Asthma Flashcards
What causes airflow obstruction?
- acute bronchoconstriction (smooth muscle cell contraction) - Primary component of the early asthmatic response.
- airway oedema (swelling of airway submucosa constricting airways) - Occurs 6-24 hrs post-allergen - late phase asthmatic response.
- mucous plug formation (increased mucus secretion) - Early & late phase response (may take weeks to resolve)
- airway remodelling (smooth muscle proliferation & fibrosis) - Structural changes following chronic inflammation (irreversible)
What releases primary mediators in the early phase response?
Primary mediators are released by Activated Mast Cells in a process called Degranulation.
What primary mediators are released in the early phase response?
Histamine - Increased vascular permeability, smooth muscle contraction & ROS
Serotonin - Increased vascular permeability, smooth muscle contraction
Proteases - Mucus secretion
ECF-A - Eosinophil chemotaxis
NCF-A - Neutrophil chemotaxis
What causes a type 1 hypersensitivity response in asthma?
Leakage of epithelial barrier (due to initial mediator release triggering tight junction opening) allows allergen to enter mucosa triggering more mast cells and eosinophils via IgE
Re-exposure to allergen causes cross linking of IgE
on mast cells, eosinophils & basophils by allergens in & around the airways
What releases secondary mediators in the late phase response?
Secondary mediators are released by activated Mast Cells, recruited inflammatory cells & structural cells
Secondary mediators must be synthesised prior to release
What secondary mediators are released in late phase asthma?
Leukotrienes - Increased vascular permeability, smooth muscle contraction, mucus secretion
Prostaglandins - Smooth muscle contraction, Vasodilation, Potentiates vascular permeability
Bradykinin - Increased vascular permeability, smooth muscle contraction
Cytokines - Inflammatory cells activation
Chemokines - Cell recruitment (eosinophils, neutrophils, basophils, lymphocytes, APCs)
- Note: Eosinophil release of Major Basic Protein & Eosinophil cationic protein causes epithelial damage
What immunoglobulin is present in atopic individuals?
IgE
present in very low levels in normal individuals
IgE binds to what receptors on mast cells?
FcEpsilon-RI
What happens when IgE binds to mast cells?
Mast cells degranulate and releases contents (e.g. Histamine)
What is the half life of IgE?
Unbound IgE: Half life in serum ~2-3 days Bound IgE (to Fc-RI): Half life in serum ~3 weeks
Where are FcEpsilon-RI receptors found?
The high affinity Fc epsilonRI receptors are found on mast cells and activated basophils & eosinophils
Describe the features of atophy
Atopic individuals have high levels circulating of IgE & Eosinophils
Genetic variables contibute to Atopy & IgE-mediated immunity
Hypersensitivity skin reaction to test for Atopy:
- (early response = wheal and flare; pink raised area within 20min)
- (late response = hard barely pigmented nodule after several hours)
What is the major inflammatory transcription factor?
NF-kB
What factors are involved in airway remodelling?
Increased Vascular Permeability Increased Epithelial cell damage/loss Goblet cell hypertrophy Smooth muscle cell hypertrophy Myofibroblast accumulation (Basement Membrane thickening)
What is the Holgate Hypothesis?
Repeated injury to airway epithelium drives disordered epithelial function with impaired anti-oxidant status leading to further episodes of inflammation within an epithelial-mesanchymal trophic (EMT) unit resulting over time in increased asthma severity & airway remodelling.
