Asthma and Allergy Flashcards
What is the defining pathological feature of asthma?
Reversible bronchoconstriction
What are the 3 types of asthma?
Atopic or allergic asthma
Non-allergic asthma
Others
What is the difference between allergic and non-allergic asthma?
In allergic asthma, serum IgE is elevated and there are specific external triggers
In non-allergic asthma, serum IgE is normal and there are non-specific triggers
What is the basic pathological mechanism in atopic asthma?
Trigger stimulates mast cells via cross-linking of IgE
Mast cells release mediators (e.g. histamine)
Mediators cause acute increased vascular permeability, increased mucus production and bronchospasm
Mediators also lead to a late-phase response which includes chemotaxis of eosinophils, mast cells, lymphocytes and macrophages, contributing to ongoing inflammation and epithelial damage
What are some of the short term complications of asthma?
Death
Atelectasis (lung collapse or closure)
Spontaneous pneumothorax and/or pneumomediastinum
What is pneumothorax?
Abnormal collection of gas or air in the pleural space
What are some of the changes that occur in severe chronic asthma?
Airway remodelling with fibrosis and irreversible obstruction
Chronic hypoxia leading to pulmonary hypertension and cor pulmonale
What is status asthmaticus?
Acute severe asthma attack which does not respond to bronchodilators
What immediate changes occur on the cellular level following activation of the FcER1 receptor?
B and y chains of the FcER1 are phosphorylated via ITAMs (immunoreceptor tyrosine-based activation motifs)
When receptors are aggregated by cross-linking, they migrate via lipid rafts and recruit kinases to initiate an intracellular signalling cascade
Phospholipase C is phosphorylated and activated, resulting in production of DAG/IP3
DAG activates PKC and IP3 mobilises Ca2+ to produce degranulation of the mast cell
What is FcER1?
High-affinity IgE receptor present on mast cell membranes and responsible for allergen-induced mast cell degranulation
What is the immediate response of mast cells to stimulation?
Release of preformed mediators within 30-45 secs
Preformed mediators include histamine, heparin (anti-coagulant), tryptase (protease activator) and TNF-a
What is the delayed response of mast cells to stimulation?
Production and release of Cys-LTs and PGD2
Onset within 5-10 mins with a peak at 10-30 mins
What is the delayed and protracted response of mast cells to stimulation?
Transcription, translation and release of cytokines, including IL-4, IL-5 and GM-CSF, within hours
List 8 important actions of histamine, making note of what receptor is responsible for each
Pain and itch (H1)
Bronchospasm (H1)
Mucus secretion (via goblet cell activation; H1)
Vasodilation leading to hypotension and oedema (H1)
Increased vascular “leak” leading to hypovolaemia (H1)
Increased wakefulness in the CNS (H1)
Positive inotropic (force of contraction) and chronotropic (HR) actions (H2)
Gastric acid secretion (H2)
What activates 5-lipoxygenase in allergy?
Increased IC Ca2+
Which Cys-LTs are active at the CysLT1 receptor?
LTC4, LTD4, LTE4
What is the role LTB4 in asthma?
Promotes leukocyte chemotaxis
Montelukast
CysLT1 receptor antagonist used prophylactically
What is the role of Cys-LTs in asthma?
Potent bronchoconstrictors
Increased vascular “leak”, leading to oedema
List 3 endogenous inhibitors of mast cell activation
PGE2
Adrenaline
Cortisol
What is the role of annexin-1?
Resolves inflammation
Omalizumab
Monoclonal antibody to alpha chain of FcER1 used to inhibit mast cell activation in asthma
Why are NSAIDs and COX-2 selective inhibitors not used in the treatment of asthma?
Prostaglandins have a mixed role in asthma (beneficial and detrimental)
May provoke symptoms due to excess production of LTs
Zafirlukast
Orally active Cys-LTRA
What are Cys-LTRAs especially indicated for?
Aspirin- and exercise-induced asthma
Allergic rhinitis
What is the difference between the role of relievers and controllers in asthma vs. preventers?
Reliever and controllers only act on bronchoconstrction
Preventers also act on oedema and mucus hypersecretion
What changes do contractile agonists (e.g. histamine, Cys-LTs) produce to regulate smooth muscle tone in asthma?
Increased frequency of Ca2+ waves
Activation of Rho kinase and PKC
What histological changes occur in asthma?
Goblet cell metaplasia Subepithelial collagen thickening Infiltration of inflammatory cells Increased mucosal vascularity Increased smooth muscle volume
What are relievers?
SABAs (B2-selective) with an onset within minutes
Salbumatol
SABA
Terbutaline
SABA
Adverse effects of SABAs
Tachycardia
Tremor
Hypokalaemia
Limitation of SABAs
Tolerance; regular use may increase morbidity and mortality
What is the cellular mechanism by which SABAs counter contractile agonists in asthma?
Increase Ca2+ reuptake Activates PKA (which decreases Ca2+ waves and activates MLC phosphatase)
What are controllers?
LABAs with slow or rapid onset but long duration (12-24 hrs)
Salmeterol
LABA
How are LABAs administered?
Co-administered with GCS in a single actuator
Ipratropium bromide
Non-selective SAMA
Tiotropium bromide
Functionally M3-selective LAMA
How are muscarinic antagonists administered?
Co-administered with SABAs and LABAs
What is the result of transactivation by GCS?
Dimerised GCS receptor binds GCS response element (GRE) and stimulates transcription of B2-adrenoceptors, annexin-1 and serpin A3
What is serpin A3?
Inhibitor of serine proteases
What is the result of transrepression by GCS?
Monomer of GCS receptor complex binds pro-inflammatory TFs (e.g. NFkB, AP-1) and prevents transcription of pro-inflammatory cytokines, inducible enzymes and adhesion molecules
When are inhaled GCS indicated in asthma?
With B2 agonist use >3 times/week
Fluticasone proprionate
Inhaled GCS available in combination with LABA
Beclomethasone diproprionate
Inhaled GCS available in combination with LABA
When are systemic GCS indicated in asthma?
Acute exacerbations (for few days only) Chronic administration only in severe asthma
How is asthma treated based on severity?
Very mild: SABA as required
Mild: low dose inhaled GCS + SABA as required
Moderate: higher dose inhaled GCS + SABA as required
Severe: high dose inhaled GCS, SABA as required, LABA, oral GCS + muscarinic antagonist
