Pathophysiology of fibrosis and restrictive lung disease

Question 1

Recall the tracheobronchial tree and its features

Answer 1

• conducting system
  
  • nasal cavity
  • paranasal sinuses
  • nasopharynx
  • note: supporting connective tissue is rich in elastin
• trachea: larger airways - cartilage rings, seromucinous submucosal glands, smooth muscle
• bronchi
  
  • main - primary
  • lobar - secondary
  • segmental - tertiary
• bronchioles < 1mm
  
  • bronchiole
  • termianl bronchiole
  • respiratory bronchioles
  • note: no cartilage, SM glands; smooth muscle only
• alveoli: ducts and sacs ^[ask Riemke what the difference is?]
  
  • very thin wall for gas exchange (can be seen clearly in histology)
  • thin interstitium

Question 2

Discuss how the mucosal/epithelial lining differs along the tree

Answer 2

1. Pseudostratified columnar ciliated with goblet cells
   
   • trachea (with submucosal seromucinous glands) to bronchioles
2. Ciliated columnar with increasing numbers of Clara cells/club cells instead of goblet cells
   
   • terminal and respiratory bronchioles
3. Simple squamous/type 1 pneumocytes, rounded type 2 pneumocytes, and clara cells/club cells
   
   • alveolar ducts and sacs

note: NE cells are scattered throughout, peptide hormones e.g. 5 HT for regulation of muscle tone

Question 3

Discuss some notable features of lung histology

Answer 3

Notice the very thin wall, the alveolar ducts and sacs

Pleura lined with mesothelium

Question 4

List and briefly describe cells of the lung

Answer 4

• ciliated columnar epithelial cell: movement of cilia clears mucus with entrapped debris
  - columnar
  - cuboidal
  - ciliated
  - located at bronchi and brinchioles
  
  • Club/Clara cell: secretion of numerous protective factors e.g. lysozyme, IgA components, and surfactant components; detoxification i.e. with CYP450; division to replace damaged epithelial cells (from progenitor cells)
    
    • columnar
    • non ciliated
    • located predominantly in bronchioles
  • Goblet cell: mucus secretion to entrap foreign material and pathogens
    
    • columnar mucus-secreting cells
    • mostly bronchi, few numbers in bronchioles
  • Type 1 pneumocyte: very thin cells to allow for gaseous diffusion and exchange
    
    • large flat squamous cells
    • located in alveoli
  • Type 2 pneumocyte: surfactant secretion, progenitor pool, to replace damaged pneumocytes
    
    • columnar alveolar lining cells
    • located in alveoli
  • Submucosal glands, line by serous and mucinous cells: seromucinous secretions to entrap foreign material and pathogens
    
    • located in bronchial submucosa
  • Alveolar macrophages: phagocytosis of foreign material and pathogens

Question 5

List some factors affecting respiration or gas exchange

Answer 5

• quality of gas inhaled or **gaseous environment
  
  • expansibility and collapsibility of the lungs i.e. ventilation
    
    • ribs
    • thoracic muscles
    • pleura
    • pulmonary parenchyma
  • exchange of gases between the alveolar space and capillaries i.e. diffusion
    
    • basemet membranes thickening
    • interstitial thickness
    • alveolar wall deposits
• status of pulmonary circulation or perfusion

Question 6

Define diffuse pulmonary diseases

Answer 6

Diffuse pulmonary diseases
is an umbrella term for diseases that usually involve the entire lung, and thus usually cause dyspnoea.

Can be acute, subacute or chronic.

Diffuse pulmonary diseases are commonly classified as per the derangemet in pulmonary physiology
- obstructive (airway obstruction) e.g. asthma if bronchospasm present and obstruction ^[can it not be? is it typically obstructive?]
- restrictive (Reduced expansion of lung parenchyma)

Obstructive: airway obstruction, often with
difficulty exhaling
Restrictive: reduced lung compliance + TLC

Question 7

Describe the different ways in which medical lung diseases can be classified and provide examples

Answer 7

• functional or clinical: restrictive vs. obstructive, acute or subacute or chronic
  
  • aetiology: e.g. idiopathic, pigeon breeders, genetic, congenital
  • HCRT findings or radiologic pattern
  • Pathologic reaction pattern (fibrotic, granulomatous) and site of injury (pleural, vascular, bronchiolar)

Question 8

Provide some examples of causes of diffuse lung disease

Answer 8

• smoking and other noxious gases
  
  • IVDU ^[usually due to impurities]
  • toxins and drugs - e.g. chemo, methotrexate
  • occupational or environmental exposures: silica dust, asbestos fibres, grain dust, bird and animal droppings
  • infectious agnets e.g. Aspergillus
  • autoimmune
  • radiation
  • idiopathic

Question 9

Provide some causes of restrictive lung disease

Answer 9

• disorders of the chest wall: neuromuscular disorders, severe obesity, kyphoscoliosis
• disorders of the pleura
• disorders of the lung: acute and chronic

Question 10

Describe the pathophysiology of ARDS

Answer 10

ARDS is the clinical term
Diffuse alveolar damage is the pathologic term.

It is:
- caused by diffuse alveolar capillary damage
- a component of shock and multisystem organ failure
- severe life-threatening respiratory insufficiency, cyanosis and arterial hypoxaemia
- refractory to oxygen therapy

Pathogenesis of ARDS
- capillary endothelial and alveolar damage
- release of cytokines and interleukins, which in turn
- activation of neutrophils (release proteases, oxidants), which migrate into interstitium–>oedema, thickened interstitium due to infiltrate
- increased vascular permeability
- exudation of fluid- alveolar flooding
End-result is decreased diffusion

Graph below shows stages

Question 11

Describe the pathology of ARDS

Answer 11

depends on the stage.

Macroscopy: heavy, boggy, oedematous and red lungs

Microscopy: hyaline membrane, and widening of interstitial space

Question 12

Describe complications of ARDS

Answer 12

• respiratory acidosis
  
  • death
  • scarring- poorly aerated fibrosed lung (Chronic)

Question 13

Describe the pathophysiology of chronic restrictive pulmonary disease

Answer 13

Pathophysiology of chronic restrictive pulmonary disease

also known as interstitial lung diseases or interstital pneumonias.

Causes include:
- environmental diseases
- granulomatous
- idiopathic
- collagen vascular diseases
- smoking related
- complication of therapies

Clinical signs and symptoms:
- dyspnoea (with different onsets, and may or amy not be progressive)
- tachypnoea
- inspiratory crackles
- reduced lung compliance and volume

Radiologic alteration:
- distribution important
- irregular lines
- small nodules
- ground glass shadows ^[?]

Note: HRCT findings constitute the macroscopy for pathologists

Pathogenesis
similar to acute

• different mechanisms leading to inflammation ofo alveoli
• accumulation of inflammatory cells in the alveolar walls and spaces
• release of mediators e..g cytokines and interleukins
• alveolar wall damage
• fibrosis of the alveolar walls (irreversible and poor prognosis)

Last image shows end stage, no resemblance to normal parenchyma

Question 14

Describe complications of chronic restrictive lung disease

Answer 14

• end stage honeycomb lung ^
• traction bronchiectasis
• pulmonary hypertension
• right sided heart failure (or cor pulmonale)

Question 15

List the two types of idiopathic interstitial pneumonias

Answer 15

Idiopathic pulmonary fibrosis can be divided into usual and nonspecific interstitial pneumonitis.

Question 16

Describe usual interstitial pneumonitis

Answer 16

• Repeated sequential cycles of acute lung injury- alveolitis leads to progressive fibrosis (Wound healing with fibroblastic proliferation)
• Early stages: fibroblastic proliferation/fresh fibrosis/fibroblast foci
• Late: collagenous, acellular scarred areas/pld

Both early and late stages are seen together:
- temporal heterogeneity: presence of both fresh and old fibrosis
- regional heterogeneity (areas of relative sparing)

Median survival 3 years, short term mortality is greater than 50%. Poor prognasis

Question 17

Describe non-specific interstitial pneumonitis

Answer 17

Diagnosis is one of exclusion, as many other diseases mimic this.
Characterised by:
- Interstitial lymphocytes and plasma cells, interstitial thickening
- Diffuse or patchy interstitial fibrosis (temporally homogenous, all old, uniform appearance)
- variably cellular (inflammatory) and
- Absence of fibroblastic proliferation (all old fibrosis)

Much better prognosis than UIP and more steroid responsive.
It worsens with increasing fibrosis.
- 90% 5y survival
- 40% 10y survival.

Question 18

Describe pneumoconioses

Answer 18

are a lung reaction to inhalation of mineral dust, organic dust, chemical fumes and vapors.

Examples include:
- carbon and coal workers pneumocnoisos
- silica or silicosis
- asbestos or asbestosis
- insecticides

Factors affecting development of lung disease
– Duration and length of exposure
– Amount of retained dust
– Size (small1-5 microns- can reach and settle in small
alveoli)
– Shape, buoyancy of the particles
– Particle solubility (insoluble particles can remain in
the lungs for years)
– Additional irritants (SMOKING!!!!)
– Preexisting lung disease

Question 19

Describe asbestosis

Answer 19

• Pleural plaques: fibrosis in parietal and visceral pleura
• Diffuse pulmonary fibrosis (Asbestosis)
• Recurrent Pleural effusions
• Lung carcinoma
• Mesothelioma (lung and abdominal) - incidence high
• Other cancers (trachea, larynx, gastrointestinal
  tract, others?)

^usually colourless, but if iron deposits, can see (ferrogenous bodies). No need to see in order to diagnose

Question 20

Describe silicosis and anthracosis

Answer 20

Silicosis

– Initial formation of nodules in the upper lobes of the
lung: fibrous scars, “hard”
- found in lymph nodes, parenchyma and pleura
* Nodules contain dust particle, macrophages and delicate network of collagen
* Macrophages secrete mediators: attract lymphocytes, fibroblasts
* Cause damage to alveolar cells and interstitium
– Disease progression leads to formation of hard
collagenous scars
– Scars may often be pigmented in coal workers

Anthracosis appear black
Silicosis is weakly birefringent/shiny white “poalrisable” appearance

Can co-occur

Question 21

Describe granulomatous lung diseases

Answer 21

Hypersensitivity pneumonitis (extrinsic allergic alveolitis): reaction to inhaled organic antigens or chemicals: e.g farmers lung, Bird-fanciers lung, hot-tub lung ^[type 4?]
- Some antigens are actually infectious agents
Features:
- nodular
- multi-nucleated giant cells
- macrophages
- surrounded by lymphocytes

Sarcoidosis: idiopathic multisystem disease

RECALL from block 1: granuloma
* Granuloma is:
– A focus of chronic
inflammation,
* Granuloma comprises of
microscopic aggregation
of:
– Activated macrophages:
epithelioid cells (resemble
epithelial cells)
– Surrounded by a collar of
lymphocytes and plasma
cells

Why do granulomas form?
Granulomas form when the immune system fends
off and isolates a poorly degradable or
particulate antigen

Hypersensitiviy pneumonitis
- allergic alveolitis
- abnormal immunologic response to antigens (spores of thermophilic bacteria, fungi, animal proteins, bacterial products)
- Immune complex (B cell) and delayed type hypersensitivity (T cell) mediated damage
- Alveolar and interstitial inflammation with granulomata formation
- Interstitial fibrosis and obliterative bronchiolitis

Removal of the antigen prevents disease progresssion.

Sarcoidosis
- Autoimmune
- Systemic disorder
- F»M
- Diagnosis of exclusion
- Disordered immune regulation (Helper T cell deregulation)
- Cell mediated immune response to an unidentified antigen
- Formation of granulomata primarily around the lymphatics, bronchi and blood vessels (bronchi and blood vessels follow each other)
- Granulomata may heal with hyalinization and fibrosis leading to pulmonary fibrosis
- Location: from specific to anywhere as it goes ^[?]

Question 22

Describe collagen vascular diseases

Answer 22

Collagen vascular diseases
often seen in patients with a history of autoimmune disorders e.g. rheumatoid arthritis (in pleura and interstitium), SLE (lung), and progressive systemic sclerosis (lung).

It is characterised by:
- Diffuse interstitial pneumonitis and fibrosis
- Vascular sclerosis
- Organizing pneumonia
- Bronchiolitis
- Often associated pleural disease

Question 23

Provide examples of smoking related lung disease

Answer 23

**Vascular disease
- atherosclerosis (..stroke, IHD, PVD…)
- microvascular diseases

Cancer of lung, liver, cervix, urothelial tract, upper aerodigestive tract…

Reproductive outcomes
- reduced male fertility
- preterm birth
- stillbirth or miscarriage
- low birth weight
- ectopic pregnancy
- birth defects inc orofacial clefts

Miscellaneous
- osteoporosis
- cataracts
- I2DM
- RA
- poor dental health
- ear infections in children, poor learning outcomes

Lung diseases
- DIP
- RB - ILD
- COPD
- ling cancer
- worseing of pre-existing disease e.g. asthma
- pulmonary hypertension

Question 24

Describe some presentations of smoking related lung disease

Answer 24

Presentations include:
- desquamative interstitial pneumonia: thick interstitium, fibrosis
- respiratory bronchiolitis associated ILD: macrophages ^[one or both?]

Stopping smoking is key

Question 25

Describe iatrogenic lung disease

Answer 25

Iatrogenic lung disease
side effects of:
Drugs
- cytotoxic drugs leading to pneumonitis and fibrosis
- amiodarone: pneumonitis and fibrosis
- nitrofurantoin: hypersensitivity pneumonitis

Radiation
- acute radiation pneumonitis
- chronic radiation pneumonitis: lymphocytic alveolitis, hypersensitivity pneumonitis, **pulmonary fibrosis