Pulmonary Toxicity

Question 1

How is the lung exposed to toxic agents?

Answer 1

Through both inhalation and systemic delivery of toxins

Question 2

What are the anatomical features of the upper respiratory tract?

Answer 2

This is lined by columnar epithelium containing both ciliated and non-ciliated cells and the sub-mucosal mucus glands. The non ciliated clara cells are capable of detoxifying many xenobiotics

Question 3

What are the anatomical and physiological features of the bronchi?

Answer 3

The ciliated cells have a co-ordinated beat of cilia which removes mucus every 24 hours towards the pharynx where it is swallowed. These cells are very sensitive to injury particularly from gases such as ozone, NO2, SO2 and cigarette smoke
The non ciliated clara cell synthesizes, stores and secretes bronchial mucus, antibacterial proteins, protease inhibitors and immunoglobulins. Clara cells contain abundant smooth endoplasmic reticulum where enzymes such as CYp and GST reside allowing these cells to detoxify chemicals, these cells also act as progenitor cells which are capable of differentiating into ciliated cells if injury occurs

Question 4

What are the anatomical and physiological features of the alveoli?

Answer 4

The alveoli are lined by two types of pneumocytes
Type 1 pneumocytes cover most of the alveolar wall and are thin with a large surface area these maintain the blood-air barrier for gaseous exchange and are very sensitive to damage
The type 2 pneumocytes are granular cuboidal cells with microvilli that protrude into the alveolar space, they secrete pulmonary surfactant and can synthesize arachidonic acid metabolites and type IV collagen, they also contain xenobiotic metabolizing enzymes and proliferate in response to injury

Question 5

What are the physiological and biochemical mechanisms in the lung which limit the impact of external factors on the lung?

Answer 5

There are clearance mechanisms such as blood and lymph drainage and the mucocillary escalator there is immune surveillance by BALT and tissue resident alveolar macrophages. Plasma cells in the submucosa beneath the columnar epithelium lining the trachea secrete IgA and act as a mucosal defence against inhaled pathogens that are trapped by the muco-ciliary apparatus
The highly oxidative environment of the lung is compensated for by well developed antioxidant enzyme systems
Hyperplastic and metaplastic changes can occur in response to inhaled irritants resulting in increased mucus secretion and mucus cell metaplasia which may obstruct airways, an increase in enzymes to detoxify xenobiotic may also occur

Question 6

What can cause direct damage to the lung?

Answer 6

Exposure to irritants and corrosive agents such as vapurs, HCl, methyl isocyanate through oxidant gases such as SO2, NO2 and O2 or through particulate matter such as asbestos, silica and wood

Question 7

How can chlorine cause corrosive damage to the lung?

Answer 7

Chlorine is a soluble corrosive gas it is also heavier than air causing it to remain near the ground increasing the length of exposure, inhalation will result in dissolving of the gas in the moist environment of the lung forming the corrosive acids hypochlorous and hydrochloric
At high concentrations these can directly damage the alveolar lining with the pneumocytes being directly damaged and undergoing oncosis, the endothelial cells lining the capillaries are also damage causing capillary fluid to leak into the air space resulting pulmonary oedema causing the lung to swell into a spongy wet mass with no gaseous exchange occurring having fatal effects

Question 8

What is the effect of a low exposure to chlorine gas?

Answer 8

This has irritant effects such as a sore throat and coughing, at low concentrations of gas these effects can limit exposure to the gas due to the constriction of the airways

Question 9

What is the effect of exposure to high concentrations of chlorine gas?

Answer 9

The corrosive effects of the gas become apparent, there is rapid breathing and wheezing along with an accumulation of fluid in the lungs, blue colouring of the skin and pain with exposure to very high levels resulting in lung collapse and death aswell as sever eye and skin burns

Question 10

What type of damage can oxidant gases cause to the lung?

Answer 10

These gases tend to damage both the bronchial epithelia and the alveolar cells in the central region of the lung rather than the periphery of the lung with the most vulnerable cells being ciliated bronchiolar cells and type 1 pneumocytes potentially due to the large surface area of these cells leading to higher exposure

Question 11

How does exposure to NO2 induce pulmonary injury?

Answer 11

NO2 initiates free radical generation in the bronchioles which causes protein oxidation and lipid peroxidation with cell membrane damage
Corrosive damage can occur as in the presence of water NO2 readily hydrolyses to NO, HNO3 and HNO2 (nitric and nitrous acid) which can have a direct toxic effect on type 1 pneumocytes and ciliated bronchiolar cells (type 2 pneumocytes, alveolar macrophages and endothelial cells appear to be resistant to this form of damage)
NO2 also alters the immune function of alveolar macrophages resulting in impaired resistance to infection

Question 12

What initially occurs following exposure to NO2?

Answer 12

The first changes will be observed in the ciliated bronchiolar regions with a loss of cilia followed by necrosis and sloughing of cells
Calar cells are more resistant but will lose their granular bodies within 24 hours of exposure
Type 1 pneumocytes swell and undergo necrosis so that the basement membrane is exposed
Cellular debris enters the alveolar space and interstitial oedema occurs

Question 13

What occurs a few days after exposure to NO2?

Answer 13

There is cellular hypertrophy and hyperplasia of the bronchial epithelium as the damaged bronchiolar cells regenerate forming both ciliated and clara cells, in the alveolar sacs the basement membrane is covered by regenerated but inappropriate epithelium due to proliferation of type 2 pneumocytes which are atypical due to their lack of lamellar bodies making them unable to produce surfactant
resulting in a thicker air-blood barrier comprised of atypical type 2 pneumocytes
the alveolar macrophages also proliferate possibly in a response to thecellualr debris, fibrblasts will also proliferate to cause fibrosis
this inappropriate repair can lead to adult respiratory distress syndrome

Question 14

What is adult respiratory distress syndrome?

Answer 14

This is a condition which affects 100,000 people each year with a high mortality of 17,000-43,000 deaths/year

Question 15

What occurs in the acute phase of adult respiratory distress syndrome?

Answer 15

This follows disruption of the epithelial barrier due to the destruction of alveolar pneumocytes where interstitial fluid escapes into the alveolar space causing oedema, inflammation and a fibrin rich exudate. The deposition of fibrin results in hyaline membrane formation with hyaline being a proteinaceous material comprised of degenerated cells/fibrin

Question 16

What occurs in the proliferative/organizing stage of adult respiratory distress syndrome?

Answer 16

If the acute phase is survived then over approximately 1 week atypical type 2 pneumocytes proliferate along with fibroblasts which lay down collagen in the interstitial spaces in the next 1 to 2 weeks worsening the interstitial thickening
Alveolar macrophages will digest hyaline membranes leading to about a month to extensive fibrosis with multiple cyst-like spaces throughout the lung which are sperated by fibrous tissue and lined with type 2 pneumocytes causing a honeycomb lung

Question 17

What are the clearance mechanisms for particles?

Answer 17

Nasal trapping of large particles of greater than 10micrometer in diameter and expulsion through sneezing
The ability of mucus to trap smaller particles of 2-10 micrometers in diameter these are then transported by the mucociliary escalator
The alveolar macrophages can pagocytose very small particles of less than 2 microns in diameter
The nose is more efficient than the mouth at removing particles from the air

Question 18

What type of damage can particles cause?

Answer 18

Soluble particles may dissolve in the fluid which lines the lungs and become irritants
Insoluble particles are largely phagocytosed however some may remaind free where they may physically damage epithelial cells leading to fibrosis
Inhaled particles may also enter the vascular or lymphatic system and be transported to other organs

Question 19

What are some examples of particles that can cause lung damage?

Answer 19

Asbestos, silica, wood and carbonaceous material

Question 20

What can cause the damage caused by a particle to vary?

Answer 20

The type of mineral particle, the size, shape, surface properties, durability of the particle and effects of cumulative exposure
Immunological processes can often be predisposing factors such as cytokine gene polymorphisms and the presence of rheumatoid disease

Question 21

Why is particle shape important to the type of damage induced?

Answer 21

Fibres and particles with an extreme shape are more likely to deposit in the airway walls while compact spheres are more likely to be deposited in the lung parenchyma along with fine particulate material, these may therefore be more harmful than the larger particles as they will be more efficiently retained in the peripheral lung tissue`

Question 22

What is fine particulate material and how is it implicated in lung diseases?

Answer 22

PM2.5 are found in the urban environment and can be a complex mixture of an inert carbonaceous core covered by multiple layers of adsorbed pollutant molecules including various metals, acid salts, organic pollutants, biological contaminants such as endotoxins, allergens and pollen fragments
The primary target of these molecules are pneumocytes and alveolar macrophages, after inhalation and deposition the majority of the absorbed pollutants are released into the surfactant allowing the particles to be cleared via the mucociliary escalator or phagocytosis, this can result In the production of free oxygen radicals and the release of cytokines damaging the surrounding tissues
They can directly damage the pneumocytes as they can adhere to the cells and become internalised, then they can perturb the cytoskeleton through associating with actin and tubulin, or they can cause ROS formation

Question 23

What is pneumoconiosis?

Answer 23

This is lung disease caused by the inhalation of particulate inorganic dust

Question 24

What damage can result from inhalation of crystalline dust?

Answer 24

This can cause fibrosis of the lung, small amounts of silica and asbestos can causes extensive fibrosis whereas coal and iron are less fibrogenic this can cause asthma, bronchitis, emphysema and neoplasia reactions in the lung

Question 25

What is silicosis?

Answer 25

This is pneumoconiosis caused by inhalation of dust with high levels of silica, crystalline silica is commonly found in sandstone, granite, slate, coal and pure silica sand resulting in this being an occupational hazard in mining processes, foundry workers, rock cutters, rock drillers and sand blasters

Question 26

What does the effect of silica depend on?

Answer 26

The dose and duration of exposure and the size of the particle and mineral form
High exposure leads to acute form of silicosis developing within 3 years of heavy exposure which is rapidly fatal
Chronic exposure to silica dust leads to a more classical nodular silicosis

Question 27

What are the symptoms of silicosis?

Answer 27

These develop over time and are a cough with or without sputum, shortness of breath particular on exertion, chest tightness and cyanosis the lung tissue becomes irreversibly damaged by fibrosis and is replaced with solid nodules of scar tissue resulting in the individual being susceptible to lung infections

Question 28

What is the mechanism of silicosis?

Answer 28

Exposure to particulate silica causes persistent inflammation due to the ingestion of silica by alveolar macrophages, the SiOH groups on the surface of the silica react with phospholipids and proteins to induce damage to macrophage membranes causing them to die and forming a constant ingestion/re-ingestion cycle with continuous macrophage recruitment and sustained and chronic release of oxidants in the alveolar space from both the surface of the particle and the macrophage attempting to digest the particle.
The inflammation affects both bronchiolar and alveolar epithelia
The mineral particles can also induce oxidative stress through inhibiting antioxidant regeneration as silica depletes antioxidants and inhibits enzymes like G6PD which affects the ability of the cell to regenerate GSH
Inflammatory mediators TNF and IL-1 promote fibroblast proliferation and collagen deposition resulting in the formation of dense collagen nodules this results in restrictive lung disease which progresses when multiple nodules coalesce to cause progressive massive fibrosis

Question 29

How can collagen nodules in silicosis be observed?

Answer 29

They are concentric layers of hyaline fibrous tissue ( a pink acellular proteinaceous material) with a peripheral zone of dust laden macrophages, fibroblasts and chronic inflammatory cells, the centre of this nodule may exhibit necrosis and calcification.
The necrosis may be a consequence of ischaemia from the nodules obliterating pulmonary arterioles and perivascular lymphatics

Question 30

What is the effect of smoking on silicosis?

Answer 30

This both aggravates the symptoms of the disease and speeds up its progression as the smoke impedes clearance of the particles through interfering with the mucociliary escalator

Question 31

What may influence the severity of the inflammatory response to silica?

Answer 31

This may relate to mutations in cytokine genes which can affect the number of cytokines produced, this is suggested as not all people develop the disease and there is evidence of increased incidence of IL-1 and TNF gene polymorphism in miners with silicosis compared to those with out the disease

Question 32

How can fibrotic damage to the lung occur as a response to therapeutic agents?

Answer 32

This can occur following systemic exposure, likely due to the metabolic activation of the drug by either the liver or clara cells. As the lung receives the entire cardiac output of the body and is an oxygen rich environment any drug capable of liberating ROS is likely to have a damaging effect this occurs most commonly in chemotherapeutic cytotoxic drugs which cause diffuse alveolar damage such as bleomycin, methotrexate, 5-FU, busulphan and cyclophosphamide.