Neurohumral control of Airways Flashcards
Where are the cell bodies of the preganglionic nerve fibres of the parasympathetic division located?
In the brainstem
Where are the cell bodies of the postganglionic nerve fibres of the parasympathetic division located?
In the walls of the bronchi and bronchioles
What does stimulation of postganglionic cholinergic nerve fibres of parasympathetic division cause?
- Bronchial smooth muscle contraction mediated by M3 muscarinic Ach receptors on airway smooth muscle cells
- Increased mucous secretion mediated by M3 muscarinic ACh receptors on gland (goblet) cells
What does stimulation of postganglionic noncholinergic fibres of parasympathetic division cause?
- Bronchial smooth muscle relaxation mediated by nitric oxide (NO) and vasoactive intestinal peptide (VIP)
Do sympathetic nerves innervate bronchial smooth muscles?
No, but postganglionic nerve fibres supply submucosal glands and smooth muscle of blood vessels
If there is no direct sympathetic innervation of bronchial smooth muscle, how does the sympathetic NS cause relaxation of bronchial SM?
Indirectly mediated - innervation of adrenal medulla (pre-ganglionic). Acetylcholine stimulates nicotinic receptors -causes the release of adrenaline which enters systemic circulation and arrives at the airways
What does stimulation of adrenal medulla by sympathetic pre-ganglionic fibres cause?
- Bronchial smooth muscle relaxation via β2-adrenoceptors on ASM cells activated by adrenaline released from the adrenal gland
- Decreased mucus secretion mediated by β2-adrenoceptors on gland (goblet) cells
- Increased mucociliary clearance mediated by β2-adrenoceptors on epithelial cells (mucociliary escalator)
- Vascular smooth muscle contraction, mediated by α1-adrenoceptors on vascular smooth muscle cells
What are the steps of excitation contraction coupling in smooth muscle?
- GPC receptors (in smooth muscle, M3 ACh receptors) are activated by transmitter/hormone
- This activates G protein Gq/11
- Gq/11 activates PLC, which converts PIP2 into IP3
- IP3 is hydrophobic and diffuses into cytoplasm where It encounters a specific IP3 receptor in the sarcoplasmic reticulum
- This triggers the release of calcium from SR via ion channels (the activated IP3 receptor acts as a calcium-specific ion channel)
- Calcium flow into cytoplasm causes contraction
What are the steps of smooth muscle contraction via depolarisation?
- If membrane becomes depolarised, voltage-activated calcium channels in the PM open
- Calcium flows down electrochemical gradient into cytoplasm where it binds to a ryanodine receptor in the sarcoplasmic reticulum
- Ryanodine is a calcium-activated ion channel - allows calcium from SR to flow out into cytoplasm, causing contraction
By which 2 means is smooth muscle contraction caused?
- By GPCR and Gq/11
* By voltage-activated calcium channels
Explain the process by which calcium causes contraction in smooth muscle
Reminder: mechanism is different for skeletal muscle
- Intracellular concentration of Ca rises - Ca binds to protein in cell called calmodulin
- Ca-calmodulin complex is a regulatory proven that binds to specific targets to change their conformation and make them active
- Ca-calmodulin complex converts MLCK (myosin light chain kinase) to active MLCK
- MLCK acts as a kinase- phosphorylates myosin light chain
- When MLC is phosphorylated, permits interaction between actin and myosin
- Cross bridge forms between actin and myosin, allowing them to slide over each other and contract the muscle
What are actin and myosin?
Fibres present in muscle cells, slide over each other causing contraction
What else is required for phosphorylation of MLC other than elevated intracellular calcium?
ATP
How is relaxation caused in smooth muscle?
Dephosphorylation of MLC by myosin phosphatase
When does the rate of phosphorylation exceed the rate of dephosphorylation?
When there is elevated intracellular calcium
When does the rate of dephosphorylation exceed the rate of phosphorylation?
When intracellular concentration of calcium falls
By what mechanisms does intracellular calcium return to basal level?
Primary and secondary active transport
How is the activity of MLCK and myosin phosphatase regulated?
By extracellular signals i.e. adrenaline
How does adrenaline cause relaxation of smooth muscle?
- Adrenaline binds to B2 adrenoceptor
- B2 adrenoceptor is a GPCR linked to Gs protein
- Gs protein activates adenylyl cyclase, which converts ATP to cyclic AMP
- cAMP acts on PKA, which inhibits myosin light chain kinase by phosphorylating it
- Loses kinase activity, cannot phosphorylate MLC, cannot contract
- PKA also stimulates action of myosin phosphatase, which desphosphorylates faster than phosphorylation resulting in relaxation
What is B2-adrenoceptor?
B2 adrenoceptor is a GPCR linked to Gs protein
How is the B2-adrenoceptor pathway ‘switched off’?
Degradation of cyclic AMP to 5’AMP switches off the pathway
How is cAMP degraded to 5’AMP?
Via phosphodiesterase enzymes
How to bronchodilators work?
Many drugs block the action of phosphodiesterase or activate B2-adrenoceptors to cause relaxation of the airways
What percentage of the population suffers from asthma in industrialised countries?
5-10%
What is asthma?
Is a recurrent and reversible (in the short term) obstruction to the airways - obstructive airway disease
What does asthma occur in response to?
Substances or stimuli that:
- Are not necessarily noxious (in normal individuals)
- Normally do not affect non-asthmatic subjects
What are some causes of asthma attacks?
- Allergens (in atopic individuals)
- Exercise (cold, dry air)
- Respiratory infections (e.g. viral)
- Smoke, dust, environmental pollutants
What is status asthmaticus?
Medical emergency: acute severe asthma that can be fatal
What do intermittent attacks of bronchoconstriction (asthma) cause?
- Tight chest
- Wheezing
- Difficulty breathing
- Cough
What can chronic asthma cause?
Pathological changes to bronchioles that result from long standing inflammation
What are pathological changes to the airways of chronic asthmatics?
- 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 (collagen laid down, reduces diameter of airway)
What does narrowing of the airway by inflammation and bronchoconsriction cause?
Increases airway resistance and decreases FEV1 and PEFR (peak expiratory flow rate)
What are the 2 phases of an asthma attack?
- Immediate phase - type I hypersensitivity reaction (bronchospasm)
- Delayed phase - type IV hypersensitivity reaction (inflammatory reaction)
Which phase of an asthma attack has a more severe fall in FEV1?
- Delayed phase - type IV hypersensitivity reaction
What is the response to an allergen in a nonatopic individual?
- Phagocytosis by antigen presenting (dendritic) cell
* Low-level TH1 response, cell-mediated response involving IgG and macrophages
What is the response to an allergen in a atopic individual?
- Phagocytosis by antigen presenting (dendritic) cell
* Strong TH2 response, antibody-mediated immune response involving IgE
Describe the process of initiation of an adaptive immune response following exposure to an allergen
- Allergen detected by airway epithelial cells
- Presented by dendritic cells to CD4+ cells via MHCII
- Promotes profliferation of TH0 cells, which results in proliferation of TH1 or TH2 cells
- In asthma, TH2 cells proliferate and make critical contact with B cells
- TH2 cells synthesise IL-4, activates B cells and stimulates expansion and differentiation of B cell population to become efector cells (plasma cells)
- Secrete IgE
What is the role of TH2 cells in asthma?
- In asthma, TH2 cells proliferate and make critical contact with B cells
- TH2 cells synthesise IL-4, activates B cells and stimulates expansion and differentiation of B cell population to become efector cells (plasma cells)
- Secrete IgE
How do TH2 cells stimulate differentiation of B cell population?
- Bind to B cells
* Secrete IL-4
What does IgE produced by plasma B cells do?
IgE binds to inflammatory cells (mast cells) by binidng to IgE receptors present on their surface
What does IgE binding to IgE receptors on the surface of mast cells stimulate?
Stimulates mast cells to release inflammatory mediators
Which inflammatory cells are activated by IL-5 released from TH2 cells?
Eosinophils
What happens once an activated mast cell encounters the antigen?
- Causes IgE receptors to cross-link, results in release of calcium from intracellular stores into cytoplasm
- Also activates ion channels specific to calcium, stimulating calcium entry into cytoplasm
What does elevated intracellular calcium cause in activated mast cells?
- Release of secretory granules containing pre-formed histamine
- Production and release leukotrienes - cause airway smooth muscle contraction
- Release of LTB4, platelet activating factor (PAF) and prostaglandins (PGD2) - attract cells that cause inflammation
What is the function leukotrienes released by mast cells?
Cause airway smooth muscle contraction
What is the function of LTB4, PAF and PGD2 released by mast cells?
Recruit inflammatory cells (mononuclear cells and eosinophils) into the area
What are histamine and leukotrienes classed as?
Spasmogens
Why are leukotrienes and histamine classes as spasmogens?
Cause airway smooth muscle contraction
What are key events in the immediate phase of asthma?
- Detection of antigen
- Mast cells activated, which recruit mononuclear cells
- Mast cells and mononuclear cells release spasmogens and chemotaxins/chemokines
- Spasmogens cause bronchospasm and inflammation
What are key events of the late phase of asthma?
- Detection of antigen
- Mast cells activated, which recruit mononuclear cells
- Chemotaxins/chemokines released by mononuclear cells
- Chemokines recruit TH2 cells, monocytes and eosinophils, which release inflammatory mediators
- Eosinophils release basic and cationic proteins
- Cause epithelial damage, which leads to airway hyper-responsiveness and inflammation
- Results in bronchospasm, cough, wheezing and mucous over-secretion
What is the function of eosinophils in a late phase asthmatic response?
Release major basic and cationic proteins
What do basic and cationic proteins released by eosinophils do?
Cause epithelial damage and airway hyper-responsiveness
