Asthma and fibrosing diseases of the lung

Question 1

What are the main symptoms of asthma?

Answer 1

Bronchospasm is the main one, followed by wheezing, coughing, sputum (nasty mucus) and dyspnea (shortness of breath).

Question 2

What are the two different types of asthma?

Answer 2

There is extrinsic and instrinsic asthma.
Extrinsic asthma is initiated by external stimuli that enter the airways and induce a type 1 hypersensitivity reaction to the allergen.
Intrinsic asthma is due to internal factors that are not immune mediated. Triggers include cold weather, exercise, inhaled irritants and stress.

Question 3

What is the new definition of asthma that factors in both extrinsic and instrinsic asthma?

Answer 3

Asthma is now defined as bronchial hyperreactivity due to inflammation in response to diverse stimuli.

Question 4

What is atopic asthma?

Answer 4

Atopic asthma has systemic effects, even though the allergen is only in the airways of the lung.

Question 5

What are the contents of mast cells and how do they induce asthma?

Answer 5

Prostaglandins, leukotrienes and thromboxanes cause the vasodilation and constriction of the lung smooth muscle.
Histamine inside the mast cell granules causes vasodilation, chemokinesis and bronchoconstriction.

Question 6

How is an allergen detected within the lungs by the immune system?

Answer 6

The Bronchus associated lymphoid tissue becomes sensitised to the the allergen and its antigen presenting cells present it to the Th2 cells. This initiates the release of IgE from B cells and triggers mast cell degranulation. The degranulation of mast cells and the inflammation caused by the IgE antibody causes smooth muscle constriction in the bronchus causing asthma.

Question 7

What role do the chemical mediators that induce inflammation have on asthma onset?

Answer 7

The chemical mediators cause the tight junctions between the epithelial cells of the bronchus to open up. This gives the chemical mediators access to the submucosal mast cells, so they are activated. The mast cells increase vascular permeability, leading to oedema and mucous hypersecretion.

Question 8

What occurs during the last phase of asthma?

Answer 8

Asthma in its last phase involves the recruitment of eosinophils to the bronchus to help eliminate the allergen. A special protein called eosinophil cationic protein, is released to recruit the eosinophils and this results in the inflammation associated with asthma. Meanwhile a second enzyme is released called major basic protein and it damages the epithelial cells.

Question 9

What are the primary chemical mediators involved in asthma?

Answer 9

The primary mediators are the biogenic amines like histamine and adenosine. Then there are the protease enzymes and lastly the eosinophil and neutrophil chemotactic factors.

Question 10

what are the secondary chemical mediators involved in asthma?

Answer 10

The secondary mediators are the leukotrienes and prostalglandins, as well as the cytokines TNF-alpha and all the one billion interleukins 1-6.

Question 11

Of these mediators, which could be targeted therapeutically to prevent asthma?

Answer 11

Acetylcholine and leukotrienes are the only mediators that can be blocked using medicine.

Question 12

Explain type 1 asthma hypersensitivity caused by a genetic predisposition.

Answer 12

Basically, this is when an individual already has a genetic predisposition to activation of the Th2 pathway. So in the presence of an allergen, the immune response will always be a Th2 response. The Th2 pathway leads to the production of the IgE antibody, which causes inflammation too.

Question 13

How does asthma cause remodelling of the airways in the individual?

Answer 13

Constant damage to the epithelial cells by the major basic protein results in remodelling of the airways to protect and repair the epithelial cells.

Question 14

What is the ADAM-33 gene and what is the proposed relationship between it and asthma?

Answer 14

The ADAM-33 gene stands for ‘A Disintegrin And Metalloproteinase’. This gene has been linked to asthma as it is expressed by smooth muscle cells and fibroblasts of the lung. It is proposed that lung fibroblasts and smooth muscle cells proliferate too fast and this leads to polymorphisms in the ADAM-33 gene, which add to airway hyperactivity and remodelling.

Question 15

what is the relationship between mast cells and asthma with regards to airway remodelling?

Answer 15

The asthma results in over proliferation of mast cells and they accumulate in the bronchus of the lungs. They secrete lots of growth factors (platelet derived growth factor) and proteases, which increase smooth muscle proliferation. Too much proliferation may cause asthma remodelling.

Question 16

What is idiopathic pulmonary fibrosis?

Answer 16

It is the chronic, progressive, irreversible fibrosing disease of the lung with an unknown cause. It is usually lethal and takes place in older individuals, (66 is the average age of incidence). Cigarrette smoking and exposure to wood and metal dust are risk factors. The symptoms are cough and dyspnea (shortness of breath).

Question 17

What are the morphological changes that indicate the presence of idiopathic pulmonary fibrosis?

Answer 17

The lungs under low magnification has a heterogenous appearance with fibrosis and scarring. Gross honeycombing, when the lungs form a network of fibrous tissue within the lungs, and there are signs of fibrous retraction and airspace enlargement in the lungs.

Question 18

what is the Bleomycin hypothesis for the idiopathic pulmonary fibrosis?

Answer 18

Bleomycin is a cancer drug that when administered to mice induced IPF in them. Whilst the progressiveness of this disease is not exactly the same in mice as in humans, sheep models are underway too.

Question 19

what is the genetic hypothesis for the idiopathic pulmonary fibrosis onset?

Answer 19

There is evidence for familial IPF, because there seems to be a link between a short chromosomes and IPF onset. This is believed to have occurred from a mutation in the telomeric lengthening proteins produced by the TERT/TERC genes. Alternatively, a mutation in the MUC5B gene results in increased mucous and gel production in the lungs, which may be a trigger for IPF.

Question 20

What is the relationship between ER stress and idiopathic pulmonary fibrosis?

Answer 20

ER stress is when protein degradation is more than protein synthesis and this causes a stress gene to be expressed within the gene which issues a state of emergency. This gene is called the UPR gene and the theory is that when a cell is in a state of stress, the UPR causes the cell to undergo apoptosis or fibrosis.

Question 21

What is the role of transforming growth factor beta and IPF?

Answer 21

Transforming growth factor beta causes the epithelial cells of the lung to undergo epithelial-mesenchymal transition (EMT). EMT is when TGF-beta turns epithelial cells into mesenchymal cells that are temporary stem cells so that they can transform into other cell types. They could become fibroblasts that produce fibrin.

Question 22

What is the role of fibrocytes in IPF?

Answer 22

Fibrocytes are mobile fibroblasts that are recruited to the lungs to produce even more fibrin and add to the effect of IPF.

Question 23

What role do macrophages play in IPF?

Answer 23

The macrophages are the first immune cell to secrete transforming growth factor beta, that causes the EMT of epithelial cells in the lungs.