Pathophysiology of Respiratory Diseases Flashcards
What is asthma?
Asthma is a chronic, inflammatory and obstructive disease of the airways
Typically categorised by episodes of reversible airflow limitation and bronchial hyperresponsiveness, where the patient experiences dyspnoea
The basic pathophysiology can be divided into two related components:
1. An inflammatory/immune system component, in which the individual develops a hypersensitivity to a specific stimulus (typically an allergen such as pollen) causing an inflammatory response upon subsequent exposure to that stimulus
2. An airway component, where the allergen-induced inflammation release mediators that affect cellular function, produce limitation in tissue function (i.e. airflow), resulting in the generation of symptoms (dyspnoea, excess mucus and cough)
How does asthma affect the airways?
Airway inflammation increases airway resistance and decreases airflow
During an asthma attack, inflammation of the airways generates pathological changes (primarily airway smooth muscle contraction and mucus hypersecretion) which reduce the size of the airway lumen and therefore increases airway resistance and decrease airflow
In the majority of asthma patients, these changes are reversible when the inflammation subsides or a bronchodilator drug is administered, the pathology subsides and airway resistance returns to normal- in contrast to the irreversible, progressive decline in airway function seen in COPD patients
How do inflammatory mediators induce ASMC contraction?
Contraction of smooth muscle cells is dependent on Ca2+-dependent processes
Therefore increasing contractile tone generally involves calcium mobilisation, or increasing the contractile machinery’s calcium sensitivity
A number of effective therapies exist for reversing bronchospasm caused by acute contraction of airway smooth muscle cells
Bronchodilator drugs act by binding to a specific receptor or enzyme expressed by the ASM cell and inducing a intracellular change which interrupts the contractile process
How does beta-2 adrenergic receptor activation induce ASMC relaxation?
Beta-2 adrenergic receptor activation induces ASMC relaxation via AC and PKA
The drugs most commonly used in asthma for this purpose are beta-2 adrenergic receptor agonists
The mechanism of action of these drugs unsurprisingly involves activation (agonism) of beta-2 adrenergic receptors present in the membrane of ASM cells
This induces a signalling cascade that increases production of cAMP and activation of protein kinase A, which reduces Ca2+ mobilisation and sensitivity, inducing relaxation
Different classes of beta-2 agonists exist, which are differentiated by their duration of action:
Short acting beta-2 agonists (SABAs) such as salbutamol are the first-line therapy in asthma and are administered when required are reliever therapy by metered-dose inhaler
Long acting beta-2 agonists (LABAs) 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) in metered-dose inhalers, with twice daily, continual dosing
How can muscarinic agonists help those with respiratory problems?
Long-acting muscarinic receptor agonists A second class of bronchodilator drug are long-acting muscarinic antagonists, such as tiotropium LAMAs are widely used to treat chronic bronchitis in COPD patients, and as an add-on, preventor therapy in asthma; daily continual basis via metered dose inhaler
What two stages do allergies involve?
Allergic responses require prior exposure and sensitisation
Like all allergies, allergic asthma involves two stages:
1. Sensitisation- where the immune system first encounters the allergen and develops an adaptive (antibody- and lymphocyte-mediated) immune response
2. The allergic response- where the allergen is subsequently re-encountered, triggering the adaptive response previous primed during sensitisation.
This generates an inflammatory response within the airways, producing symptoms
What happens during the sensitisation stage of allergic asthma?
The asthmatic response is triggered by allergen-induced degranulation and airway inflammation
Sensitisation:
1. During sensitisation, the allergen is inhaled and enters the airway tissue
This by itself often stimulates parts of the innate immune system, such as the epithelium, to release pro-inflammatory signals
2. The allergen is then encountered by antigen presenting cells (APCs), such as dendritic cells and macrophages, which patrol tissues searching for foreign particles to present to the adaptive immune system
3. After engulfing and processing the allergen, a fragment of the allergen (an antigen) is displayed externally so that when the APC encounters a naive helper T cell with an appropriate T cell receptor, the antigen will be presented to the T cell, activating it an enabling it to mature into a Th2 cell, depending on the cytokine environment
4. 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
5. The IgE antibodies produced then circulate and bind to IgE receptors on granulocytes such as mast cells
6. When IgE is bound to its receptor in this way, the light chain/Fab region is still displayed, enabling antigen binding
7. During sensitisation, Th2 cells will 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 of eosinophils.
What happens in the re-exposure stage (allergic response) of allergic asthma?
- Upon subsequent re-exposures, the antigens within the allergen are recognised by IgE molecules bound to mast cells within the airways
- Multiple IgE molecules are cross-linked by the allergen, triggering degranulation, where the granulocyte releases its contents of the inflammatory mediators
- These mediators (e.g. prostaglandins, cytokines) then bind to receptors present on multiple cell types within the airway that induce pathological changes, such as contraction of airway smooth muscle cells, microvascular leak (oedema), stimulation of goblet cells (mucus secretion) and activation of eosinophils, another granulocyte within the airways, triggering further release of inflammatory mediators
- The immediate effect of this process is rapid bronchospasm and a sharp decrease in airflow (due to increased airway resistance)
- At the same time as activating mast cell degranulation, the presence of allergen within the airways also induces further activation of Th2 cells, which often induces eosinophils trafficking the airways, where they become activated and release further pro-inflammatory mediators
- Th2 cells release Il-4,5 and 13, eosinophils release reactive oxygen species, leukotrienes and proteolytic enzymes
- The net effects of this can be a second decrease in airway function and a period of airway hyper-responsiveness ( a period where the threshold of allergen exposure required to elicit further asthma attacks is greatly reduced)
How do corticosteroids reduce asthmatic inflammation?
Corticosteroid drugs reduce asthmatic inflammation by modulating the function of multiple immune and structural cells
Corticosteroids (e.g. fluticasone, beclomethasone and budesonide) are the most effective and widely used drug for reducing allergic inflammation in asthma
In the first instance, drugs such as fluticasone and budesonide are administered by metered-dose inhaler in order to maximise the relative exposure of the drug to respiratory tissue vs. the systemic circulation
Corticosteroids achieve their anti-inflammatory effect by binding to glucocorticoid receptors present within the cytosol of immune and structural cells
The bounds drug-receptor complex then migrates to the nucleus of the cell where it binds to DNA, modulating transcription, translation and protein expression
By acting in this way, corticosteroids are able to decrease pro-inflammatory mediator and increase anti-inflammatory mediator expression in a wide variety of cell types, therefore shifting the balance and reducing the overall level of inflammation
What is Chronic oBstructive Pulmonary Disease?
COPD- an umbrella term used for a mixture of chronic bronchitis and emphysema, and encompasses a long-term, progressive and accelerated decline in respiratory function
90% of COPD cases are associated with long term, repeated respiratory exposure to tobacco (or other plants) smoke, as occurs in individuals that smoke for a prolonged period of time
The remaining cases are due to exposure to pollution or genetic disorders such as alpha-1-antitrypsin deficiency
Only around 30% of long term smokers develop COPD so genetic and environmental factors influence vulnerability
How does smoking reduce respiratory function and lead to COPD?
Long term respiratory exposure to tobacco smoke is dangerous as the smoke contains many harmful chemicals which cause acute damage to respiratory tissue, generating an inflammatory response
Immune cells such as neutrophils and macrophages are attracted to tissues damaged by tobacco smoke due to acute local inflammation caused by the chemicals in tobacco smoke
When immune cells infiltrate the affected areas, they attempt to resolve the inflammation and repair damaged tissue
However, these mechanisms become pathological with chronic smoke exposure, due to the constant cycles of damage and incomplete or faulty tissue repair and because the balance between proteases is disrupted
Furthermore, the damage to airway tissue also impairs host defence against invading organisms as mucociliary clearance is impaired due to increased mucus secretion and damage to cilia
Pathological changes within the airways generate the symptoms associated with chronic bronchitis, whereas pathological changes within the lung tissue and alveoli are reflected in emphysema
What pathological features are observed within the airways of COPD patients? (Chronic bronchitis)
Chronic bronchitis:
Long term inflammation of the bronchi is characterised by chronic and excessive sputum production, coughing and airway obstruction
The coughing and mucus production is a consequence of inflammation within the airway tissue, activating sensory neurons and stimulating mucus glands
Similar to asthma, chronic bronchitis involves impaired airflow through the airways due to reduced airway lumen radius and increased airway resistance
However whilst these changes are typically reversible in asthma, the changes in chronic bronchitis are generally progressive and irreversible
In chronic bronchitis airway lumen size is reduced by excessive mucus secretion, tissue swelling and degradation of the overall airway structure, rather than being caused by airway smooth muscle contraction so therefore beta-2 bronchodilators don’t work
Impaired mucociliary clearance= increased risk on infection= recurrent infection
Irritation of sensory neurons= cough
Decreased luminal area= increased airway resistance and airway obstruction
What pathological features are observed within the airways of COPD patients? (Emphysema)
Emphysema
The term emphysema describes pathological enlargement of alveolar airspaces due to destruction and degradation of lung tissue
This results in loss of structural fibres such as elastin (increasing compliance) as well as reduced surface area and damage to the pulmonary vasculature (decreasing gas exchange)
What are the effects of chronic respiratory failure on the body? (Summarise)
The net effect of these two conditions is that ventilation and gas exchange become severely reduced, resulting in respiratory failure and the symptoms of COPD in patients
Respiratory function declines in a progressive and irreversible manner, resulting in gradually increasing disability due to hypoxaemia and acidosis
Furthermore, patients experience acute exacerbations characterised by a temporary (several days) but drastic decline in symptoms and respiratory function caused by acute inflammation brough about by infection
Whilst exacerbations do resolve, patients with existing severe COPD are at acute risk of death, and lung function often fails to completely return to previous levels, further hastening long term respiratory decline
Respiratory failure also burdens the cardiovascular system (pathology known as pulmonary heart disease)
Chronic hypoventilation of alveoli results in prolonged and widespread hypoxic vasoconstriction.
Constriction of the pulmonary vasculature increases vascular resistance, in turn increasing the force required to pump blood through the system and the pressure of blood within it (pulmonary hypertension).
This requires the heart to work harder to maintain normal blood flow against increased resistance, resulting in right ventricular hypertrophy and worsening efficiency
Eventually the heart becomes unable to cope with the increasing demands placed upon in resulting in heart failure, increased venous pressure and right ventricular afterload
Also increases risk of cardiovascular events such as myocardial infarction
What is pneumonia?
Pneumonia- infection of the lung parenchyma, resulting in inflammation and oedema
Pneumonia is classified into different types based on the infectious agent (bacterial, viral, fungal), tissue effects (lobar) and where the infection was acquired (community vs. hospital)
Here we are referring to pneumonia in general, as a potential cause of pulmonary oedema and acute lung injury/hyaline membrane formation
