Pathophysiology of asthma Flashcards
Define asthma
chronic inflammatory condition categorised by episodes of reversible airflow limitation + bronchial hyperresponsiveness, where difficulty breathing (dyspnoea)
How can asthma be divided?
Inflammation
Airway dysfunction
How does the inflammatory response to asthma start?
hypersensitivity to stimulus (allergen - pollen, house dust mites)
Describe airway dysfunction of asthma
allergen-induced inflammation release mediators
affecting cellular function, produce limitations in tissue function (airflow) –> symptoms (dyspnoea, excess mucus, cough)
What happens to the airways during an asthma attack?
- inflammation –> pathological changes
- smooth muscle contraction + mucus hypersecretion
- reducing lumen size
- increases airway resistance + decreases airflow
What are the stages of allergic asthma?
Sensitisation
Allergic response
What’s sensitisation
immune system 1st encounters allergen + develops an
adaptive (antibody lymphocyte-mediated) immune response
What’s an allergic response
allergen re-encountered, triggering adaptive response generating inflammatory response within airways producing symptoms
Describe the process of sensitisation
-allergen enters airways
-stimulates epithelium releasing proinflammatory signals
-APCs (dendritic cells + macrophages) engulf + process allergen
-presents antigen to naïve (CD4+) Th
-activated, matured into Th2
-interacts w B cell, initiating class-switching,proliferation, production of IgE
-bind the antigen in allergen
-circulate, bind (via heavy chain/Fc region) to IgE
(FcεRI) receptors on mast cells
-light chain/Fab region still displayed for antigen binding
-Th2 cells secrete ‘Th2 cytokines’ : IL-4, IL-5, IL-13,
-modulates immune system
-IL-5 promotes survival, proliferation, trafficking (to airways) of eosinophils
How does Th mature into Th2?
depending on the cytokine environment- levels of inflammatory mediators (IL-4 +TNF-∝)
Define class-switching
class of Ig antibody the B cell produces
Role of mast cells?
immune cells has responses to parasitic helminths infections, contain granules containing pro-inflammatory mediators such as histamine, leukotrienes, prostaglandins
What are eosinophils + role?
polymorphonuclear granulocyte
parasite defence that’s heavily implicated in asthma
Describe allergic repsonse process
- re-exposure
- antigens recognised by IgE bound to mast cells within the airways
- multiple IgE molecules cross-linked by allergen
- triggers degranulation
- granulocyte releases contents of inflammatory mediators
- binds to receptors on multiple cell types in airway inducing pathological changes
- contraction of airway smooth muscle cells, microvascular leak (oedema), activation of goblet cells (mucus secretion)
- bronchospasm
- mediators also induce secondary proinflammatory changes
- Th2 + eosinophils activated
- triggering wave of inflammation as they migrate to airways + release further pro-inflammatory mediators
eg of inflammatory mediators in granulocytes?
prostaglandins, leukotrienes, cytokines
Immediate effect of pathological changes?
rapid bronchospasm =sharp decrease in airflow (due to airway resistance).
Why are anti-histamines ineffective in treating asthma?
histamine released from mast cells have small role in the pathophysiology of asthma
What do Th2 release?
IL-4, IL-5, IL-13,
What do eosinophils release?
reactive oxygen species, leukotrienes, toxic enzymes
Phases of airway dysfunction?
Early response (0-1 hrs) Late response
Describe early response of asthma attack
- (0-1 hrs) w acute bronchoconstriction by initial wave of degranulation,
- extended period (<12 hours)- symptoms improve before worsening
Describe late response of asthma attack
- secondary inflammation
- migration of Th2 + eosinophils to airways
What contributes to night-time asthma?
Early + late asthmatic responses
What’s night-time asthma?
worse symptoms at night, during sleep causing them to wake up
Define airway remodelling
long term irreversible reductions in airway function due to repeated waves of inflammation + tissue damage
What are the pathological changes of airway remodelling?
smooth muscle hypertrophy, increased secretion of highly-viscous mucus, goblet
cell hyperplasia, immune cell infiltration, disrupted epithelium (enabling greater infiltration of allergens), basement membrane thickening, fibrosis
What does Anti-IgE mAb (omalizumab) affect?
Antibody binds IgE
What does Corticosteroids (fluticasone) affect?
Airway inflammation
What does Leukotriene receptor antagonists (montelukast) affect?
Airway inflammation
What does IL-4, IL-5, IL-13 mAb affect?
Airway inflammation
What does β2 adrenergic receptor agonists (salbutamol) affect?
Airway smooth muscle contraction
What does Muscarinic receptor antagonists (tiotropium) affect?
Airway smooth muscle contraction
Mucus secretion
What does Corticosteroids affect?
Mucus secretion
Oedema
Why are specific treatments not always effective?
asthma is a complex + heterogeneous condition w multiple endotypes
