Pathophysiology of resp disease p1 Flashcards
What is asthma
Chronic inflammatory condition, categorised by episodes of reversible airflow limitation and bronchial hyperresponsiveness, difficulty of breathing
Describe the two components of pathophysiology of asthma
Inflammatory component -> Hypersensitivity to a specific stimulus (E.g. pollen), causing response upon exposure to stimuli
Airway component -> Allergen-induced inflammation releases mediators that affect cellular function, produce limitations in tissue function, resulting in dyspnoea, excess mucus and cough for example
What is pathophysiology
Physiological mechanism by which pathology is produced
Airway smooth muscle conrtaction and mucus hypersecretion cause the lumen to
Reduce in size, increasing airway resistance and decreasing airflow.
Describe the two stages of allergic asthma
Sensitisation - Immune system first encounters the allergen, and develops an adaptive immune response
Allergic response - Where allergen is re-encountered, the adaptive response is triggered, generating response in airways, producing symptoms.
Why is the immune response bad
Produces limitations on breathing for the individual, due to reduced lumen size.
In sensitisation, what happens when the allergen is initially inhaled
The allergen enters the airway, stimulating the immune system, and releasing pro-inflammatory signals. APCs encounter the allergen and engulf and process the allergen, to leave the antigen behind. APCs can present the antigen to naive helper T cells, which can mature to a T2 cell.
What happens following the activation of a T2 cell
Interacts with s B cell to initiate class-switching, proliferation and production of IgE antibodies. These antibodies circulate and bind to IgE receptors on granulocytes. The granulocytes contain histamine, leukotrienes and prostaglandins.
What is a naive helper T cell
Lymphocyte that acts to regulate immune response
How do IgE antibodies bind to IgE receptors and where are the receptors located
Bind via heavy chain region
Receptors located on granulocytes such as mast cells
What are mast cells
Immune cells involved responses to parasitic helminth infections, which contain pro-inflammatory mediators
Which cytokines to T2 cells secrete and what do they do
IL-4, IL-5, and IL-13, which modulate the immune system.
IL-5 promotes survival, proliferation and trafficking of eosinophils (big role in parasite defence)
What is degranulation
Granulocyte releases its contents of inflammatory mediators
Describe the changes in the airway that occur in the asthmatic immune response
IgE molecules cross-linked by allergen.
Degranulation occurs, mediators bind to receptors on cells in the airway -> Changes include contraction of airway smooth muscle cells, microvascular leak, stimulation of goblet cells and activation of eosinophil granulocytes.
This causes bronchospasm and a decrease in airflow
Why are antihistamines ineffective for treating asthma despite the involvement of allergen
Histamine release has a very limited role in the pathophysiology of asthma
A later response of the presence of the allergen would be
T2 cell activation, inducing secondary pro-inflammatory changes hours after. Cytokine release.
Net effect - Decrease in airway function and period of airway hyper-responsiveness
Eosinophils release
Reactive oxygen species, leukotrienes and proteolytic enzymes
The long term pathology of asthma leads to
Long-term cycles of tissue injury and repair leads to irreversible structural changes -> Smooth muscle hypertrophy, goblet cell hyperplasia, epithelium disruption
What is airway remodelling
Progressive and irreversible decline in airway and respiratory function
How do epithelial cells display a sentinel function
Capable of detecting specific molecular patterns on microbial/non-microbial allergens via pattern recognition receptors
When epithelial cells are activated, inflammation occurs and release of alarmins.
What are alarmins
Epithelial-derived mediators which prime antigen presenting cells, trigger downstream inflammatory responses
What are type-2 innate lymphoid cells
ILC2s release cytokines and coordinate inflammatory response, but have no lymphocyte surface markers and antigen-specific receptors. They are important in the pathophysiology of asthma
How do bronchodilator drugs work
Bind to specific receptor or enzyme expressed by airway smooth muscle cell, induces intracellular change to cause relaxation.
How do beta-2 agonists treat asthma
Activation of beta-2 adrenergic receptors in the membrane of ASM cells. Signalling cascade that increases production of cAMP, and activation of protein kinase A, which reduces Ca2+ mobilisation and sensitivity. Relaxation occurs
What is the difference between SABAs and LABAs
SABA - e.g. salbutamol, administered as reliever therapy (e.g. asthma attack)
LABA - e.g. salmeterol, administered as an add-on/preventative treatment with corticosteroids in inhalers.
What are long-acting muscarinic receptor antagonists
E.g. tiotropium -> LAMAs are used as preventer therapy in asthma. Blocks acetylcholine receptors on ASM cells. Reduces level of contraction.
LAMAs also reduce mucus secretion and inhibit coughs.
When treating airway inflammation, the efficacy of a treatment will depend
On its individual mechanism of action. - e.g. monoclonal antibodies targeting IgE will only be effective if IgE plays a prominent role in the patient’s pathology
What is a corticosteroid
Most effective and widely used drug for reducing allergic inflammation in asthma e.g. fluticasone, budesonide.
Administered by inhaler. Bind to glucocorticoid receptors within cytosol of immune + structural cells.
Drug-receptor complex is lipid soluble, moves to nucleus of the cell, binding to DNA and modulating transcription, translation and protein expression. Decreases pro-inflammatory mediator and increases anti-inflammatory mediator expression.
