Pathophysiology of respiratory diseases Part 1 Flashcards
What is asthma?
Asthma is a chronic, inflammatory &
obstructive disease of the airways
What happens in asthma that causes inflammation leading to airway dysfunction?
- Starts of with allergen inhalation(HDM, pollen), exercise
- This leads to an immune response which leads to release of IgE antibodies, Mast cells, Eosinophil and TH2 cells which cause airway inflammation
- This results in impaired airway function which causes symptoms such as wheezing, coufh, dyspnoea and a reduction in FEV1/FVC
What happens in an asthmatic airway and what is the overall effect?
- contraction of smooth muscle, excess mucus secretion, oedema/swelling and irritation of sensory neurons
- The overall effect is decreased luminal area which results in an increase in airway resistance and decrease in airflow
What does allergen-induced degranulation do to the lumen of airways?
- Leads to contraction which that causes contracted, smaller smooth muscle cells and a decrease in lumen diameter
- This leads to decrease in luminal area which results in an increase in resistance and decrease in air flow
How does relaxation work in airways and using what?
- Bronchodilators such as beta 2 agonists reverse airway obstruction by causing ASMCs to relax
- This causes an increase in luminal area and hence a decrease in resistance and increase in airflow
What are the steps involved in inflammatory mediators inducing ASMC contraction?
- Contractile mediators such as cysLTs, ACh, PGs activate G protein coupled receptor like M3
- Gq triggers intracellular signalling pathways which act on sarcoplasmic reticulum
- Increases Ca2+ mobilisation and sensitivity leading to muscle contraction
What are the steps involved in beta-2 adrenergic receptor activation to induce relaxation of ASMC?
- Beta 2 agonist binds to beta-2 adrenoceptor which triggers Gs which activates adenylyl cyclase which converts ATP into cAMP that triggers protein kinase A
- This decreases Ca2+ mobilisation and sensitivity which results in muscle relaxation
What is the allergic response require prior-exposure and sensitization?
- Allergen sensitisation occurs by allergen exposure from HDM and pollen
- The allergen encountered is then processed by adaptive immune system
- This leads to antibodies being generated and the immune system is primed
- This leads to the allergic response
- In the allergic response, there’s the same allergen exposure
- This causes allergen to bind to antibodies formed in allergen sensitisation
6.Causes symptoms
What is the asthmatic response triggered by?
The asthmatic response is triggered by allergen-
induced degranulation and airway inflammation
What are the steps in the inflammatory response stimulated by allergens?
- Allergen is inhaled and enters airway tissue.
- Allergen binds IgE on mast cells, which induces degranulation with inflammatory mediators like PGs, LTs and chemokines being involved which recruits eosinophil
- Inhaled allergens also cause T helper-2 cell activation which activated Il-4,5 and 13 which recruits eosinophils to the airway and degranulate
- Inflammatory mediators from both mast cells and eosinophils will cause contraction of smooth muscle, excess mucus secretion and oedema/swelling
- This causes the lumen diameter to decrease which reduces luminal area and hence increases resistance and decrease airflow
What inflammatory cells do glucocorticoids act on for asthmatic inflammation and what does it do to them?
- Reduces number of Eosinophils by apoptosis
- Reduces cytokines which inhibit T-lymphocytes
- Reduce number of mast cells
- Reduce cytokines which inhibit macrophage
- Reduce number of dendritic cells
What structural cells do glucocorticoids act on for asthmatic inflammation and what does it do them?
- Acts on epithelial cells and reduces cytokines mediators
- Act on endothelial cells to reduce leaking of air
- Act on airway smooth muscle to increase beta 2 receptor activation
- Act on mucus gland to reduce mucus secretion
What are the steps involved in corticosteroid to mediate its effects?
- CS diffuses through membrane & binds
intracellular GR - Drug-receptor complex translocates to the nucleus
- Drug-receptor complex binds DNA affects transcription
- Altered transcription of gene
- Translation of gene into protein
- Corticosteroids increase or decrease
expression depending on the specific
gene/protein (e.g. ↑anti-inflammatory
genes, ↓pro-inflammatory genes)
