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Systems Pharmacology 3320 2017
A/Professor Peter Henry 1
Respiratory Pharmacology
Associate Professor Peter Henry (Rm 1.34)Peter.Henry@uwa.edu.au
Division of Pharmacology, School of Biomedical Sciences
Systems Pharmacology 3320 – 2017
1 Asthma: interactions between allergens & epithelium
2 Allergic inflammation: Th2 cells, Il-4 and mast cells
3 Allergic inflammation: Th2 cells, Il-5 and eosinophils
4 Inhibiting allergic airways inflammation
5 Key mediators of allergic airways inflammation
6 Bronchodilators and Airway Hyperresponsiveness
Lecture series : General outline
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Allergen, dendritic cell & Th2 cell interactions
Drugs that block IL-4 and IgE
Targeting IL-4 and IgE
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b2-AR agonists
Muscarinic antagonists
New corticosteroids
IL-4 inhibitors
IL-5 inhibitors
Macrolides
Current therapies
Future therapies?
Relievers Preventers
Corticosteroids
Antileukotrienes
Anti-IgE antibodies
Prostaglandin E2
Targeting IL-4
Th2cell
Il-4
Il-4R
B cell
IgE production
It is possible to block:
cytokine synthesis
secreted cytokines
cytokine receptors
signal transduction
cytokine
bronchoconstrictionairway inflammation
Inhibiting cytokines: several strategies
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Dupilumab – IL-4 receptor antibody binds to IL-4Ra, and blocks binding of IL-4 and IL-13
fewer exacerbations (A) & a longer time to exacerbation (B) improvements in lung function & fewer nocturnal awakenings
Wenzel S et al. N Engl J Med 2013;368:2455-2466.
Also Wenzel S et al. (2016) Lancet 388:31-44,Effective as add-on therapy in uncontrolled asthma
Inhibiting IL-4 receptor signalling
b2-AR agonists
Muscarinic antagonists
New corticosteroids
IL-4 inhibitors
IL-5 inhibitors
Macrolides
Current therapies
Future therapies?
Relievers Preventers
Corticosteroids
Antileukotrienes
Anti-IgE antibodies
Prostaglandin E2
Targeting IgE
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Mast cell
Th2 cell
IL-4 IL-4R
STAT-6
IgE synthesis
B cell
Anti-IgE antibody
bronchoconstrictionairway inflammation
Targeting IgE
Omalizumab (XolairTM)
approved for use in severe allergicasthma not controlled by glucocorticoids.
is a humanised monoclonal antibody that binds free IgE at the site that binds to the IgE receptor.
is the first biological used for the treatment of asthma.
improves lung function, fewer symptoms & exacerbations decreased usage of steroids and b-AR agonists fewer hospitalisations & work / school days lost
is expensive and given by subcutaneous injections (every couple of weeks for 16 weeks) and continued in those whose asthma improves significantly (‘responders’).
Anti-IgE antibodies
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Omalizumab (XolairTM)
effective in children (6-18 years)
benefits persist for years
now on PBS for patients aged 12 years or older withuncontrolled severe allergic asthma (elevated IgE)
Deschildre A et al (2015) Eur Resp J. 46(3):856-9
Anti-IgE antibodies
When Th2 cells come in contact with APCs that are presenting their specific antigen (via MHC II), then the T cells become activated and increase production and release of a series of cytokines, most notably a number of interleukins (IL), including IL-4, IL-5, Il-9 and IL-13.
Th2 cell
Th2 cells are like the Generals in this war against allergen
waves of released cytokines(Il-4, Il-5)
How do Th2 cells orchestrate allergic inflammation ?
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is produced primarily by Th2 lymphocytes
expression is increased in asthmatic airways
is a major cytokine involved in the:
production of eosinophils by bone marrow (eosinophilopoiesis)
activation of eosinophils survival of eosinophils in tissues
acts via Il-5 receptors (mostly on eosinophils)
together with the chemokine eotaxin, provides an important signal for the selective and synergistic accumulation of eosinophils.
Eosinophils were
first described in
1879 by Ehrlich
Interleukin-5 (IL-5)
are granulocytes, that are present in high numbersin asthmatic airways, but not non-asthmatic airways
develop in bone marrowin response to IL-5, and are released into blood
contain many granules, which store a range of preformed proteins, the most abundant being major basic protein.
EOSINOPHILS do not effectively present antigen (unlike dendritic cells) and are not phagocytic (unlike neutrophils or macrophages).
EOSINOPHILS produce and liberate cytotoxic proteins, weapons used to kill worms that infect the gut.
In the airways, the cytotoxic proteins cause significant collateral damage, an inappropriate immune response.
https://www.youtube.com/watch?v=fw_I21RnBWg
Eosinophils
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the main protein found in eosinophil granules, and is not found in other cells.
single 117 aa chain, rich in arginine (basic).
does not have enzymatic activity.
is cytotoxic to worms and bacteria (important in host defense), but also to airway epithelium (damage to the epithelium can lead
to airway obstruction through a variety of mechanisms, including impaired degradation of sensory neuropeptides, stimulation of sensory
nerve endings etc.).
competitively inhibits the auto-inhibitory M2-cholinoceptor on parasympathetic nerves, resulting in increased Ach release and increased bronchoconstriction.
Major Basic Protein
Cytotoxic proteins, such as MBP, released from eosinophils can damage airway epithelium …
Epithelium
Eosinophil
eosinophils are like the armoured tanks in this war against allergen
MBP damages epithelial cells
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Epithelium damage can expose sensory nerve endings, stimulation of which causes reflex mucus gland stimulation & ASM contraction
Exposed sensorynerve ending
Damaged epithelium
MBP exposes sensory nerve endings
Vagal sensory nerve endings are present in the epithelium and are activated by irritants, cold dry air, exercise, etc.
Activation of sensory nerves causes a reflex bronchoconstrictorresponse (via brainstem, parasympathetic vagal efferents, Ach release)
Sensory nerve endings
Cholinoceptors on ASM and glands:Site of action of muscarinic antagonists
Sensory nerve activation causes airway narrowing
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b2-AR agonists
Muscarinic antagonists
New corticosteroids
IL-4 inhibitors
IL-5 inhibitors
Macrolides
Current therapies
Future therapies?
Relievers Preventers
Corticosteroids
Antileukotrienes
Anti-IgE antibodies
Prostaglandin E2
Targeting muscarinic cholinoceptors
Leaves of Dutara (Jimson weed or thorn apple) contain atropine, and were smoked in India for several centuries as a treatment for respiratory diseases including asthma.
Ancient Egyptians also inhaled the vapour of heated henbane (Hyoscyamus muticus), which contained another muscarinic cholinoceptor antagonist, scopolamine
Muscarinic cholinoceptor antagonists
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Ipratropium bromide
quaternary ammonium compound & with less CNS actions than atropineand scopolamine.
inhibits cholinergic reflex bronchoconstriction.
administered by aerosol, but slower onset of action than short-acting b2-AR agonists – so not used as reliever
used as a adjunct to b2-AR agonists & glucocorticoids
effective against bronchoconstriction induced by acetylcholine, but not histamine, LTs, etc.
Also tiopropium – longer-acting than ipratropium bromide because it dissociates slowly from M3 AchR – once daily dosing
Muscarinic cholinoceptor antagonists
M3 M3
M3
M3
M2ACh
ACh
Airway smooth muscle contraction
Mucus gland
secretion
Stimulation of parasympathetic vagal efferents that innervate the airways causes airway smooth muscle contraction and mucus gland secretion
M2 & M3 are muscarinic cholinoceptors
Muscarinic cholinoceptorantagonists
Major basic protein blocks M2 autoreceptor increases ACh release
Action of muscarinic cholinoceptor antagonists
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1. Approaches used to block the effects of Il-4 & IL-13 includeinhibiting the IL-4 Ra with a receptor antibody such as …………..……
2. The levels of …… can be reduced with omalizumab which is a ………………………………………………… used in ……………………..
3. Il-5 regulates the generation, activation and survival of ….……………. which release proteins such as …………………………… that are cytotoxic to ……………………… in the airway.
4. Epithelial cell damage can expose ………………………………… , whose activation can cause reflex ……………………………… & ………………………….
5. The effects of sensory nerve activation can be inhibited by muscarinic cholinoceptor antagonists such as …………………and the longer acting drug …………………
Five key revision points
At the completion of this lecture you will be able to:
describe pharmacologic strategies for inhibiting IL-4, IL-13& IgE.
describe the role of eosinophils and major basic protein in allergic inflammation.
describe how muscarinic cholinoceptor antagonists exert anti-asthma actions.
Lecture 3: Outcomes
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Read and understand the handout for our lab sessions on 28th, 29th and 30th August.
A pre-lab on-line quiz is to be completed prior to attending the lab session. It is now open & will close at 11:00 AM Monday 28th August.
The quiz will cover: - general aspects of the lab session- drugs used in the lab session- the process of allergic inflammationUse lab handout, lecture material and online resources.
Once you start the quiz on the LMS (PHAR3321), you will have 1 hour to complete it and you will get one attempt at it.
The quiz will be in the MCQ/cloze test format (31 questions) and will count for 10% of your lab mark.
Notices (for PHAR3321)
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