Lecture 1: Respiratory system (part 1)
Monday 1-9-2025 R. Gosens
Epithelial cell types
Ciliated cell: mucus transport (mainly in the large airways).
Goblet/ mucous cell: mucus production to trap inhaled particles.
Basal cells: airway progenitor cells, can become ciliated/ goblet cells.
Club cell: produce less sticky mucus for lower airways to prevent obstruction.
Type 1 alveolar cell: gas transport (O2/CO2) so very thin walls.
Type 2 alveolar cell: produce surfactant (lower surface tension) and a progenitor cell.
Asthma
= a heterogeneous disease, characterized by chronic airway inflammation. Respiratory symptoms: wheeze,
shortness of breath, chest tightness and cough. Can vary over time and in intensity with variable expiratory
airflow limitation.
Gender paradox
In children asthma is more common in boys than girls. In adults it is more common in woman than in men.
This is due to the effects of estrogen, which enhances inflammation and airway hyperresponsiveness.
Airway hyperresponsiveness (AHR)
Excessive/inappropriate narrowing of the airways in response to non-specific stimuli. Start with genetic or
environmental factors causing cellular inflammation = transient airway hyperresponsiveness. Then when
continuously exposed, structural changes take place and permanent airway hyperresponsiveness develops.
Early and late asthmatic response
Early response: minutes – 1 hour after exposure. Driven by
mast cells, so IgE-dependent, leading to bronchoconstriction.
Late response: 4-12 hours after initial exposure. The
inflammatory response is driven by T cells and eosinophils.
These cells release cytokines and proteases leading to oedema
formation and mucus production. Because it is driven by
inflammation, bronchodilators are not very useful.
Inflammation
First the APC cells activate the TH2 cells. The TH2 cell
then releases 4 types of inflammatory cytokines:
IL-4 activating B cells
IL-4 and IL-9 activating mast cells
IL-5 activating eosinophils
IL-13 leading to increased mucus production
The activated B cells start producing IgE, which
activates mast cells, leading to the production of: histamine, proteases, leukotrines and prostaglandins. The
effects of these mediators are:
1. Airway hyper-responsiveness
2. Goblet cell metaplasia (increased number) – leading to mucus overproduction
3. Mucosal oedema
All these three factors lead to narrowing of the lumen.
1
,Neural regulation of bronchoconstriction
Acetylcholine (ACh): work on the Nervus
Vagus (= cholinergic efferent nerve, so from
CNS lung). ACh released by
parasympathetic nerves works on the M3
receptors present in smooth muscle to result in
bronchoconstriction. This is the main goal in
asthma therapies is to block the M3.
Tachykinins: like substance P and neurokinin A
are released by the eNANC nerve fibers
(excitatory noradrenergic noncholinergic =
neural pathway). In asthma there is an increase in tachykinin release.
o SP binds to the NK1 receptor, present in vessels and glands, leading to edema formation.
o NKA binds to the NK2 receptor, present in muscle, leading to bronchoconstriction.
iNANC (inhibitory neural pathway): release neurotransmitters to act on the airway smooth muscle
o NO (nitric oxide) is released upon increase Ca2+ levels in the iNANC nerve, leading to
increased cGMP levels in the smooth muscle – resulting in bronchodilation. In asthma cNOS
(NO precursor) gets consumed by L-arginine leading to less NO.
o VIP (vasoactive intestinal polypeptide) directly causes bronchodilation – linked to NO.
Asthma pharmacotherapy
Asthma is treated with bronchodilators, which are B2-agonists. The requirements are that they are orally
active, only work on the B2 receptor (otherwise lead to cardiac side effects).
Short-acting 2 agonists
Immediate relieve, fast onset (minutes) and short duration (4-6 hours). They are hydrophilic, so they stay in
the aqueous biophase leading to direct interaction with the receptor.
Terbutaline
Salbutamol
Fenoterol
Long-acting 2 agonists
These drugs have a slower onset of action, but provide long-lasting bronchodilation (12+ hours). Lipophilic
drugs, can diffuse into the membrane next to the B2 receptor, acting like a drug reservoir and then slowly
diffuse into the receptor.
Formoterol (intermediate)
Salmeterol
The beta-2 agonists are inhaled (local administration) with the side effects kept in mind. Common SE:
Increased FEV, increase HR, lower diastolic BP and increased tremor ratio.
Beta-2 agonists are poor anti-inflammatories, because their effects are short-lived. This is due to the
reducing number of cytokines. When frequently used, there is a reduction of inhibition of inflammatory
mediators (histamines and leukotrines). Leading to desensitization of the cell, this is by phosphorylation of
the B2 receptor by GRK and PKA. (when LABA’s are combined with ICS the desensitization is prevented
and the underlying inflammation is kept under control which is behind the airway hyperresponsiveness).
Question 1: Which of the following statements is correct? Question 2: Compared to the use of adrenaline i.v., what are
a. Neurokinin A and substance P both induce the benefits of the use of inhaled salbutamol to induce
bronchoconstriction. broncho protection?
b. VIP is a bronchoconstrictor derived from the nervous
system
c. Substance P mainly affects edema and mucus
secretion
1c 2: inhaled salbutamol provides broncho protection with
d. Sympathetic control of the airway smooth muscle is high efficacy and no cardiac side effects like decrease HR, BP
2
, mainly via neuron-derived noradrenaline. and tremors.
Lecture 2: Respiratory system (part 2)
Tuesday 2-9-2025 R. Gosens
PDE inhibitors
A problem with the use of B2 agonists is the
desensitization of the receptor by PKA and GRK. This
happens mainly in inflammatory cells due to the increased
GRK expression. To work around this,
phosphodiesterase’s must be inhibited.
Theophylline works by inhibiting PDE, decreasing
degradation of cAMP, and thus increased cAMP levels.
Which then lead to activation of PKA, relaxing smooth
muscle and thus leading to bronchodilation.
Desensitization of the receptors is not an issue with theophylline. Theophylline inhibits different PDE
enzymes subtypes. This all leads to increased cAMP and cGMP. These also both repress inflammation. So:
theophylline suppresses inflammation and leads to bronchodilation.
Theophylline has a narrow therapeutic window and a lot of side effects: hypotension (due to smooth
muscle relaxation), restlessness, nausea and vomiting, tachycardia. These all lead to only used in
clinic for COPD.
Anticholinergics (= LAMA and SAMA)
The main mechanism of action is blocking the muscarinic
receptor, normally after ACh binds, bronchoconstriction follows.
Blocking the M3 receptor leads to bronchodilation. The M2
receptor has an autoinhibitory effect. When M2 receptors
(presynaptic) get blocked, the inhibition of ACh release gets
blocked, thus more ACh gets released. This then leads to
bronchoconstriction, thus M2 receptor blockade is unwanted.
Ipratropium is a short-acting (4-6 h) anticholinergic. Used for quick symptom relief. Non-selective
blocker of M1 M2 and M3. Can thus lead to increased ACh release.
Tiotropium is a long-acting (24 h) anticholinergic. Used in maintenance therapy. Rapid dissociation
from M2 and slowly from M3.
The single mediator approach: a lot of inflammatory mediators also influence the bronchoconstriction. They
do not work directly on the smooth muscle, but rather on the sensory nerves. Their effects are then via ACh
working on the M3 receptor. To block all the inflammatory mediators at once, the pathway of ACh on M3 is
blocked. The single mediator that is blocked is then ACh, regardless of by what the release was triggered.
Corticosteroids:
Used to manage inflammatory conditions by binding to the glucocorticoid receptor (GR) in the cytoplasm.
Inhalation corticosteroids (ICS): fluticasone, budesonide, beclomethasone, ciclesonide (=is the pro-drug
of budesonide, activated by esterases present in airways. Reduced side effects due to no leaking into the
blood stream).
Oral corticosteroids (OCS): prednisolone. The inflammation treated by OCS is in eosinophils from the
bone marrow, not from the lungs. Inhaled GCS do not affect systemic eosinophil production. Only effects on
the late response in asthma patients due to the MOA through gene-expression.
Mechanism of action (MOA): corticosteroids have anti-inflammatory effects through gene-expression:
Trans-activation: promote the transcription of anti-inflammatory genes (like lipocortin-1).
Trans-repression: the glucocorticoid receptor-steroid complexes interfere with transcription factors,
without binding to DNA, this is done with nGRE (negative- glucocorticoid responsive element).
Lipocortin-1 (= annexin-1): inhibition of phospholipase A2. This is a precursor for the arachidonic acid
pathway, which is thus also inhibited. This is the pathway that produces leukotrienes and prostaglandins.
Side effects: More side effects when used orally.
3
Monday 1-9-2025 R. Gosens
Epithelial cell types
Ciliated cell: mucus transport (mainly in the large airways).
Goblet/ mucous cell: mucus production to trap inhaled particles.
Basal cells: airway progenitor cells, can become ciliated/ goblet cells.
Club cell: produce less sticky mucus for lower airways to prevent obstruction.
Type 1 alveolar cell: gas transport (O2/CO2) so very thin walls.
Type 2 alveolar cell: produce surfactant (lower surface tension) and a progenitor cell.
Asthma
= a heterogeneous disease, characterized by chronic airway inflammation. Respiratory symptoms: wheeze,
shortness of breath, chest tightness and cough. Can vary over time and in intensity with variable expiratory
airflow limitation.
Gender paradox
In children asthma is more common in boys than girls. In adults it is more common in woman than in men.
This is due to the effects of estrogen, which enhances inflammation and airway hyperresponsiveness.
Airway hyperresponsiveness (AHR)
Excessive/inappropriate narrowing of the airways in response to non-specific stimuli. Start with genetic or
environmental factors causing cellular inflammation = transient airway hyperresponsiveness. Then when
continuously exposed, structural changes take place and permanent airway hyperresponsiveness develops.
Early and late asthmatic response
Early response: minutes – 1 hour after exposure. Driven by
mast cells, so IgE-dependent, leading to bronchoconstriction.
Late response: 4-12 hours after initial exposure. The
inflammatory response is driven by T cells and eosinophils.
These cells release cytokines and proteases leading to oedema
formation and mucus production. Because it is driven by
inflammation, bronchodilators are not very useful.
Inflammation
First the APC cells activate the TH2 cells. The TH2 cell
then releases 4 types of inflammatory cytokines:
IL-4 activating B cells
IL-4 and IL-9 activating mast cells
IL-5 activating eosinophils
IL-13 leading to increased mucus production
The activated B cells start producing IgE, which
activates mast cells, leading to the production of: histamine, proteases, leukotrines and prostaglandins. The
effects of these mediators are:
1. Airway hyper-responsiveness
2. Goblet cell metaplasia (increased number) – leading to mucus overproduction
3. Mucosal oedema
All these three factors lead to narrowing of the lumen.
1
,Neural regulation of bronchoconstriction
Acetylcholine (ACh): work on the Nervus
Vagus (= cholinergic efferent nerve, so from
CNS lung). ACh released by
parasympathetic nerves works on the M3
receptors present in smooth muscle to result in
bronchoconstriction. This is the main goal in
asthma therapies is to block the M3.
Tachykinins: like substance P and neurokinin A
are released by the eNANC nerve fibers
(excitatory noradrenergic noncholinergic =
neural pathway). In asthma there is an increase in tachykinin release.
o SP binds to the NK1 receptor, present in vessels and glands, leading to edema formation.
o NKA binds to the NK2 receptor, present in muscle, leading to bronchoconstriction.
iNANC (inhibitory neural pathway): release neurotransmitters to act on the airway smooth muscle
o NO (nitric oxide) is released upon increase Ca2+ levels in the iNANC nerve, leading to
increased cGMP levels in the smooth muscle – resulting in bronchodilation. In asthma cNOS
(NO precursor) gets consumed by L-arginine leading to less NO.
o VIP (vasoactive intestinal polypeptide) directly causes bronchodilation – linked to NO.
Asthma pharmacotherapy
Asthma is treated with bronchodilators, which are B2-agonists. The requirements are that they are orally
active, only work on the B2 receptor (otherwise lead to cardiac side effects).
Short-acting 2 agonists
Immediate relieve, fast onset (minutes) and short duration (4-6 hours). They are hydrophilic, so they stay in
the aqueous biophase leading to direct interaction with the receptor.
Terbutaline
Salbutamol
Fenoterol
Long-acting 2 agonists
These drugs have a slower onset of action, but provide long-lasting bronchodilation (12+ hours). Lipophilic
drugs, can diffuse into the membrane next to the B2 receptor, acting like a drug reservoir and then slowly
diffuse into the receptor.
Formoterol (intermediate)
Salmeterol
The beta-2 agonists are inhaled (local administration) with the side effects kept in mind. Common SE:
Increased FEV, increase HR, lower diastolic BP and increased tremor ratio.
Beta-2 agonists are poor anti-inflammatories, because their effects are short-lived. This is due to the
reducing number of cytokines. When frequently used, there is a reduction of inhibition of inflammatory
mediators (histamines and leukotrines). Leading to desensitization of the cell, this is by phosphorylation of
the B2 receptor by GRK and PKA. (when LABA’s are combined with ICS the desensitization is prevented
and the underlying inflammation is kept under control which is behind the airway hyperresponsiveness).
Question 1: Which of the following statements is correct? Question 2: Compared to the use of adrenaline i.v., what are
a. Neurokinin A and substance P both induce the benefits of the use of inhaled salbutamol to induce
bronchoconstriction. broncho protection?
b. VIP is a bronchoconstrictor derived from the nervous
system
c. Substance P mainly affects edema and mucus
secretion
1c 2: inhaled salbutamol provides broncho protection with
d. Sympathetic control of the airway smooth muscle is high efficacy and no cardiac side effects like decrease HR, BP
2
, mainly via neuron-derived noradrenaline. and tremors.
Lecture 2: Respiratory system (part 2)
Tuesday 2-9-2025 R. Gosens
PDE inhibitors
A problem with the use of B2 agonists is the
desensitization of the receptor by PKA and GRK. This
happens mainly in inflammatory cells due to the increased
GRK expression. To work around this,
phosphodiesterase’s must be inhibited.
Theophylline works by inhibiting PDE, decreasing
degradation of cAMP, and thus increased cAMP levels.
Which then lead to activation of PKA, relaxing smooth
muscle and thus leading to bronchodilation.
Desensitization of the receptors is not an issue with theophylline. Theophylline inhibits different PDE
enzymes subtypes. This all leads to increased cAMP and cGMP. These also both repress inflammation. So:
theophylline suppresses inflammation and leads to bronchodilation.
Theophylline has a narrow therapeutic window and a lot of side effects: hypotension (due to smooth
muscle relaxation), restlessness, nausea and vomiting, tachycardia. These all lead to only used in
clinic for COPD.
Anticholinergics (= LAMA and SAMA)
The main mechanism of action is blocking the muscarinic
receptor, normally after ACh binds, bronchoconstriction follows.
Blocking the M3 receptor leads to bronchodilation. The M2
receptor has an autoinhibitory effect. When M2 receptors
(presynaptic) get blocked, the inhibition of ACh release gets
blocked, thus more ACh gets released. This then leads to
bronchoconstriction, thus M2 receptor blockade is unwanted.
Ipratropium is a short-acting (4-6 h) anticholinergic. Used for quick symptom relief. Non-selective
blocker of M1 M2 and M3. Can thus lead to increased ACh release.
Tiotropium is a long-acting (24 h) anticholinergic. Used in maintenance therapy. Rapid dissociation
from M2 and slowly from M3.
The single mediator approach: a lot of inflammatory mediators also influence the bronchoconstriction. They
do not work directly on the smooth muscle, but rather on the sensory nerves. Their effects are then via ACh
working on the M3 receptor. To block all the inflammatory mediators at once, the pathway of ACh on M3 is
blocked. The single mediator that is blocked is then ACh, regardless of by what the release was triggered.
Corticosteroids:
Used to manage inflammatory conditions by binding to the glucocorticoid receptor (GR) in the cytoplasm.
Inhalation corticosteroids (ICS): fluticasone, budesonide, beclomethasone, ciclesonide (=is the pro-drug
of budesonide, activated by esterases present in airways. Reduced side effects due to no leaking into the
blood stream).
Oral corticosteroids (OCS): prednisolone. The inflammation treated by OCS is in eosinophils from the
bone marrow, not from the lungs. Inhaled GCS do not affect systemic eosinophil production. Only effects on
the late response in asthma patients due to the MOA through gene-expression.
Mechanism of action (MOA): corticosteroids have anti-inflammatory effects through gene-expression:
Trans-activation: promote the transcription of anti-inflammatory genes (like lipocortin-1).
Trans-repression: the glucocorticoid receptor-steroid complexes interfere with transcription factors,
without binding to DNA, this is done with nGRE (negative- glucocorticoid responsive element).
Lipocortin-1 (= annexin-1): inhibition of phospholipase A2. This is a precursor for the arachidonic acid
pathway, which is thus also inhibited. This is the pathway that produces leukotrienes and prostaglandins.
Side effects: More side effects when used orally.
3
