Neurohumeral Control of Airways and Asthma

Question 1

explain the role of the parasympathetic division of the autonomic nervous system in the regulation of airway function

Answer 1

cell bodies of preganglionic fibres in brainstem
cell bodies of postganglionic fibres in walls of bronchi and bronchioles
stimulation of postganglionic cholinergic fibres - bronchial smooth muscle CONTRACTION mediated by M3 muscarnic ACh receptors on ASM (air way smooth muscle) cells
increased mucus secretion mediated by M3 muscarinic ACh receptors on gland (goblet) cells
stimulation of postganglioc noncholinergic fibres cause bronchial smooth muscle relaxation mediated by nitric acid and vasoactive intestinal peptide (VIP)

Question 2

describe the principle transduction pathways that regulate airway smooth muscle tone - excitation contraction

Answer 2

feedforward

transmitter/hormone activates Gq/11 (G protein coupled receptor)
Gq/11 activates PLC (released from cell membrane)
PLC then goes to IP3
IP3 is a calcium channel and so calcium is released (calcium stored in sarcoplasmic reticulum is cell membrane)
contraction of smooth muscle

depolarisation activates calcium channel (voltage activated)
calcium released to calcium activated calcium change; (ryanodine receptor)
this release calcium
contraction of smooth muscle

as calcium concentration rises it interacts and binds to calmodulin
Ca-Calmodulin then phosphorylates (activates) MLCK (myosin light chain kinase)
MLCK then phosphorylates myosin corse bridges (binds actin)

Question 3

explain the role of the sympathetic division of the autonomic nervous system in the regulation of the airway function

Answer 3

no innervation of bronchial smooth muscle
postganglionic fibres supply submucosal glands and smooth muscle of blood vessels
stimulation causes;
bronchial smooth muscle RELAXATION via beta2-adrenoceptors (beta2-ADR) on ASM cells activated by adrenaline released from adrenal gland (nAChR - located on chromatin cells of adrenal medulla)
decreased mucous secretion mediated by beta2-ADR on gland (goblet) cells
increased mucociliary clearance mediated by beta2-ADR on epithelial cells (mucociliary escalator)
vascular smooth muscle contraction, mediated by alpha-ADR on vascular smooth muscle

Question 4

describe the principle transduction pathways that regulate airway smooth muscle tone - relaxation

Answer 4

dephosphorylation of myosin light chain by myosin phosphatase which has constitute activity
requires return of intracellular calcium concentration to basal level - achieved by primary and secondary active transport

regulated by extracellular signals
adrenaline activated by beta2-adrenoceptor
adrenaline activates Gs
Gs activates AC (adenylyl cyclase, enzyme)
AC catalyses ATP–>cAMP (cyclin AMP)
PDE (phosphodiesterase) degrades cAMP to PKA (protein kinase A)
PKA phosphorylates and inhibits myosin light chain kinase (contraction) or phosphorylates and stimulates myosin phosphatase (relaxation)

Question 5

provide a simple definition of asthma, noting its incidence and common causes

Answer 5

5-10% of population
recurrent and reversible (short term) obstruction to the airways in response to substances;
not necessarily noxious
do not affect non-asthmatic subjects

causes of asthma attack;
allergens 
exercise (cold, dry air)
respiratory infections (e.g. viral)
smoke
dust
environmental pollutants 

acute severe asthma (status asthmaticus) is medical emergency and can be fatal

Question 6

describe in outline the pathological changes in the airways that occur in chronic, poorly controlled asthma

Answer 6

chronic asthma - pathological changes to bronchioles from long standing inflammation;
increased mass of smooth muscle (hyperplasia and hypertrophy)
accumulation of interstitial fluid (oedema)
increased secretion of mucus
epithelial damage (exposing sensory nerve endings)
sub-epithelial fibrosis

airway narrowing by inflammation and bronchoconstriction increase airway resistance decreasing FEV1 and peak expiratory flow rate

dominated by Th2 response but Th1 also contributes

Question 7

explain what is meant by bronchial hyper-responsiveness, noting hypersensitivity and hyper-reactivity

Answer 7

epithelial damage, exposing sensory nerve ending (C-fibres, irritant receptors), contributes to increased sensitivity of the airways to broncoconstrcitor influences (and may cause neurogenic inflammation by the release of various peptides from sensory nerve endings)

2 components - hypersensitivity and hyper-reactivity

provocation tests with inhaled bronchoconstrictors (spasmogens) e.g. histamine (activates ASM H1 receptors) or metacholine (activates ASM M3 receptors) reveal hyper-responsiveness

*refer to PP

Question 8

appreciate that one major cause of asthma is thought to be due to an immune imbalance between Th1 and Th2 lymphocyte-mediate responses

Answer 8

atopic individuals (genetic tendency to develop allergies) and nonatopic individuals exposed to allergy
phagocytosis by antigen presenting (dendritic) cell
nonatopic - low level Th1 response (cell mediated immune response involving IgG and macrophages)
atopic - strong Th2 response (antibody mediated immune repose involving IgE)

Question 9

appreciate the key events in the immediate and delayed phases of an asthma attack

Answer 9

immediate phase (type I hypersensitivity reaction);
eliciting agent - allergen or non-specific stimulus
mast cells, mononuclear cells activated
spasmogens, CysLTs and histamine released - bronchospasm and acute inflammation (decrease in FEV1)
chemotaxins and chemokine resealed;

delayed phase (type IV hypersensitivity reaction) -
infiltration of cytokine releasing Th2 cells and monocytes, activation of inflammatory cells, particularly eosinophils
epithelial damage, airway hyper-responsiveness, bronchospasm, wheezing, mucous over secretion, cough and delayed airway inflammatory reaction (further decrease in FEV1)

dominated by Th2 response

Question 10

describe the vents that occur subsequent to Th2 lymphocyte activation noting in particular the role of mast cells and various inflammatory cells and their products

Answer 10

induction phase;
antigen presentation - aeroallergen trapped in airway epithelium
antigen presenting cells (dendritic cells) signal to T CD4+ cells
clonal expansion and maturation
CD4+ cells signal to Th0 cells Th0 cells preferentially mature to Th2 cells that produce cytokine environment
Th2 cells activate B cells by binding to them and IL-4 production
B cells mature to IgE excreting P cells

effector phase;
eosinophils differentiate and activate in response to IL-5 released from Th2 cells
mast cells in airway tissue (express IgE receptors in response to IL-4 and IL-13 released from Th2 cells)

Stimulates - calcium entry into mast cells and release of Ca2+ from intracellular stores evoking;
release of secretory granules containing preformed histamine and the production and release of other agents (e.g. leukotrienes LTC4 and LTD4) that cause airway smooth muscle contraction
release of substances [e.g. LTB4 and platelet-activating factor (PAF) and prostaglandins (PGD2)] that attract cells causing inflammation (e.g. mononuclear cells and eosinophils) into the area