD with unknown cause

9. ILD with known cause
1. Occupational and environmental exposures
a) Inorganic:
1. Pneumoconiosis
1. Asbestosis**
2. Silicosis**
3. Coal worker’s pneumoconiosis**
4. Berylliosis*
b) Organic
 Hypersensitivity pneumonitis **
2. Drug or treatment related
 Chemotherapeutic agents:
 Busulfan, bleomycin, methotrexate
 Ionizing radiation

10. ILD with unknown cause
 Sarcoidosis**
 Idiopathic pulmonary fibrosis*
 Pulmonary hemorrhage syndrome:
1. Goodpasture syndrome*
2. Wegener’s granulomatosis
3. Idiopathic hemosiderosis
 Collagen vascular diseases
 Eosinophilic granuloma

11. Pneumoconioses
 The most common cause of ILD
 Refers to a group of occupational lung diseases
characterized by
 inhalation of mineral dust particles (coal dust,
silica, asbestos, beryllium) that leads to
interstitial fibrosis.
 Coal Dust : coal workers pneumoconiosis
(CWP)
 Silica : silicosis
 Asbestos : asbestosis
 Beryllium : berylliosis
 Coal dust is least fibrogenic
 Silica, asbestos and beryllium are very fibrogenic.

12.  Reaction of lung to mineral dust depends on:
 Size, shape, solubility and reactivity of particles
 Most inhaled dust removed by ciliary action.
 Some get impacted at bifurcation of alveolar ducts.
 Macrophages accumulate and engulf the particles.
 Macrophage release a number of factors:
 Fibrogenic factors
 Proinflammatory factors
 Toxic factors
 These factors cause lung injury, inflammatory
reaction, collagen deposition and fibrosis.
Pathogenesis

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14.  Caused by inhaling coal dust for prolonged
periods.
 Source of coal dust (anthracotic pigment) :
 coal mines, large urban centers, cigarette
smoke
 Three forms of Coal worker's pneumoconiosis:
1. Asymptomatic anthracosis = pulmonary
anthracosis
2. Simple CWP and
3. Complicated CWP (progressive massive
fibrosis = PMF).
Coal worker's pneumoconiosis(CWP)

15. Coal worker's pneumoconiosis(CWP)
 Pulmonary anthracosis:
 Usually asymptomatic
 Carbon pigment (anthracotic pigment) accumulates in
macrophages along lymphatics and in interstitial lung
tissue.
 Alveolar macrophages with anthracotic pigment are
called dust cells.
 Simple CWP
 Characterized by presence of nodular masses in lung
composed of collagen fibers and anthracotic pigment.
 X ray: opacities <1 cm.
 Little pulmonary dysfunction.

16.  Characterized by : fibrotic opacities >1 cm on X ray.
 Microscopically:
 Opacities show dense collagen and anthracotic
pigment.
 Complications:
 Crippling lung disease (black lung disease)
 Pulmonary hypertension  cor pulmonale
 No increased risk of TB or lung cancer.
 Associations:
 Caplan’s syndrome.
 CWP plus Rheumatoid nodule in the lungs***.
Complicated CWP
or Progressive massive fibrosis (PMF)

17. "Black lung disease"

18. Silicosis
 Most common occupational
disease in the world
 Due to inhalation of crystalline
silicone dioxide (found in
quartz)  inflammation and
fibrosis of the lung tissue.
 Occupations associated with
development of silicosis:
1. Foundries
2. Sandblasting
3. Mining, Drilling
4. Tunneling ,Stone cutting

19.  Silica is highly fibrogenic.
 Chronic exposure:
 nodular opacities in lungs
 Concentric layers of collagen.
 Birefringent silica particles can be seen with
Polarized light.
 Complications:
 Cor pulmonale, Caplan syndrome
 Increased risk of developing lung cancer and
TB
Silicosis

20. Silicotic nodule

21. Lungs, silicosis - Radiograph

22. Asbestos related disease
 Due to inhalation of
asbestos fibers.
 Occupations:
 Pipe fitting in
shipyards,
 roofing,
 insulation and
construction
industries,
 demolition of building
containing asbestos..

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Pathogenesis
 Asbestos exposure causes fibrosis of lung by
interacting with lung macrophages.
 Asbestos a crystalline silicate with two
subfamilies:
 Serpentine (Chrysotile)
 Curley and flexible fibers
 Tend to be in upper airway
 Cause interstitial fibrosis and lung cancer.
 Amphibole (Crocidolite)
 Straight, stiff, needle like
 Delivered deep
 Cause lung cancer and mesotheliomas.

24. Asbestos related diseases
1. Benign pleural plaques: Most common lesion***.
• Calcified plaques on pleura and domes of diaphragm.
• Not a precursor for mesothelioma
2. Diffuse Interstitial Fibrosis .
3. Primary bronchogenic carcinoma***:
• Risk further increases if person smokes
• Occurs ~20 years after first exposure.
4. Malignant mesothelioma of pleura***:
• No etiologic relationship with smoking***
• Arises from cells lining the pleura
• Occurs ~25-40 years after 1st exposure.
5. Complications: Cor pulmonale and Caplan’s
syndrome.

26. Interstitial fibrosis

27. Asbestos: appearance in tissue
1. Asbestos body
2. Asbestos fibers coated by iron and protein are
called
 Ferruginous bodies (Look like a dumbbell)
 Macrophages phagocytose and coat fibers
with ferritin***
 Golden beaded appearance in sputum or in
airways of lung.

28. Asbestos body: high power****
A
B
“Ferruginous body"

29. Berylliosis
 Exposure in nuclear and aerospace industry.
 Lesion:
 Diffuse interstitial fibrosis with noncaseating
granulomas
 Increased incidence of cor pulmonale and
primary lung cancer.

30. Sarcoidosis
 Multisystem granulomatous diseases of unknown
etiology characterized by
 Noncaseating granulomas in many tissues and
organs**.
 Most commonly targets the lungs, face,
salivary glands and skin***.
 Epidemiology:
 Second most common ILD
 More common in African American women**.
 Occurs in adults of 20-40 yrs age**.

31. Sarcoidosis
 Pathogenesis:
 An unknown antigen interacts with CD4 helper
T cells , leading to formation of non-caseating
granulomas.
 Sarcoidosis is a diagnosis of exclusion
 Must rule out other granulomatous diseases

32. Clinical and pathological findings:
 Primarily targets the lungs
 Noncaseating granulomas in the lung
interstitium and hilar lymphnodes (potato
nodes)***.
 Granulomas contain multinucleated giant cells
with laminated calcium concretions (Schaumann
bodies) and stellate inclusions (Asteroid
bodies)***
 Diffuse interstitial fibrosis
 Cough and shortness of breath is the most
common CF

33. Laminated calcium
Concretions
= Schaumann bodies
Stellate inclusions
=asteroid bodies

34.  Skin lesions : 2 types
 Erythema nodosum: raised, red, tender
nodules (anterior aspect of legs), no
granulomas
 Nodular, painless lesions containing granulomas
 Eye lesion ; produces uveitis  blurry vision**.
 Mikulicz syndrome: involvement of lacrimal gland
and parotid (enlargement).
 Liver: granulomatous hepatitis  hepatomegaly
 Diabetes insipidus ( hypothalamic and or
posterior pituitary disease)
 Other organs: granulomas in spleen, CNS , heart
and bone marrow.

35.  Major clinical findings: dyspnea, cough ,fever
and night sweats.
 Laboratory findings:
 Hypercalcemia:** due to synthesis of 1 alpha
hydroxylase by macrophages in granulomas
(increases vit D)
 Elevated serum angiotensin converting enzyme
(ACE)***
 Chest X ray:
 Enlarged hilar lymphnodes – potato nodes***
 Prognosis:
 Majority of patients recover with
corticosteroid therapy.

37. Giant cell
Granuloma

38. Hypersensitivity pneumonitis
 Immunologically mediated disorder caused by
repetitive exposure to a known inhaled antigen.
 Does not involve IgE ab or have eosinophilia***
 Primarily affects the alveoli
 Also known as allergic alveolitis.
 Microscopy:
 Mononuclear cell infiltrate in the interstitium.
 Interstitial noncaseating granulomas (in >2/3rd of
cases)***
 Advanced cases show diffuse interstitial fibrosis.
 Clinical presentation:
 Acute reaction: fever, cough, dyspnea ( hours
after exposure)***
 Chronic disease: cough, dyspnea, weight loss.

39. Noncaseating
granuloma

40. Selected hypersensitivity pneumonitis
 Farmer’s lung**
 associated with
exposure to moldy
hay containing
thermophilic
actinomycetes
 Silo filler’s disease**
 Inhalation of wheat
weevil protein ( in
fumes originating
from fermenting
corn)

41. Other hypersensitivity pneumonitis
1. Byssinosis:* *
1. Occurs in workers in textile factories
2. Associated with exposure to cotton, hemp or
linen (“Monday morning blues”)
2. Bagassosis: lung disease that develops after
repeated exposure to moldy sugar cane.
3. Pigeon breeders lung: proteins from bird
feathers or excreta.
4. Humidifier or air conditioner lung: thermophilic
bacteria.

42. Diffuse alveolar hemorrhage syndromes
 A group of immune mediated diseases that present as
the triad of:
 Hemoptysis, Anemia and diffuse pulmonary
infiltrates. Examples:
1. Goodpasture syndrome
2. Wegener Granulomatosis
 GOODPASTURE SYNDROME:***
 Male predominant disease characterized by:
 Glumerulonephritis and
 Hemorrhagic interstitial pneumonitis.
 Both lesions caused by anti-basement membrane
antibodies directed against BM of pulmonary and
glomerular capillaries.

43.  Patients first present with hemoptysis and then
acute glomerulonephritis.***
 Micro:
 Focal necrosis of alveolar walls
 Intra-alveolar hemorrhage
 Intra or extracellular hemosiderin
 Fibrous thickening of septa
 Immunofluorescence:
 Linear pattern of immunoglobulin deposition**
 Kidney and lungs
 Treatment:
 Plasmapheresis and immunosuppressive therapy.

44. Goodpasture’s Syndrome, Hemorrhage, Necrosis
and IgG Deposits

45. Idiopathic pulmonary fibrosis
 A disorder of unknown cause.
 Pathogenesis:
 Repeated cycles of alveolitis triggered by an
unknown ag.
 Release of cytokines produces interstitial
fibrosis.
 Alveolar fibrosis leads to dilatation of airways
 Lung has a honeycomb appearance
 Course:
 Progression  pulmonary insufficiency, cor
pulmonale and cardiac failure.

46. Honeycomb lung.

47. Spr 09 47
 Drugs producing ILD include:
 Nitrofurantoin, amiodarone, bleomycin,
busulfan and cyclophosphamide.
 Collagen vascular diseases producing restrictive
lung disease: SLE, RA, systemic sclerosis.
Other Restrictive lung diseases