Systems Pharmacology Respiratory Pharmacology. Lecture series : General outline

Transcription

1 Systems Pharmacology Respiratory Pharmacology Associate Professor Peter Henry (Rm 1.34) Division of Pharmacology, School of Biomedical Sciences Lecture series : General outline 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 A/Professor Peter Henry 1

2 Allergen, dendritic cell & Th2 cell interactions Targeting IL-4 and IgE Drugs that block IL-4 and IgE A/Professor Peter Henry 2

3 Targeting IL-4 Current therapies Relievers b 2 -AR agonists Muscarinic antagonists Preventers Corticosteroids Antileukotrienes Anti-IgE antibodies Future therapies? Prostaglandin E 2 New corticosteroids IL-4 inhibitors IL-5 inhibitors Macrolides Inhibiting cytokines: several strategies Th2 cell It is possible to block: cytokine synthesis Il-4 Il-4R cytokine secreted cytokines cytokine receptors B cell signal transduction IgE production bronchoconstriction airway inflammation A/Professor Peter Henry 3

4 Inhibiting IL-4 receptor signalling 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: Also Wenzel S et al. (2016) Lancet 388:31-44, Effective as add-on therapy in uncontrolled asthma Targeting IgE Current therapies Relievers b 2 -AR agonists Muscarinic antagonists Preventers Corticosteroids Antileukotrienes Anti-IgE antibodies Future therapies? Prostaglandin E 2 New corticosteroids IL-4 inhibitors IL-5 inhibitors Macrolides A/Professor Peter Henry 4

5 Targeting IgE Th2 cell B cell IL-4 IL-4R STAT-6 Mast cell Anti-IgE antibody IgE synthesis bronchoconstriction airway inflammation Anti-IgE antibodies Omalizumab (Xolair TM ) approved for use in severe allergic asthma 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 ). A/Professor Peter Henry 5

6 Anti-IgE antibodies Omalizumab (Xolair TM ) effective in children (6-18 years) Deschildre A et al (2015) Eur Resp J. 46(3):856-9 benefits persist for years now on PBS for patients aged 12 years or older with uncontrolled severe allergic asthma (elevated IgE) How do Th2 cells orchestrate allergic inflammation? Th2 cell waves of released cytokines (Il-4, Il-5) Th2 cells are like the Generals in this war against allergen 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. A/Professor Peter Henry 6

7 Interleukin-5 (IL-5) 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) Eosinophils were first described in 1879 by Ehrlich together with the chemokine eotaxin, provides an important signal for the selective and synergistic accumulation of eosinophils. Eosinophils are granulocytes, that are present in high numbers in asthmatic airways, but not non-asthmatic airways develop in bone marrow in response to IL-5, and are released into blood 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. contain many granules, which store a range of preformed proteins, the most abundant being major basic protein. 1RnBWg In the airways, the cytotoxic proteins cause significant collateral damage, an inappropriate immune response. A/Professor Peter Henry 7

8 Major Basic Protein 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 M 2 -cholinoceptor on parasympathetic nerves, resulting in increased Ach release and increased bronchoconstriction. MBP damages epithelial cells Cytotoxic proteins, such as MBP, released from eosinophils can damage airway epithelium eosinophils are like the armoured tanks in this war against allergen Epithelium Eosinophil A/Professor Peter Henry 8

9 MBP exposes sensory nerve endings Epithelium damage can expose sensory nerve endings, stimulation of which causes reflex mucus gland stimulation & ASM contraction Exposed sensory nerve ending Damaged epithelium Sensory nerve activation causes airway narrowing 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 bronchoconstrictor response (via brainstem, parasympathetic vagal efferents, Ach release) Cholinoceptors on ASM and glands: Site of action of muscarinic antagonists Sensory nerve endings A/Professor Peter Henry 9

10 Targeting muscarinic cholinoceptors Current therapies Relievers b 2 -AR agonists Muscarinic antagonists Preventers Corticosteroids Antileukotrienes Anti-IgE antibodies Future therapies? Prostaglandin E 2 New corticosteroids IL-4 inhibitors IL-5 inhibitors Macrolides Muscarinic cholinoceptor antagonists 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 A/Professor Peter Henry 10

11 Muscarinic cholinoceptor antagonists Ipratropium bromide quaternary ammonium compound & with less CNS actions than atropine and scopolamine. inhibits cholinergic reflex bronchoconstriction. administered by aerosol, but slower onset of action than short-acting b 2 -AR agonists so not used as reliever used as a adjunct to b 2 -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 M 3 AchR once daily dosing Action of muscarinic cholinoceptor antagonists Stimulation of parasympathetic vagal efferents that innervate the airways causes airway smooth muscle contraction and mucus gland secretion Major basic protein blocks M 2 autoreceptor increases ACh release Muscarinic cholinoceptor antagonists M 2 ACh ACh M 2 & M 3 are muscarinic cholinoceptors M 3 M 3 M 3 M 3 Airway smooth muscle contraction Mucus gland secretion A/Professor Peter Henry 11

12 Five key revision points 1. Approaches used to block the effects of Il-4 & IL-13 include inhibiting 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 Lecture 3: Outcomes 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. A/Professor Peter Henry 12

13 Notices (for PHAR3321) Read and understand the handout for our lab sessions on 28 th, 29 th and 30 th 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 28 th August. The quiz will cover: - general aspects of the lab session - drugs used in the lab session - the process of allergic inflammation Use 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. A/Professor Peter Henry 13