2. Asthma inflammation and
cancer
Eman abd el-raouf ahmed
Immunology department
Medical research institute

3. The content
Introduction
Causes
Amine mediators
Lipid mediators
Cytokines and asthma
Focus on IL-13 role
Asthma and cancer
pathophysiology
treatment

4. What’s the relation
between asthma and
lung cancer?

5. introduction
Asthma is a complex chronic inflammatory disease of the
airways that involves the activation of many inflammatory
and structural cells
all of which release inflammatory mediators that result in
the typical pathophysiological changes of asthma

8. A-Cellular Origin of Mediators
Many inflammatory cells are recruited to asthmatic
airways or are activated in situ.
These include mast cells, macrophages, eosinophils, T
lymphocytes, dendritic cells, basophils, neutrophils, and
platelets.
Indeed, these cells may
become the major sources of
inflammatory mediators in the
airway, and this may explain
how asthmatic inflammation
persists even in the absence
of activating stimuli.

9. B. Synthesis and Metabolism
Many of the key enzymes have now been cloned; in several cases,
specific inhibitors have been developed that may have useful
therapeutic effects. 5-Lipoxygenase (5-LO)b inhibitors, which inhibit
the synthesis of leukotrienes (LTs), have already been shown to
have beneficial effects in the control of clinical asthma and are now
available for clinical use .
There have been major advances in our
understanding of the synthetic pathways involved
in the synthesis of inflammatory mediators.

10. C-Mediator Receptors
The receptor for platelet-
activating factor (PAF)
was the first inflammatory
mediator receptor to be
cloned
The receptors for many
inflammatory mediators
have the typical seven-
transmembrane domain
structure that is expected for
G protein-coupled receptors.
Cytokine receptors signal
through complex pathways,
including MAP kinases and
other protein kinases, that
result in the activation of
transcription factors.
Transcription factors regulate
the expression of many
genes, including inflammatory
genes themselves.

11. D. Mediator Effects
Inflammatory
mediators
produce many
effects in the
airways,
including
bronchoconstric
tion, plasma
exudation,
mucus
secretion,
neural effects,
and attraction
and activation
of inflammatory
cells.
there is
increasing
recognition
that mediators
may result in
long-lasting
structural
changes in the
airways that
are also
mediated by
the release of
inflammatory
mediators
These
changes may
include
fibrosis
resulting from
the
deposition of
collagen,
which is seen
predominantl
y under the
epithelium
even in
patients with
mild asthma.
The airway
smooth
muscle layer is
also thickened
in asthma, and
this is likely
the result of
increases in
the number of
smooth
muscle cells
(hyperplasia)
and increases
in their size
(hypertrophy)
There may be
proliferation of
airway vessels
(angiogenesis)

12. Chronic Inflammation
Although in the past
much attention has
been paid to acute
inflammatory
responses (such as
bronchoconstriction,
plasma exudation, and
mucus hyper
secretion) in asthma, it
is being increasingly
recognized that
chronic inflammation is
an important aspect of
asthma
This chronic inflammation may
result in structural changes in the
airway, such as fibrosis
(particularly under the
epithelium), increased thickness
of the airway smooth muscle
layer (hyperplasia and
hypertrophy), hyperplasia of
mucus-secreting cells, and new
vessel formation (angiogenesis).
Some of these changes may be
irreversible, leading to fixed
narrowing of the airways.

13. Transcription Factors
Transcription
factors are DNA-
binding proteins
that regulate the
expression of
inflammatory
genes, including
enzymes involved
in the synthesis of
inflammatory
mediators and
protein and peptide
mediators.
Transcription factors
therefore play a
critical role in the
expression of
inflammatory
proteins in asthma,
because many of
these proteins are
regulated at a
transcriptional level
These transcription
factors include
nuclear factor-κB
(NF-κB) and
activator protein-1
(AP-1), which are
universal
transcription factors
that are involved in
the expression of
multiple
inflammatory and
immune genes and
may play a key role
in amplifying the
inflammatory
response.
Other transcription
factors, such as
nuclear factor of
activated T cells
(NF-AT), are more
specific and
regulate the
expression of a
restricted set of
genes in particular
types of cell; NF-AT
regulates the
expression of
interleukin (IL)-2
and IL-5 in T
lymphocytes.

14. Amine mediators
Histamine [2-(4-imidazole)ethylamine]
was the first mediator implicated in the
pathophysiological changes of asthma
Histamine increases the concentration of inositol-1,4,5-trisphosphate (IP3) in airway smooth
muscle, although the magnitude of the increase is less than with cholinergic
agonists, which may reflect lower receptor density .
Bronchoconstriction was one of the first recognized effects of histamine. Inhaled or
intravenously administered histamine causes bronchoconstriction.
Asthmatic patients are more sensitive to the bronchoconstriction effects of inhaled and
intravenously administered histamine than are normal individuals

15. Role of histamine:
Histamine may also
have effects on
inflammatory cells, and
it has been found to
influence the release of
cytokines and
inflammatory mediators
from a variety of
inflammatory and
immune cells
Histamine is a selective
chemoattractant for
eosinophils

16. Role in asthma
Measurement of histamine in the circulation is complicated by
the spontaneous release from basophils, and measurement of
stable metabolites in the urine may not reflect release from
mast cells in the airways.
It is possible that basophils from patients with asthma may be
more “leaky” and that this may contribute to the higher
concentrations measured in asthmatic patients.

17. Lipid-Derived Mediators
Prostanoids
Prostanoids
include PGs
and
thromboxane
(Tx), which are
generated from
arachidonic
acid,
COX-1 is
constitutive and
is responsible for
basal release of
prostanoids,
whereas COX-2
is inducible by
inflammatory
stimuli, such as
endotoxin and
proinflammatory
cytokines

19. Cytokines and asthma

23. Lung inflammation:
Inflammation is an
essential component of
many lung diseases,
including asthma, COPD,
lung cancer, and
granulomatous lung
diseases.

24. Asthma and cancer

26. Asthma and lung cancer
The researchers found asthmatics
were affected by lung cancer more
frequently than the general
population - the cancers registered
over the course of the study
exceeded the anticipated level by
58%.
Bronchial inflammation
generates free radicals,
and there is evidence that
the antioxidant levels in
the respiratory tract lining
of asthmatics are
reduced.
As free radicals have the
potential to cause genetic
damage, they may be
linked to the development
of tumours

27. References:
http://www.theasthmacenter.org/index.php/disease_information/ski
n_allergy/hives_or_urticaria/
http://www.cir.ed.ac.uk/
http://www.arthritis.co.za/arachid.html
http://www.clinicaltrials.gov/ct2/results?term=NIAID&recr=Open&rs
lt=&type=&cond=asthma&intr=&outc=&lead=&spons=&id=&state1
=&cntry1=&state2=&cntry2=&state3=&cntry3=&locn=&gndr=&rcv_
s=&rcv_e=&lup_s=&lup_e
http://www.worldallergy.org/professional/allergic_diseases_center/
cytokines/
http://www.centreforcancerbiology.org.au/molsig.htm
http://www.lrri.org/exploring-respiratory-inflammation-
immunology.aspx

28. www.sciencedirect.com/shttp://
1081120613cience/article/pii/S
006467