Asthma Flashcards
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Activation of beta-adrenergic receptors leads to relaxation of smooth muscle in the lung, and dilation and opening of the airways.
Beta-adrenergic receptors are coupled to a stimulatory G protein ofadenylyl cyclase. This enzyme produces the second messenger cyclic adenosine monophosphate (cAMP). In the lung, cAMP decreases calcium concentrations within cells and activates protein kinase A. Both of these changes inactivate myosin light chain kinase and activate myosin light chain phosphatase. In addition, beta-2 agonists open large conductance calcium-activated potassium channels and thereby tend to hyperpolarize airway smooth muscle cells. The combination of decreased intracellular calcium, increased membrane potassium conductance, and decreased myosin light chain kinase activity leads to smooth muscle relaxation and bronchodilation.
Myosin light-chain kinasealso known asMYLKorMLCKis aserine/threonine-specific protein kinasethatphosphorylatesthe regulatory light chain ofmyosin II.[3] Theseenzymesare important in the mechanism of contraction inmuscle. Once there is an influx ofcalciumcations (Ca2+) into the muscle, either from thesarcoplasmic reticulumor from theextracellular space, contraction of smooth muscle fibres may begin. First, the calcium will bind tocalmodulin. This binding will activate MLCK, which will go on to phosphorylate themyosin light chainatserineresidue 19. This will enable the myosincrossbridgeto bind to theactin filamentand allow contraction to begin (through thecrossbridge cycle). Since smooth muscle does not contain atroponincomplex, asstriated muscledoes, this mechanism is the main pathway for regulating smooth muscle contraction. Reducing intracellular calcium concentration inactivates MLCK but does not stop smooth muscle contraction since the myosin light chain has been physically modified through phosphorylation. To stop smooth muscle contraction this change needs to be reversed. Dephosphorylation of the myosin light chain (and subsequent termination of muscle contraction) occurs through activity of a second enzyme known asmyosin light-chain phosphatase(MLCP).
Incell biology,Protein kinase A(PKA) is a family ofenzymeswhose activity is dependent on cellular levels ofcyclic AMP(cAMP). PKA is also known ascAMP-dependent protein kinase(EC2.7.11.11). Protein kinase A has several functions in the cell, including regulation ofglycogen,sugar, andlipidmetabolism.
It should not be confused withAMP-activated protein kinase- which, although being of similar nature, may have opposite effects -[1]nor be confused withcyclin-dependent kinases(Cdks), nor be confused with theacid dissociation constantpKa.
In the field ofmolecular biology, thecAMP-dependent pathway, also known as theadenylyl cyclasepathway, is aG protein-coupled receptor-triggeredsignaling cascadeused incell communication.[1]
G protein-coupled receptors(GPCRs) are a large family ofintegral membrane proteinsthat respond to a variety of extracellular stimuli. Each GPCR binds to and is activated by a specificligandstimulus that ranges in size from small moleculecatecholamines, lipids, orneurotransmittersto large protein hormones. When a GPCR is activated by its extracellular ligand, a conformational change is induced in the receptor that is transmitted to an attached intracellularheterotrimeric G proteincomplex. TheGsalpha subunitof the stimulated G protein complex exchangesGDPforGTPand is released from the complex.
In a cAMP-dependent pathway, the activated Gsalpha subunit binds to and activates an enzyme calledadenylyl cyclase, which, in turn, catalyzes the conversion ofATPintocyclic adenosine monophosphate(cAMP).[2]Increases in concentration of thesecond messengercAMP may lead to the activation of
cyclic nucleotide-gated ion channels[3]
exchange proteins activated by cAMP (EPAC)[4]such asRAPGEF3
popeye domain containing proteins (Popdc)[5]
an enzyme calledprotein kinase A(PKA).[6]
The PKA enzyme is also known as cAMP-dependent enzyme because it gets activated only if cAMP is present. Once PKA is activated, it phosphorylates a number of other proteins including:[7]
enzymes that convertglycogenintoglucose
enzymes that promote muscle contraction in the heart leading to an increase in heart rate
transcription factors, which regulate gene expression
Specificity of signaling between a GPCR and its ultimate molecular target through a cAMP-dependent pathway may be achieved through formation of a multiprotein complex that includes the GPCR, adenylyl cyclase, and the effector protein
Aetiology
the cause, set of causes, or manner of causation of a disease or condition:
Asthma is an —— ——– disease
obstructive airway
In asthma the spirometry will show:
1 = Increased FVC > 70%
2 = Reduced FVC < 70%
3 = Increased FEV1 > 70%
4 = FEV1/FVC of > 70%
5 = FEV1/FVC of < 70% i
5
Its obstructive and hence FEV will reduce
Obstructive Airway Disease
- conditions that cause narrowing of the large, medium sized and small airways (bronchi)
- asthma, COPD, bronchiectasis
- results in air-trapping and hyperinflation
Obstructive Airways Disease Spirometry
↓ FEV1
↔ FVC (unchanged)
↓ FEV1/FVC < 70%
FEV1 = forced expiratory volume in 1 second
FVC = forced vital capacity
Asthma definition
- reversible, obstructive airways disease
- caused by inflammation, hyper-responsiveness and narrowing of the bronchial tree
- occurs in a susceptible individual secondary to a variety of stimuli
- FEV1/FVC <70%
Asthma is characterised by (2):
- recurrent attacks of breathlessness and wheezing
- varies in severity and frequency from person to person
obstructive airways disease
Diagnosis of asthma
- clinical diagnosis
- no consistent gold standard diagnostic criteria
- central to diagnosis is presence of symptoms:
- more than one of wheeze, breathlessness, chest tightness, cough
- variable airflow obstruction
Epidemiology of asthma:
- incidence
- prevalence
- mortality in the UK
- hospital admissions
- money
- deaths compared to EU
- incidence is 2.6-4/1000 individuals year in UK (3-34% worldwide)
- prevalence is 8% of adults and 20% of children: 5.4M people in UK
- mortality is 4/100,00 in the UK with 1500 deaths every year
- 185 hospital admissions every day
- 1bn spent by NHS treating asthma
- deaths from asthma in UK is 50%> in EU
Aetiology of Asthma
- multifactorial; genetic factors(polygenic) and environmental
- airway inflammation occurs when a genetically susceptible individual with atopy is exposed to certain environmental factors
- atopy is the tendency to produce high amounts of IgE when exposed to small amounts of an antigen
- atopic individuals have a high prevalence of asthma, allergic rhinitis, urticaria and eczema
- atopic individuals will demonstrate positive reactions to antigens on skin prick testing
The genetic predisposition is actually disposition to atopy; hence will always ask patient about hayfever, eczema and family history of asthma
Genetics of asthma
- atopy and asthma show polygenic inheritance and genetic heterogeneity, with gene linkages on chromosome 11q13
- allergen exposure in early life may determine sensitisation foe example to HDM, pet allergens and viral infections
- hygiene hypothesis postulates that LACK of infections in childhood results in alteration of T cell function and a predisposition to developing asthma
Atopy
- atopic individuals produce IgE antibodies to specific allergens, which can be measured in the serum
- atopic conditions include asthma, hayfever, allergic dermatitis, allergic rhinitis
- always ask about family history of atopy
- individuals with asthma are highly likely to have other atopic conditions
- skin prick testing can be used to demonstrate allergy to a specific allergen
pathophysiology of asthma: airway inflammation:
- sensitisation of atopic individuals
- inhalation of allergen
Pathophysiology of asthma: two phase response:
- early reaction (20minutes) and late reaction (6-12 hours later)
- T helper lymphocytes regulate the inflammatory response
- Th2 cells secrete pro-inflammatory interleukins which lead to the release of IgE antibodies by plasma cells
- Th1 cells down regulate the atopic response
Pathophysiology of asthma: IgE antibodies bind to receptors on mast cells and eosinophils and stimulate them to release:
- histamine, prostaglandins, cysteinyl leukotrienes
- these mediators cause bronchoconstriction of airways within minutes
What are targets for therapies for asthma?
Mediators: histamines prostaglandins, cysteinyl leukotrienes
What distinguishes asthma from COPD?
Reversibility of bronchoconstriction
Pathophysiology of asthma: Late phase response:
- infiltration of the smooth muscle layer by eosinophils, basophils, neutrophils, monocytes and dendritic cells
- results in patchy desquamation of epithelial cells
- increase in number of mucous glands and goblet cell hyperplasia
- hypertrophy and hyperplasia of airway smooth muscle
- cytokines cause contraction of smooth muscle and narrowing of airways
- increased permeability of blood vessels
- increased mucous production and mucous plugging
- acute inflammation results in oedema
Pathophysiology of asthma: dynamic hyperinflation:
- polyphonic wheezing caused by narrowing of bronchi of different calibers
- narrowing of bronchi <2cm leads to closure at low lung volumes leading to air trapping an increase in residual volume and increase in total lung capacity
What type of immune cells are associated with acute asthma?
Eosinophils
What are neutrophils associated with (asthma)?
- persistent airway inflammation
- steroid dependent asthma
Pathophysiology of asthma
Normal vs asthmatic patient airway diagram
With increased severity and chronicity of asthma (if untreated):
- remodelling of the airways
- collagen deposition
- fibrosis of the airway wall
- fixed narrowing
Environmental triggers for acute asthma:
- animal dander
- HDM
- grass and tree pollen
- mould
- viral and bacterial infection
- atmospheric pollution: ozone, SO2, NO, fumes, thunder storms
- perfumes, hair sprays, plug-ins
- cigarette smoking, passive smoking
- indoor fire, chlorine, paints
- cold air/change in temperatue
Drug triggers for acute asthma:
- aspirin
- NSAIDS ( non-steroidal anti-inflammatory drugs)
- beta blockers
Physiological triggers for acute asthma:
- pregnancy
- premenstrual
- exercise
- occupational asthma
Symptoms of acute asthma during exacerbation (4):
- breathlessness
- chest tightness
- wheeze
- cough
Symptoms of acute asthma between exacerbations(4):
- completely well
- mild chest tightness
- occasional wheeze
- dry cough (cough-variant asthma)
Diurnal variability of asthma:
- worse at night and early morning
- linked to circadian rhythm
Signs of acute asthma during exacerbation(4):
- tachypnoea (breathlessness with raised respiratory rate)
- tachycardia
- polyphonic wheeze during inspiration and expiration
- signs of hyperinflation
Signs of severe asthma:
- cyanosis
- silent chest = air can’t go in and out, cant hear anything
- bradycardia
An 18-year-old woman attends her GP surgery complaining of a dry cough and chest tightness. Her GP thinks she might have asthma. Which of the following investigations would be most helpful in making a diagnosis of asthma?
1 = blood test for neutrophil count
2 = chest X-ray
3 = CT thorax
4 = spirometry
5 = sputum analysis
4=spirometry
Investigation for suspected asthma:
- blood tests: full blood count; raised eosinophil count
- raised IgE, radioallergosorbent test (RAST) if a specific allergy is suspected
- skin prick test
- chest x ray
- peak flow/diary
- spirometry
- full lung function test with reversibility to bronchodilator
If eosinophil count is normal, if spirometry/peak flow is normal, not reversible and a dry cough then:
- HRCT if emphysema or bronchiectasis suspected
- Methacholine or histamine provocation
- Sputum (microbiological analysis, differential cell count)
Peak flow measurements
- diurnal variation: lower value in the morning compared to the evening
- records of PEF measurements taken in the mornings and the evenings for several weeks can be helpful
- 20% or greater variability between mornings and evenings
What is this?
What does it show?
Shows diurnal variation; needs to be significant difference
Spirometry
- show obstruction:
- reduced FEV1
- FEV1/FVC<70%
- reversibility to bronchodilator 20 minutes after 200mcg inhaled salbutamol with the FEV1
- patient with COPD little to no reversibility
Lung Function Test for asthma:
- increase in TLC and RV due to air trapping (total lung capacity and residual volume)
- normal transfer factor/diffusing capacity (TLCO/DLCO)
FENO
- fractional exhaled nitric oxide
- measure of eosinophilic inflammation in the airways
- a positive test (>40ppb) supports a diagnosis of asthma
- can also be used to monitor treatments/ look at compliance
What test is this?
What is the control in a skin prick test?
Saline
Chest X-Ray in asthma:
- if mild may be normal
- may show hyperinflation with increased lung volumes and flat diaphragms
- > 6 anterior ribs or 10 posterior ribs in the mid-clavicular line
- heart is vertical and narrow
HRCT in asthma:
- shows air trapping
Which of these statements about asthma is true?
1 = is an irreversible obstructive airways disease
2 = is a restrictive lung disease
3 = is associated with increased eosinophil
count
4 = is rare in patients with atopy
5 = does not usually run in families
3
Management of asthma:
- avoid allergens if possible
- inhaled therapy
- oral therapy
Aims of pharmacological management of asthma:
- symptom control: minimal symptoms during day and night, minimal need for reliever, no limitation of physical activity
- achieve best possible pulmonary function: FEV1, PEF>80% predicted or best
- prevent exacerbations
- reduce morbidity and mortality
- minimal side effects
2 main receptors in bronchial mucosa are
- Beta 2 adrenoreceptors in the smooth muscle of the airways from the trachea to the terminal bronchioles
- muscarinic cholinergic receptors: receive parasympathetic nerve supply
Route of Medication for Lung Diseases:
- Inhaled: inhaler, nebuliser (acute setting)
- Oral
- Intravenous
- Intramuscular
- Subcutaneous
Advantages of inhaled route of medication:
- direct deposition into lungs
Disadvantages of Inhaled route of medication:
- technique dependent
Corticosteroid mechanism
