Neurohumoral Control of Airways and Asthma Flashcards
Describe Airway Smooth Muscle (ASM)
Involuntary and regulated by autonomic nervous system; main influence is parasympathetic
Ganglia are always within airway smooth muscle itself
Location of pre- and post-ganglionic cell bodies involved?
Cell bodies of pre-ganglionic fibres are located in brainstem
Cell bodies of post-ganglionic fibres and embedded in walls of bronchi and bronchioles
Parasympathetic neurotransmitters?
Acetylcholine is NOT ALWAYS used.
Some receptors are noncholinergic and others are cholinergic.
What do post-ganglionic cholinergic fibres (parasympathetic) stimulate?
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
How are post-ganglionic NON-CHOLINERGIC fibres stimulated?
Bronchial smooth muscle RELAXATION mediated by soluble nitric oxide (NO) - short-lived neurotransmitter - and Vasoactive Intestinal Peptide (VIP)
What are the nerve fibres?
Axons in vagus nerve (CN X)
Sympathetic nerve supply to airway smooth muscle?
No innervation of bronchial smooth muscle in humans but post-ganglionic sympathetic fibres supply sub-mucosal glands and smooth muscle of blood vessels
What does sympathetic stimulation cause?
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
How is adrenaline secreted during stimulation causing bronchial smooth muscle relaxation when there is no sympathetic innervation?
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
How is excitation contraction of smooth muscle achieved?
One pathway is:
1. Transmitter/hormone activates G-protein coupled receptors (GCPR)
- In ASM, mediated by M3 ACh receptors activated by parasympathetic stimulation and this couples preferentially with Gq/11
- Gq/11 activates phospholipase C (PLC) which degrades PIP2 and produced two products - one is a soluble molecule IP3
- This binds to IP3 receptors in sarcoplasmic reticulum membrane, activating them - IP3 receptors are Ca2+ selective ion channels
- 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
- AMPLIFICATION, as Ca2+ binds to Ca2+ activated Ca+ channels (ryanodine receptors) in sarcoplasmic reticulum membrane
- Ca2+ released from stores into cytoplasm to stimulate contraction
Describe Ca2+ initiation of smooth muscle contraction?
- The increase in Ca2+ ion conc. is detected by a Ca2+ binding molecule (CALMODULIN - binds 4 Ca2+ ion)
- Activation to Ca2+ Calmodulin
- Ca2+ calmodulin wraps around Inactive Myosin Light Chain Kinase (MLCK)
- Phosphorylated to produce Active MLCK
- Causes inactive myosin cross bridge to phosphorylate to phosphorylated myosin cross bridge - binds actin via Pi + Myosin light chain?
- Myosin and actin slide over one another to generate force and contraction
Summary of Ca2+ initiation of smooth muscle contraction
Contraction results from phosphorylation of regulatory myosin light chain (MLC) in presence of elevated intracellular Ca2+ (and ATP)
Describe how relaxation of airway smooth muscle occurs?
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
How is activity of MLCK and myosin phosphatase regulated in parasympathetic stimulation of AMS?
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
Describe asthma
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
Causes of asthma attacks?
Allergens (in atopic individuals)
Exercise (cold, dry air)
Respiratory infections (e.g: viral)
Smoke, dust, environmental pollutants
Symptoms of asthma?
Intermittent attacks of bronchoconstriction cause:
“tight chest”
Wheezing
Difficulty in breathing (expiration usually)
Cough
Why do pathological changes occur in asthma?
Chronic asthma involves pathological changes to bronchioles resulting from long-standing inflammation due to inflammatory cells
What causes obstruction in asthma?
Contraction of AMS
Over-production of mucous
Airway inflammation
Changes in asthma?
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
What causes bronchial hyper-responsiveness (increased sensitivity) in asthma?
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
How can hyper-responsiveness be revealed?
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
Phases of asthma attacks?
In many, Immediate phase (bronchospasm mainly) Delayed phase (inflammatory reaction)
Describe what would happen if an allergic individual inhaled grass pollen
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)
One major cause of asthma?
Immune imbalance between TH1 (T helper 1) and TH2 (T helper 2) lymphocyte-mediated responses
Response to an allergen in non-atopic individuals?
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
Response to an allergen in atopic individual?
Allergen is phagocytosed by dendritic cells and this stimulates a strong TH2 response (antibody-mediated immune response involving IgE)
Responses occurring asthma?
In mild to moderate asthma - a TH2 response predominates, but, in severe asthma, a TH1 response also contributes
Reason for more common allergies?
Hygienic “western” lifestyle
Exposure to microbes early in life favours TH1 response
During allergic asthma, what occurs during the initial presentation of an antigen on an allergen and after (induction phase)?
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
What would occur in this pathway in a non-atopic individual?
TH0 cells would preferentially mature to TH1 cells
What occurs after induction phase in an atopic individual?
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
What is involved in subsequent presentation of antigen?
Antigen binds to IgE receptors and cross-links IgE receptors - form a dimeric complex and stimulate:
1. Calcium entry into mast cells
- 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
2 phases of asthma?
Immediate phase
Late phase
Describe immediate phase of asthma
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
Describe late phase of asthma
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
