23/09/2013

Asthma:
Molecular mechanism and drug
development

Prof Dr. Zullies Ikawati, Apt

Dept of Pharmacology & Clinical Pharmacy

Asthma
Asthma is a heterogeneous disorder that is characterized by
variable airflow obstruction, airway inflammation
and hyperresponsiveness, and reversibility
either spontaneously or as a result of treatment.

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Pulmonary Function Test

Specimen of Bronchial Mucosa from a Subject without Asthma (Panel A)

and a Patient with Mild Asthma (Panel B) (Hematoxylin and Eosin).
• In the subject without asthma, the epithelium is intact; there is no
thickening of the sub-basement membrane, and there is no cellular
infiltrate.
• In contrast, in the patient with mild asthma, there is evidence of
goblet-cell hyperplasia in the epithelial-cell lining. The sub-basement
membrane is thickened, with collagen deposition in the submucosal
area, and there is a cellular infiltrate.

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The Underlying Mechanism

Risk Factors (for development of asthma)

INFLAMMATION

Airway Airflow
Hyperresponsiveness Limitation

Risk Factors Symptoms- (shortness of

(for exacerbations) breath, cough, wheeze)

Pathophysiology of asthma

Nature Reviews Drug Discovery 3, 831-844 (October 2004)

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At molecular level …

Characterized by chronically increased

expression of multiple inflammatory proteins,
including cytokines, chemokines, adhesion
molecules, enzymes, and receptor

Molecular Mechanism of Th2 Helper cell’s

Inflammatory Action in Asthma
Dendritic Cells secrete IL-10  stimulating Th2 cells
Th2 Cells response in two ways:
 1st Way:
 Secreting cytokines including IL-4, IL-5 and IL-13.
 IL-4 and IL-13 cytokines stimulates B-Cells and Plasma cells  IgE
 IgE stimulate mast cells maturation
 Maturation of mast cells  mediators (Histamine and Leukotriene)
 2nd Way:
 Secreting IL-5 & IL-4  mast cells  histamine, chymase, tryptase, cysteinyl
& leukotriene
 IL-5 from these lymphocytes stimulates eosinophil.
 They released (ECP), (MBP), Eosinophil Peroxidase and Eosinophil-derived
Neurotoxin.
 All of above collectively  hyperactivity & production of transmural edema.

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(J Allergy Clin Immunol 2010;125:S95-102.)

The pathway begins with the development of TH2 cells and their
production of the cytokines IL-4, IL-5 and IL-13. These cytokines
stimulate allergic and eosinophilic inflammation as well as
epithelial and smooth-muscle changes that contract airways.

Nature Medicine Vol 18,Pages:716–725, (2012)

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Targets and mechanisms

Acute Chronic Airway

Inflammation Inflammation Remodelling

Bronchoconstriction Cell recruitment

Cellular proliferation
Oedema Epithelial damage
Extra-cellular matrix
Secretions Early structural
increase
Cough changes

Pharmacological therapy

Reliever/acute Controller/maintenance

 short-acting ß2-agonists  Corticosteroids inhalation

inhalation (salbutamol,
terbutalin)
 Anticholinergics (ipratropium
bromide)
 corticosteroids (short-term
use for exacerbations)
 Epinefrin injection
 Aminofilin injection
(beclomethasone dipropionate ,
budesonide, fluticasone, etc)
 cromolyn sodium dan
nedocromil
 long-acting ß2-agonists
(salmeterol, formoterol)
 Methylxanthines (aminofilin,
teofilin)
 leukotriene modifiers
 Imunomodulator (anti-IgE)

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Beta-2 agonis

Short acting Long acting

 salbutamol (albuterol)  formoterol

 terbutaline  Salmeterol
 adrenaline (epinephrine)  Last up to 12 hours
 (isoprenaline)
 Minutes - 4 hours

Useful Beta Adrenergic Effects

 Relax bronchial smooth muscle

 Inhibit mediator release from mast cells, eosinophils,
macrophages
 Increase mucous secretion (submucosal gl)
 Increase mucociliary transport
 Inhibit bronchial oedema
 Inhibit cholinergic transmisssion
 Decrease airway hyperresponsiveness

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Molecular mechanisms

• Activating adenylyl
cyclase  increase
cAMP level  activating
Protein Kinase A (PKA) 
bronchial muscle
relaxation
• Relaxation of bronchial
smooth muscle mediated
through action of
Salbutamol on β2
receptors may be used to
reverse the bronchial
constriction induced by
methacholine challenge
(muscarinic effect)

Theophylline

Theophylline inhibit
selectively PDE3
enzyme  increase
level of cAMP 
produce
bronchodilatation

Nature Reviews Drug Discovery 3, 831-844 (2004)

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Anticholinergics
Blockade of
muscarinic M3
receptor at
bronchial muscle

Inhibit
contraction
mediated by PLC
signaling

Relaxation of
bronchial
smooth muscle

Corticosteroids for asthma

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Corticosteroids

 Acting at intracelullar
receptors, both inside or
outside of nucleus
 Results in regulation of
gene transcriptions
resulting new proteins
 Up-regulate anti-
inflammatory enzymes
 Down-regulate pro-
inflammatory enzymes
 Used for acute asthma
exacerbation and
maintenance therapy

Regulation by corticosteroid

POMC : pro-opiomelanocortin
SLPI : secretory leukocyte protease inhibitor

http://chem4513.pbworks.com/The+Chemistry+of+Pain+Control

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EFFECTS :

Leukotriene
modifiers

 Zileuton
 Montelukast
 Pranlukast
 Zafirlukast

J Allergy Clin Immunol, 124 (3) 422-427 (2009)

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Anti-IgE : Omalizumab (Xolair)

New molecular target of

asthma medication

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Inhibition of eosinophil inflammation

Several strategies includes :
• immunomodulators (for example,
CyA, tacrolimus, rapamycin,
mycophenolate, brequinar and
suplatast tosylate),
• inhibitors of pro-inflammatory
cytokines (for example, interleukin
(IL)-4 and IL-5),
• inhibition of adhesion molecules (
exp: very late antigen-4, selectins,
intercellular adhesion molecule-1),
• blockade of chemokine receptors on
eosinophils (for example, chemokine
receptor-3 (CCR3))
• and induction of apoptosis by
corticosteroids, lidocaine and p38
(MAPK) inhibitors.
Nature Reviews Drug Discovery 3, 831-844 (2004)

Inhibit IL-5 mediated signalling

• Therapeutics that bind to

IL-5, antagonize IL-5Rα
or decrease the
expression of the βc
subunit inhibit IL-5-
mediated effects on
eosinophils.
• The activation of
inhibitory receptors,
such as CD300A, has also
been shown to inhibit IL-
5-mediated survival. Ab,
antibody.

Nature Reviews Drug Discovery 12, 117-129 (2013)

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Nature Reviews Immunology 13, 9-22 (January 2013)

Inhibition of cytokine synthesis

These include:
• inhibition of cytokine synthesis
(exp: corticosteroids),
• inhibition of transcription factors
regulating cytokine expression
(exp: calcineurin inhibitors or
decoy oligonucleotides),
• inhibition of secreted cytokines
with blocking antibodies (exp:
anti-IL-5 antibody) or soluble
receptors (exp: soluble IL-4
receptors),
• blocking cytokine receptors (exp:
chemokine receptor antagonists),
• blocking signal-transduction
pathways (exp: p38 mitogen-
activated protein kinase
inhibitors) or transcription factors
activated by cytokines (fexp:TAT6
inhibitors).

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Blocking of IL-13
• IL-13 has several effects relevant to
allergic inflammation in asthma,
including production of IgE from B
lymphocytes, increased expression
for the low-affinity receptor for IgE
(FCRII, CD23) on several
inflammatory cells, increased
mucus secretion and fibrosis and
eotaxin release from airway
epithelium.
• In addition, IL-13 induces steroid
resistance (probably by activating
p38 mitogen-activated protein
kinase).
• IL-13 can be blocked by a high-
affinity soluble receptor (shu IL-
13R2), a blocking antibody or an
inhibitor of STAT6, which is also
activated by IL-4.
Nature Reviews Drug Discovery 3, 831-844 (2004)

Anti-inflammatory action by PDE-4 inhibitor

Phosphodiesterase-4 (PDE4)
inhibitors inhibit :
• the recruitment and
activation of key
inflammatory cells,
including mast cells,
eosinophils, T lymphocytes,
macrophages and
neutrophils,
• hyperplasia and
hypertrophy of structural
cells, including airway
smooth-muscle cells,
epithelial cells and sensory
and cholinergic nerves.
Nature Reviews Drug Discovery 3, 831-844 (2004)

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Strategies to
inhibit allergic
response

• IgE can be inhibited by omalizumab (a) and low-affinity

IgE receptors by anti-CD23 (b).
• Mast cells can also be blocked by cromones and
furosemide (c), probably acting on a Cl channel and by
inhibitors of Syk kinase, which inhibit the signal-
transduction pathways activated by IgE receptors (d).
• Antigen presentation can be blocked by inhibitors of co-
stimulatory molecules (e), including B7.2, CD28, inducible
co-stimulatory molecule (ICOS) and cytotoxic T-
lymphocyte antigen-4 (CTLA4).
• TH2 cells can also be directly inhibited by IFN, IL-12 and
IL-18 (f).
Nature Reviews Drug Discovery 3, 831-844 (2004)

• Several chemokines are likely to be involved in the pathophysiology of asthma. There are3
major chemokine receptor (CCR) targets in asthma: CCR2, CCR3 and CCR4.
• CCR3 is most advanced in terms of the development of small-molecule inhibitors; in
addition, small-molecule inhibitors are now in development for CCR2 and CCR4 (for
example, INCB003344 for CCR2).
• Eotaxins, RANTES (released by activated normal T cells expressed and secreted) and
monocyte chemotactic protein-4 (MCP4) all activate CCR3, monocyte chemotactic proteins
1–5 activate CCR2, whereas monocyte-derived chemokine (MDC) and thymus and
activation-dependent chemokine (TARC) activate CCR4 and CCR8, which are predominantly
expressed on TH2 cells

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The end

LET’S DISCUSS

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