Obstructive and Restrictive Lung Diseases

Question 1

Describe the normal anatomy of lung airways:

Answer 1

1. Trachea branches into 2 main bronchi
2. Main bronchi branch into segmental bronchi
3. Segmental bronchi branch into bronchoiles within the lobes of the lung
4. Bronchioles branch into terminal bronchioles
5. Terminal bronchioles branch into respiratory bronchioles
6. Respiratory bronchioles feed into alveoli which contain alveolar sacs

Question 2

Describe the normal layers of airway walls:

Answer 2

Mucosa:

1. Epitheilum (pseudostratified, ciliated)
2. Basement membrane
3. Lamina propria

Underlying smooth muscle
5. Smooth muscle

• Also contains some globlet cells

Question 3

What is FEV1?

Answer 3

• FEV1 = forced expiratory volume 1, it is the volume of air that can be exhaled with force in the first second after maximal inhalation

Question 4

What are the main characteristics of obstructive vs restrictive lung disease?

Answer 4

1. Obstructive Lung Disease:
   - Decreased FEV1 but normal total lung capacity
   - Due to an increase in resistance to airflow, due to partial of complete obstruction
2. Restrictive Lung Disease:
   - Normal FEV1 but reduced total lung capacity

Question 5

What is an obstructive lung disease?

Answer 5

• Increase in resistance to airflow due to partial or complete obstruction
• Diagnosed by decreased FEV1 but normal total lung capacity
• Can be due to:
  1. Airway narrowing: e.g. due to chronic bronchitis (inflammation of the airways) or asthma
  2. Loss of elastic recoil of the lung: e.g. emphysema due to a lack of elastic recoil to keep airways open

Question 6

Describe asthma:

Answer 6

• A type of obstructive lung disease
• Due to a type 1 hypersensitivity reaction characterised by mast cell activation
• Differentiated from chronic bronchitis by presence of goblet cell metaplasia and immune cell (mast cell + eosinophil) infiltration into lamina propria

Question 7

Describe chronic bronchitis:

Answer 7

• Obstructive Lung Disease
• Defined clinically as persistent cough with sputum production and eventually dyspnea on exertion
• Chronic obstructive bronchitis causes:
  1. Sputum production
  2. Inflammation in small airways
  3. Obliteration of small airways
  4. Cor pulmonale (right ventricular hypertrophy and failure)
  5. Atypical metaplasia in respiratory epithelium- squamous epithelia develops in place of psuedostratified (can cause bronchial cancer)

Question 8

Describe the histopathology of chronic bronchitis:

Answer 8

1. Significant mucosa expansion (causes airway narrowing)

2. Excessive mucous production: hypertrophy of mucous glands and goblet cell metaplasia

Question 9

What are the causes of chronic obstructive bronchitis?

Answer 9

Two main causes:

1. Chronic irritation:
   E.g.Tobacco smoke
2. Infection
   - The culmination of these factors in a chronic manner results in inflammation, hypersecretion of mucous and then irreversible scarring

Question 10

Describe emphysema:

Answer 10

• Obstructive lung disease
• Defined anatomically as permanent abnormal increase in size of airspaces distal to terminal bronchioli along with destruction of alveolar sac walls
• Leads to loss of elastic recoil of lungs, airway obstruction (but normal airway resistance)
• Characterised by progressive dyspnea (severe and early)
• There are two types of emphysma:
  1. Centracinar emphysema
  2. Panacinar emphysema

Question 11

Describe centiacinar vs panacinar emphysema:

Answer 11

1. Centriacinar:
   - Proximal acinus (terminal portion of respiratory bronchiole) is damaged
   - Associated with upper lobe damage
   - Central areas (terminal respiratory bronchioles) show marked damage surrounded by relatively spared alveolar damage
2. Panacinar:
   - Acinus universally damaged (both terminal respiratory bronchiole and alveolar sac)
   - Associated with lower lobe damage
   - Emphysematous damage involving entire pulmonary lobule

Question 12

Describe histopathology in emphysema:

Answer 12

• Alevolar walls are made up of type 1 pneumocytes and elastin proteins
• If elastin is degraded due to the action of proteases, the epithelial cells are no longer supported and they collapse
• This is observed histologicaly as:

1. Large alveolar sacs

Question 13

What is the cause of emphysema?

Answer 13

• Smoking/air pollutant and/or genetic predisposition leads to:
  1. Oxidative stress, increased apoptosis and senescence
  2. Inflammation
  3. Protease-antiprotease imbalance: causes elastin degradation and alveolar wall breakdown

Question 14

What are the key protease and anti-proteases involved in the development of emphysema?

Answer 14

1. Proteases:
   - Neutrophil elastase
   - Proteinase-3
   - Cathespin
   - MMPs
2. Antiproteases:
   - a1-anti-trypsin (inhibits elastase)
   - a2-macroglobulin

Question 15

What is COPD?

Answer 15

• A condition characterised by a combination of chronic bronchitis and emphysema
• Leads to pulmonary and systemic inflammation; inflammatory cytokines exacerbate conditions such as atherosclerosis

Question 16

What is a restrictive lung disease?

Answer 16

• Restrictive lung diseases are due to reduced capacity for lung parenchyma expansion and decreased total lung capacity
• Still has normal FEV1
• There are 2 types of restrictive lung disease:

1. Chest wall disorders with normal lungs:
   - Neuromuscular disease (poliomyelitis)
   - Severe obesity
2. Acute/Chronic Interstitial and infiltrative disease
   - Silicosis
   - IPF
   - ARDS

Question 17

What are the characteristics of coal worker’s lung?

Answer 17

• Progressive massive fibrosis superimposed on coal worker’s pneumoconiosis
• Characterised by large, blackened areas of fibrotic tissue located principally in the upper lobe
• Results in restrictive lung disease as chronic irritation and inflammation causes normal lung parenchyma including the alveoli to be replaced with fibrotic tissue (results in less lung capacity for gas exchange)

Question 18

What are the characteristics of asbestosis?

Answer 18

Histological:

1. Formation of asbestos bodies
2. Chronic inflammation

Gross:
1. Asbestos-related pleural plaques: formation of discrete fibro-calcific plaques on pleural surface of lung

Question 19

What is idiopathic pulmonary fibrosis?

Answer 19

• Chronic, progressive, irreversible and usually lethal lung disease of unknown cause
• Disease limited to lungs
• Histological and radiological pattern known as usual interstitial pneumonia
• Risk factors: smoking, exposure to metal and wood duct and genetic predisposition
• Lethal disease
• Symptoms are cough and dyspnea
• Acute exacerbations e.g. infections, accelerate the progress of the disease

Question 20

Describe the gross pathology of IPF:

Answer 20

1. Pleural (outer) surface of lung has cobblestone appearance
2. Airspace enlargement
3. Generation of fibrotic tissue around airspaces
   - Known as gross honeycombing

Question 21

Describe the HRCT scan appearance of IPF:

Answer 21

• Patchy, sub-pleural reticular opacities

- Honeycombing with basal predominance

Question 22

Give an overview of the histological features seen in usual interstitial fibrosis (IPF):

Answer 22

• Patchy fibrotic reaction
• Fibrosis prominent in peripheral secondary pulmonary lobule
• Central portion of lobule spared
• Temporal and spatial heterogeneity

Question 23

What are fibroblastic foci?

Answer 23

• An occurance in IPF
• Have surface of cuboidal epithelial cells
• Inner portion consisting of fibroblast cells and collagen (pale in H&E stain)

Question 24

What are the other important histological features in IPF?

Answer 24

• Aside from usual intertitial fibrosis and the appearance of fibroblastic foci, the following are seen:

1. Paucity of inflammation:
   - Compared to other diseases such as COPD and asthma, there is a comparative lack of immune infiltration
2. Lack of uniform involvement:
   - Fibroblastic foci appear in certain areas of the lung but not others, disease can be concentrated in certain areas of the lung
3. Diffuse aveolar damage:
   • Type II pneumocyte hyperplasia (these cells are usually low in number as they cannot conduct gaseous exchange)
   • Oedematous alveolar septa (thickening of septa between alveoli with fluid)
   • Hyaline membranes (the membranes are thickened with hyaline cartilage- appears pink in H&E stain)
   • Distal airway squamous metaplasia
   • Thrombi in small pulmonary arteries

Question 25

How is IPF modelled in mice?

Answer 25

• IPF is induced in mice using the drug bleomycin

Question 26

What is the current understanding of IPF pathobiology?

Answer 26

Predisposition:
1. Begins as aberrant wound healing at the lung epithelium

Mechanism:

2. This leads to the production of growth factors and other products that activate effector cells (myofibroblasts)
3. Unfolded protein response occurs which causes cells to undergo apoptosis and reprogramming (leading to fibrosis)
4. Epithelial- mesenchymal transition: leads to accumulation of fibroblasts and fibrosis of tissue
5. TGFB activation: causes epithelial cell inflammation, EMT and myofibroblast differentiation

Progression:
6. Secretion of massive amount of collagen by myofibroblast cells

Question 27

What are the therapeutic strategies for treating IPF:

Answer 27

• Very poor

1. N-acetyl cysteine (NAC)
   - an antioxidant, used in the management of COPD
2. Endothelin receptor antagonists
   - Aim to block the action of this pro-inflammatory and pro-fibrotic molecule
3. Pirfenidone
   - Main treatment currently used
   - anti-inflammatory/anti-oxidant/anti-fibrotic agent, has mixed results (very mild and relatively ineffective)
4. Lung Transplant:
   - Only proven treatment
   - However this can result in chronic lung allograft dysfunction (CLAD)- rejection of the lung not due to immunological reasons but due to the development of fibrosis around the airways
   - Potential new treatment could be the combination of anti-fibrotic drugs with transplant lungs