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Respiratory: Pharmacology > Neurohumral control of Airways > Flashcards

Neurohumral control of Airways Flashcards

1
Q

Where are the cell bodies of the preganglionic nerve fibres of the parasympathetic division located?

A

In the brainstem

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2
Q

Where are the cell bodies of the postganglionic nerve fibres of the parasympathetic division located?

A

In the walls of the bronchi and bronchioles

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3
Q

What does stimulation of postganglionic cholinergic nerve fibres of parasympathetic division cause?

A
  • 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
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4
Q

What does stimulation of postganglionic noncholinergic fibres of parasympathetic division cause?

A
  • Bronchial smooth muscle relaxation mediated by nitric oxide (NO) and vasoactive intestinal peptide (VIP)
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5
Q

Do sympathetic nerves innervate bronchial smooth muscles?

A

No, but postganglionic nerve fibres supply submucosal glands and smooth muscle of blood vessels

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6
Q

If there is no direct sympathetic innervation of bronchial smooth muscle, how does the sympathetic NS cause relaxation of bronchial SM?

A

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

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7
Q

What does stimulation of adrenal medulla by sympathetic pre-ganglionic fibres cause?

A
  • 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
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8
Q

What are the steps of excitation contraction coupling in smooth muscle?

A
  • 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
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9
Q

What are the steps of smooth muscle contraction via depolarisation?

A
  • 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
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10
Q

By which 2 means is smooth muscle contraction caused?

A
  • By GPCR and Gq/11

* By voltage-activated calcium channels

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11
Q

Explain the process by which calcium causes contraction in smooth muscle

Reminder: mechanism is different for skeletal muscle

A
  • 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
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12
Q

What are actin and myosin?

A

Fibres present in muscle cells, slide over each other causing contraction

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13
Q

What else is required for phosphorylation of MLC other than elevated intracellular calcium?

A

ATP

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14
Q

How is relaxation caused in smooth muscle?

A

Dephosphorylation of MLC by myosin phosphatase

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15
Q

When does the rate of phosphorylation exceed the rate of dephosphorylation?

A

When there is elevated intracellular calcium

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16
Q

When does the rate of dephosphorylation exceed the rate of phosphorylation?

A

When intracellular concentration of calcium falls

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17
Q

By what mechanisms does intracellular calcium return to basal level?

A

Primary and secondary active transport

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18
Q

How is the activity of MLCK and myosin phosphatase regulated?

A

By extracellular signals i.e. adrenaline

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19
Q

How does adrenaline cause relaxation of smooth muscle?

A
  • 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
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20
Q

What is B2-adrenoceptor?

A

B2 adrenoceptor is a GPCR linked to Gs protein

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21
Q

How is the B2-adrenoceptor pathway ‘switched off’?

A

Degradation of cyclic AMP to 5’AMP switches off the pathway

22
Q

How is cAMP degraded to 5’AMP?

A

Via phosphodiesterase enzymes

23
Q

How to bronchodilators work?

A

Many drugs block the action of phosphodiesterase or activate B2-adrenoceptors to cause relaxation of the airways

24
Q

What percentage of the population suffers from asthma in industrialised countries?

A

5-10%

25
Q

What is asthma?

A

Is a recurrent and reversible (in the short term) obstruction to the airways - obstructive airway disease

26
Q

What does asthma occur in response to?

A

Substances or stimuli that:

  • Are not necessarily noxious (in normal individuals)
  • Normally do not affect non-asthmatic subjects
27
Q

What are some causes of asthma attacks?

A
  • Allergens (in atopic individuals)
  • Exercise (cold, dry air)
  • Respiratory infections (e.g. viral)
  • Smoke, dust, environmental pollutants
28
Q

What is status asthmaticus?

A

Medical emergency: acute severe asthma that can be fatal

29
Q

What do intermittent attacks of bronchoconstriction (asthma) cause?

A
  • Tight chest
  • Wheezing
  • Difficulty breathing
  • Cough
30
Q

What can chronic asthma cause?

A

Pathological changes to bronchioles that result from long standing inflammation

31
Q

What are pathological changes to the airways of chronic asthmatics?

A
  • 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)
32
Q

What does narrowing of the airway by inflammation and bronchoconsriction cause?

A

Increases airway resistance and decreases FEV1 and PEFR (peak expiratory flow rate)

33
Q

What are the 2 phases of an asthma attack?

A
  • Immediate phase - type I hypersensitivity reaction (bronchospasm)
  • Delayed phase - type IV hypersensitivity reaction (inflammatory reaction)
34
Q

Which phase of an asthma attack has a more severe fall in FEV1?

A
  • Delayed phase - type IV hypersensitivity reaction
35
Q

What is the response to an allergen in a nonatopic individual?

A
  • Phagocytosis by antigen presenting (dendritic) cell

* Low-level TH1 response, cell-mediated response involving IgG and macrophages

36
Q

What is the response to an allergen in a atopic individual?

A
  • Phagocytosis by antigen presenting (dendritic) cell

* Strong TH2 response, antibody-mediated immune response involving IgE

37
Q

Describe the process of initiation of an adaptive immune response following exposure to an allergen

A
  • 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
38
Q

What is the role of TH2 cells in asthma?

A
  • 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
39
Q

How do TH2 cells stimulate differentiation of B cell population?

A
  • Bind to B cells

* Secrete IL-4

40
Q

What does IgE produced by plasma B cells do?

A

IgE binds to inflammatory cells (mast cells) by binidng to IgE receptors present on their surface

41
Q

What does IgE binding to IgE receptors on the surface of mast cells stimulate?

A

Stimulates mast cells to release inflammatory mediators

42
Q

Which inflammatory cells are activated by IL-5 released from TH2 cells?

A

Eosinophils

43
Q

What happens once an activated mast cell encounters the antigen?

A
  • 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
44
Q

What does elevated intracellular calcium cause in activated mast cells?

A
  • 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
45
Q

What is the function leukotrienes released by mast cells?

A

Cause airway smooth muscle contraction

46
Q

What is the function of LTB4, PAF and PGD2 released by mast cells?

A

Recruit inflammatory cells (mononuclear cells and eosinophils) into the area

47
Q

What are histamine and leukotrienes classed as?

A

Spasmogens

48
Q

Why are leukotrienes and histamine classes as spasmogens?

A

Cause airway smooth muscle contraction

49
Q

What are key events in the immediate phase of asthma?

A
  • 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
50
Q

What are key events of the late phase of asthma?

A
  • 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
51
Q

What is the function of eosinophils in a late phase asthmatic response?

A

Release major basic and cationic proteins

52
Q

What do basic and cationic proteins released by eosinophils do?

A

Cause epithelial damage and airway hyper-responsiveness

Respiratory: Pharmacology (4 decks)

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