Pathophysiology of respiratory diseases 1 Flashcards
What is asthma?
A chronic, inflammatory and obstructive disease of the airways
What are 2 subsets of asthma brought on by allergies?
Th2 mediated asthma
IgE mediated asthma
Describe the process of inflammation and airway dysfunction as a result of asthma
Inflammation:
- Allergen inhalation (HDM, pollen), exercise
- This induces an immune system response, leading to inflammation of the airways
Airway dysfunction:
- Inflammation of the airways leads to impaired airway function
- This causes symptoms such as wheezing, coughing, dyspnoea and decreased FEV1/FVC
What happens during airway inflammation in an asthma attack?
Airway inflammation increases airway resistance and decreases airflow.
During an asthma attack, inflammatory mediators induce:
- Contraction of smooth muscle
- Excess mucus secretion
- Oedema/swelling
- Irritation of sensory neurones (cough)
Overall, this leads to a decrease luminal area, resulting in increased airway resistance and decreased airflow, resulting in symptoms
What can occur as an effect of frequent or severe asthma attacks?
Inflammation triggered within the airway can result in tissue injury as the noxious mediators released from immune cells cause cellular damage.
If this process is repeated frequently, or occurs severely enough, the cycles of tissue injury and repair can have irreversible changes (e.g. fibrosis, smooth muscle hypertrophy, goblet cell hyperplasia, epithelium disruption)- This process is ‘airway remodelling’
Airway remodelling involves progressive and irreversible decline in airway + respiratory function, occurs in patients with severe, poorly managed asthma, patients asthma not adequately managed with drugs such as corticosteroids
What does the contraction of airway smooth muscle cells lead to?
Airway obstruction and increased airway resistance.
Allergen-induced degranulation induces smooth muscle contraction, decreasing the lumen diameter, resulting in decreased luminal area and airflow, and increased airway resistance.
Describe allergen sensitisation and allergic response
Allergen sensitsation:
- Allergin exposure (HDM, pollen etc.)
- Allergen encountered and processed by adaptive immune system. Allergic sensitisation involves presentation of antigens to T cells, which then act to stimulate antigen-specific IgE production by B cells. IgE binding to FceRI then ‘primes’ mast cells for degranulation
- Antibodies generated, so the immune system is ‘primed’
Allergic response:
- The priming of the immune system prepares the body for exposure to the same allergen again
- When this happens, the allergen binds to antibodies, further inducing immune cell activation, and an inflammatory response
- These responses leads to symptoms
Describe in detail the mechanism of allergen sensitisation
- Allergen inhaled and enters the airway tissue. This on its own often stimulates part of the innate immune system, e.g. epithelium, inducing it to release pro-inflammatory signals.
- The allergen is then encountered by APCs, such as dendritic cells and macrophages.
- After these engulf and process the allergen, a fragment of the allergen (antigen) is displayed externally, so that when an APC encounters a naive Th cell with an appropriate T cell receptor, the antigen will be presented to T cell, activating it, allowing it to mature and become a Th2 cell, depending on the cytokine environment (the relative levels of inflammatory mediators such as IL-4 and TNF alpha)
- The activated Th2 cell then interacts with a B cell to initiate class-switching, proliferation, and production of IgE antibodies that bind the antigen present in the original allergen.
- The IgE antibodies produced then circulate and bind (via their heavy chain/Fc region) to IgE (FceRI) receptors on granulocytes such as mast cells. When IgE is bound to its receptor in this way, the light chain/Fab region is still displayed, enabling antigen binding
- The Th2 cells also secrete Th2 cytokines, such as IL-4, IL-5 and IL-13, which act to modulate the immune system. IL-5 in particular promotes survival, proliferation and trafficking (e.g. to the airways) of eosinophils
How does the asthmatic immune system respond to allergens?
The antigens within the allergen are recognise by IgE molecules bound to mast cells within the airways. Multiple IgE molecules are cross-linked by the allergen (if the allergen is an epitope, so has multiple antibody binding sites), triggering degranulation, so that the granulocyte releases its contents of inflammatory mediators (e.g. prostaglandins, leukotrienes, cytokines)
These mediators then bind to receptors on multiple cells types within the airway that induce pathological changes (e.g. contraction of SM, oedema, mucus secretion by goblet cells, eosinophil activation)
The immediate effect of this process is rapid bronchospasm + a sharp decrease in airflow
The presence of an allergen in airways also induced further Th2 activation, inducing secondary pro-inflammatory changes hrs later, as Th2 cytokine release induces eosinophils, where they become activated and release further pro-inflammatory mediators. Th2 cells release IL-4, IL-5 and IL-13, eosinophils release reactive oxygen species, leukotrienes and proteolytic enzymes.
Net effects of this can be second decrease in airway function, period of airway hyper-responsiveness (period where threshold of allergen exposure required to elicit further asthma attacks is greatly reduced
What do allergic responses require?
Prior-exposure and sensitisation
How do inflammatory mediators induce ASMC (airway smooth muscle cell) contraction?
- Contractile mediators such as cysLTs, Ach, PGs bind to G protein-coupled receptors such as M3 (Gq)
- This induces the G protein to send intracellular signals
- These signals lead to the opening of the ligand gated channels on the sarcoplasmic reticulum, resulting in the release of Ca2+
- This increases Ca2+ mobility, and it therefore binds to calmodulin, forming the Ca2+/Calmodulin complex, which activates MLCK, which will then induce contraction
How does beta 2 adrenergic receptor activation induce ASMC relaxation?
Via AC & PKA
Beta 2 agonists (such as salbutamol) bind to beta 2 adrenoceptors, stimulating the Gs pathway.
The Gs pathway increases the activity of adenyl cyclase, increasing the conversion of ATP to cAMP.
Increasing levels of cAMP leads to increased activity of protein kinase A. This decreases calcium mobilisation and sensitivity, therefore inducing muscle relaxation
How do corticosteroid drug reduce asthma inflammation?
They modulate the function of multiple immune and structural cells
They reduce activity, proliferation and cytokine production by various leukocytes and structural cells:
- They decrease T-lymphocyte induced eosinophil activation, and the activation of mast cells, macrophages, dendritic cells as well as cytokines
- They decrease cytokine production of epithelial cells, they decrease microvascular leakage of endothelial cells, they increase activation of B2 receptors, and they decrease mucus gland secretion
How do long acting muscarinic receptor antagonists (LAMAs such as tiotropium) acts as bronchodilators?
Block Ach receptors on airway SM cells. Ach induces bronchoconstriction when it binds to M3 receptors on airway ASMCs. Blocking this receptor reduces the level of contraction in situations where Ach plays a prominent role in inducing ASMC contraction.
This is the reason why they’re less effective as bronchodilators in asthma therapy, where Ach typically has a more minor role in ASMC contraction.
LAMAs also reduce mucus secretion and inhibiting coughing.
Describe the mechanism of action of corticosteroids
- Corticosteroids diffuse through the membrane and bind to intracellular glucocorticoid receptors
- The drug-receptor complex translocates to the nucleus
- The drug-receptor complex binds to DNA, altering transcription, leading to altered transcription of gene
- Corticosteroids increase or decrease expression depending on the specific gene/protein (e.g. It can increase the activity of anti-inflammatory genes, or can decrease the activity of pro-inflammatory genes)
- The gene is then translated into protein
