Asthma Flashcards
How does inflammation cause airway dysfunction? (briefly)
→ Allergen inhalation → Immune system response → Airway inflammation → Impaired airway function → Wheezing, coughing, dyspnoea
What lifestyle factors make it more likely to get asthma?
→ Urban dwelling
→ Pollution
→poor diet
→ obesity
What is Ohms law?
→ Airflow is proportional to 1/resistance
What does the Hagen-Poiseuille law state?
→ As an airways radius decreases the resistance increases and airflow decreases dramatically
What determines the radius of the lumen?
→ The level of contraction of smooth muscle
What factors decrease the radius of the lumen even further?
→ Hypersecretion of mucus
→ Swelling
What is wheezing caused by?
→ Turbulent airflow
→ Increases resistance and decreases airflow
What is the first stage in the allergic response?
→sensitization
→ person breathes in allergen
→ Gets stuck in the airways
→ APC recognizes allergen as being harmful
→ Processes antigen to a helper T cell
→T cells mature and become TH2 cells
→ TH2 cells secrete cytokines like IL5
→ IL4 interacts with B cells and stimulates them
→ B cells proliferate and produce IgE antibodies
→ Antibodies bind to mast cells
What is the second stage in the allergic response?
→ Exposure → Allergen binds to antibodies → Mast cells degranulate →Prostaglandins, LTs and chemokines are secreted → Mediators bind to receptors →cause smooth muscle to contract → Mediators attract TH2 and eosinophils → Eosinophils migrate to airways and release reactive O2 species → Second round of inflammation occurs
What is the early phase of the asthmatic response?
→ Initial degranulation of mast cells
→ After the first response the mediators are cleared and effects resolve themselves
What is the secondary phase of the asthmatic response?
→ Eosinophils and T cells being recruited several hours later
What are the changes in respiratory function observed in asthma?
→ FEV1 decreases
→ FVC is unchanged
→ FEV/FVC decreases <70%
What are the long term changes caused by uncontrolled asthma?
→ Smooth muscle is being constantly worked → Hypertrophy of smooth muscle → More muscle takes up more space and contracts harder → More goblet cells and mucus glands → Infiltration of immune cells → Epithelium Distruption → Basement Membrane thickening → ECM deposition and Fibrosis
What are the most effective treatments for asthma?
→ Beta 2 agonists and corticosteroids
What happens during sensitisation?
→the allergen is inhaled and enters the airway tissue
→stimulates parts of the innate immune system, such as the epithelium
→allergen is them encountered by antigen presenting cells (APCs), such as dendritic cells and macrophages
How is class switching initiated?
→The activated Th2 cell then interacts with a B cell to initiate class-switching
What do the released IgE do?
circulate and bind (via their heavy chain/Fc region) to IgE (FcεRI) receptors on granulocytes such as mast cells
What does IL-5 particularly do?
promotes survival, proliferation and trafficking (e.g. to the airways) of eosinophil
What is the result of inflammatory responses?
rapid bronchospasm and a sharp decrease in airflow
What role does histamine play in asthma?
→histamine release from mast cells appears to play a very limited role in the pathophysiology of asthma
What do eosinophils release?
reactive oxygen species, leukotrienes and proteolytic enzymes
What is hyper-responsiveness?
a period where the threshold of allergen exposure required to elicit further asthma attacks is greatly reduced
What is airway remodelling?
→the inflammation triggered within the airway can result in tissue injury as the noxious mediators released from immune cells cause cellular damage.
→the cycles of tissue injury and repair can lead to irreversible structural changes
(↑obstruction, ↓FEV1, respiratory failure
What are some structural changes that can occur due to repeated asthma cycles?
fibrosis, smooth muscle hypertrophy, goblet cell hyperplasia, epithelium disruption
How does activation of epithelial generate local inflammation?
the release of alarmins, epithelial-derived mediators (TSLP, IL-25, IL-33) that prime antigen presenting cells and trigger downstream inflammatory responses.
What are type-2 innate lymphoid cells?
→ILC2s are similar to Th2 cells (in terms of their role in releasing cytokines
→but lack lymphocyte surface markers and antigen-specific receptors
How are ILC2s activated?
activated by alarmins, triggering release of the type 2 cytokines IL-5 and IL-13.
How do beta agonists work?
activation (agonism) of beta-2 adrenergic receptors present in the membrane of airway smooth muscle cells
→induces a signalling cascade that increases production of cAMP
→ activation of protein kinase A, which reduces Ca2+ mobilisation, inducing relaxation
What are short acting beta-2 agonists?
such as salbutamol are the first-line therapy in asthma and are administered when required as reliever therapy
What are long-acting beta-2 agonists?
such as salmeterol or formoterol are used as an add-on, preventer treatment, in combination with inhaled corticosteroids
→because there is evidence that the use of LABAs without corticosteroids increases the risk of sudden death
What are long acting muscarinic receptor antagonists?
→bronchodilators
→widely used to treat chronic bronchitis in COPD patients,
→dosed on a daily, continual basis via metered-dose inhalers
How do LAMAs work?
involves blocking acetylcholine receptors present on ASM cells.
→blockade of this receptor reduces the level of contraction
→may also provide benefit in patients with obstructive airway diseases by reducing mucus secretion and inhibiting cough
Examples of corticosteroids?
fluticasone, beclometasone, and budesonide
How is corticosteroid helpful?
Reduction in inflammatory cells and their numbers:
cytokines, mast cells, dendritic cells
Structural cells:
→endothelial cell leak
→increased beta-2 receptors
reduced mucus secretion
How do corticosteroids achieve their anti-inflammatory effect?
by binding to glucocorticoid receptors present within the cytosol of immune and structural cells
→ bound drug-receptor complex then migrates to the nucleus of the cell where it binds to DNA, modulating transcription, translation, and protein expression
How do leukotriene antagonists like montelukast work?
Competitive antagonism (blockade) of leukotriene receptors, by which pro-inflammatory LT mediators act.
