Neurohumoral Control of Airways and Asthma

Question 1

Describe Airway Smooth Muscle (ASM)

Answer 1

Involuntary and regulated by autonomic nervous system; main influence is parasympathetic

Ganglia are always within airway smooth muscle itself

Question 2

Location of pre- and post-ganglionic cell bodies involved?

Answer 2

Cell bodies of pre-ganglionic fibres are located in brainstem

Cell bodies of post-ganglionic fibres and embedded in walls of bronchi and bronchioles

Question 3

Parasympathetic neurotransmitters?

Answer 3

Acetylcholine is NOT ALWAYS used.

Some receptors are noncholinergic and others are cholinergic.

Question 4

What do post-ganglionic cholinergic fibres (parasympathetic) stimulate?

Answer 4

Bronchial smooth muscle CONTRACTION mediated by M3 muscarinic ACh receptors on ASM cells

Increased muscous secretion mediated by M3 muscarinic ACh receptors on goblet cells

Question 5

How are post-ganglionic NON-CHOLINERGIC fibres stimulated?

Answer 5

Bronchial smooth muscle RELAXATION mediated by soluble nitric oxide (NO) - short-lived neurotransmitter - and Vasoactive Intestinal Peptide (VIP)

Question 6

What are the nerve fibres?

Answer 6

Axons in vagus nerve (CN X)

Question 7

Sympathetic nerve supply to airway smooth muscle?

Answer 7

No innervation of bronchial smooth muscle in humans but post-ganglionic sympathetic fibres supply sub-mucosal glands and smooth muscle of blood vessels

Question 8

What does sympathetic stimulation cause?

Answer 8

Bronchial smooth muscle relaxes via β2-adrenoceptors (β2-ADR) on ASM cells; activated by ADRENALINE released from adrenal gland

Decreased mucous secretion mediated by β2-ADR on goblet cells

Increased mucociliary clearance mediated by β2-ADR on epithelial cells of mucociliary escalator

Vascular smooth muscle contraction, mediated by α1-ADR on vascular smooth muscle

Question 9

How is adrenaline secreted during stimulation causing bronchial smooth muscle relaxation when there is no sympathetic innervation?

Answer 9

Chromaffin cells of adrenal medulla are analogous to to post-ganglionic neurones in the sympathetic system

nAChR located on chromaffin cells are activated to release adrenaline

Question 10

How is excitation contraction of smooth muscle achieved?

Answer 10

One pathway is:
1. Transmitter/hormone activates G-protein coupled receptors (GCPR)

2. In ASM, mediated by M3 ACh receptors activated by parasympathetic stimulation and this couples preferentially with Gq/11
3. Gq/11 activates phospholipase C (PLC) which degrades PIP2 and produced two products - one is a soluble molecule IP3
4. This binds to IP3 receptors in sarcoplasmic reticulum membrane, activating them - IP3 receptors are Ca2+ selective ion channels
5. Ca2+ is released from Ca2+ stores into cytoplasm to stimulate contraction

Another pathway is:
1. Depolarisation of the action potential activates voltage activated Ca2+ channels

2. AMPLIFICATION, as Ca2+ binds to Ca2+ activated Ca+ channels (ryanodine receptors) in sarcoplasmic reticulum membrane
3. Ca2+ released from stores into cytoplasm to stimulate contraction

Question 11

Describe Ca2+ initiation of smooth muscle contraction?

Answer 11

1. The increase in Ca2+ ion conc. is detected by a Ca2+ binding molecule (CALMODULIN - binds 4 Ca2+ ion)
2. Activation to Ca2+ Calmodulin
3. Ca2+ calmodulin wraps around Inactive Myosin Light Chain Kinase (MLCK)
4. Phosphorylated to produce Active MLCK
5. Causes inactive myosin cross bridge to phosphorylate to phosphorylated myosin cross bridge - binds actin via Pi + Myosin light chain?
6. Myosin and actin slide over one another to generate force and contraction

Question 12

Summary of Ca2+ initiation of smooth muscle contraction

Answer 12

Contraction results from phosphorylation of regulatory myosin light chain (MLC) in presence of elevated intracellular Ca2+ (and ATP)

Question 13

Describe how relaxation of airway smooth muscle occurs?

Answer 13

Dephosphorylation of myosin light chain by myosin phosphatase, which has constitute activity (constantly dephosphorylating MLC)
Activities of MLCK and myosin phosphatase oppose each other (MLCK phosphorylates MLC causing contraction)

In the presence of elevated intracellular Ca2+, rate of phosphorylation exceeds rate of dephosphorylation

Relaxation requires return of intracellular Ca2+ conc. to basal level - achieved by primary and secondary active transport

Question 14

How is activity of MLCK and myosin phosphatase regulated in parasympathetic stimulation of AMS?

Answer 14

By extracellular signals
Adrenaline activates β2-adrenoceptor which activates Gs, which activates adenylyl cyclase to degrade ATP to cAMP (cyclic AMP)
cAMP binds to PKA and this becomes active and phosphorylates and inhibits MLCK (inhibits contraction)
It phosphorylates and stimulates myosin phosphatase, causing relaxation of bronchial smooth muscle

An alternate pathway is PDE (phosphodiesterase) degrading cAMP to inhibit contraction by phosphorylating and inhibiting MLCK

Question 15

Describe asthma

Answer 15

Affects 5-10% population in industrialised countries
Recurrent and reversible (in short-term) obsrtruction to airways in response to substances that:
are not necessarily noxious
do not normally affect non-asthmatics

Acute severe asthma - AKA status asthmaticus is a medical emergency

Question 16

Causes of asthma attacks?

Answer 16

Allergens (in atopic individuals)
Exercise (cold, dry air)
Respiratory infections (e.g: viral)
Smoke, dust, environmental pollutants

Question 17

Symptoms of asthma?

Answer 17

Intermittent attacks of bronchoconstriction cause:
“tight chest”
Wheezing
Difficulty in breathing (expiration usually)
Cough

Question 18

Why do pathological changes occur in asthma?

Answer 18

Chronic asthma involves pathological changes to bronchioles resulting from long-standing inflammation due to inflammatory cells

Question 19

What causes obstruction in asthma?

Answer 19

Contraction of AMS
Over-production of mucous
Airway inflammation

Question 20

Changes in asthma?

Answer 20

Increased mass of smooth muscle (hyperplasia and hypertrophy)
Accumulation of interstitial fluid (oedema)
Increased secretion of mucous
Epithelial damage (which exposes the sensory nerve endings)
Sub-epithelial fibrosis

Airway narrowing by inflammation & bronchoconstriction increase airway resistance, decreasing FEV1 and PEFR

Question 21

What causes bronchial hyper-responsiveness (increased sensitivity) in asthma?

Answer 21

Two components:
Hyper-sensitivity
Hyper-reactivity

Epithelial damage, exposing sensory nerve ending (C-fibres, irritant receptors) contributes to hyper-sensitivity of airways to bronchoconstrictor influences
May cause neurogenic inflammation by release of various peptides from sensory nerve endings

Question 22

How can hyper-responsiveness be revealed?

Answer 22

Using provocation tests with inhaled bronchoconstrictors (spasmogens), like histamine or metacholine reveal hyper-responsiveness

A patient with severe asthma can inhale very little bronchoconstrictor (hyper-sensitivity) before their hyper-reactivity increase, decreasing FEV1% (forced expiratory volume in 1 sec)
Patient with mild asthma will inhale less than normal

Question 23

Phases of asthma attacks?

Answer 23

In many, 
Immediate phase (bronchospasm mainly)
Delayed phase (inflammatory reaction)

Question 24

Describe what would happen if an allergic individual inhaled grass pollen

Answer 24

FEV1 starts out normal but:

Type I hypersensitivity reaction causes early phase bronchospasm and acute inflammation, which decrease FEV1

This increases slightly till there is a:
Type IV hypersensitivity reaction which causes the late phase (bronchospasm and delayed inflammation)

Question 25

One major cause of asthma?

Answer 25

Immune imbalance between TH1 (T helper 1) and TH2 (T helper 2) lymphocyte-mediated responses

Question 26

Response to an allergen in non-atopic individuals?

Answer 26

Allergen is phagocytosed by antigen presenting (dendritic) cell
This stimmulates a low-level TH1 response (cell-mediated immune reponse involving IgG and macrophages) - low level-grade inflammation

Question 27

Response to an allergen in atopic individual?

Answer 27

Allergen is phagocytosed by dendritic cells and this stimulates a strong TH2 response (antibody-mediated immune response involving IgE)

Question 28

Responses occurring asthma?

Answer 28

In mild to moderate asthma - a TH2 response predominates, but, in severe asthma, a TH1 response also contributes

Question 29

Reason for more common allergies?

Answer 29

Hygienic “western” lifestyle

Exposure to microbes early in life favours TH1 response

Question 30

During allergic asthma, what occurs during the initial presentation of an antigen on an allergen and after (induction phase)?

Answer 30

Initiates adaptive immune response antigen presentation and clonal expansion & maturation (induction phase)

Allergen recognised by major histocompatibility complex class II on antigen presenting cells

Activates T CD4+ to TH0, which preferentially matures to TH2 cells that produce a cytokine environment so B cells arrive
TH2 activates B cell by binding to them and by producing IL-4

Causes clonal expansion of B cells, which mature into plasma cells that produce IgE

Question 31

What would occur in this pathway in a non-atopic individual?

Answer 31

TH0 cells would preferentially mature to TH1 cells

Question 32

What occurs after induction phase in an atopic individual?

Answer 32

Mast cells in airway tissue express IgE receptors in response to IL-4 and IL-13 released from TH2 cells; IgE produced by plasma cells than bind

Eosinophils differentiate and activate in response to IL-5 released from TH2 cells

Question 33

What is involved in subsequent presentation of antigen?

Answer 33

Antigen binds to IgE receptors and cross-links IgE receptors - form a dimeric complex and stimulate:
1. Calcium entry into mast cells

2. Release of Ca2+ from intracellular stores evoking:
   Release of secretory granules containing PREFORMED HISTAMINE and PRODUCTION & release of other agents, e.g: leukotrienes (LTC4, LTD4) - all SPASMOGENS (cause airway smooth muscle contraction)

Release of substances, e.g: LTB4, platelet-activating factor (PAF) and prostaglandins (PGD2), that attract cells (chemotaxins and chemokines) causing inflammation by recruitment of eosinophils and mononuclear cells

Question 34

2 phases of asthma?

Answer 34

Immediate phase

Late phase

Question 35

Describe immediate phase of asthma

Answer 35

Allergen will attract mast cells and mononuclear cells which produce:
Spasmogens, like cysLTs (leukotrienes) and histamine, which cause bronchospam and early inflammation
Chemotaxins and chemokines which are involved with the late phase

Question 36

Describe late phase of asthma

Answer 36

Infiltration of cytokine releasing TH2 cells and monocytes, activation of inflammatory cells, particularly eosinophils

Produce mediators like cysLTs and others - cause airway inflammation, hyper-responsiveness & bronchospasm

Also eosinophils produce major basic and cationic proteins (cytotoxin proteins) - cause epithelial damage leading to airway hyper-responsiveness (due to exposure of sensory nerve ending) and bronchospasm