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)