Asthma inflammation and cancerEman abd el-raouf ahmed

Immunology department

Medical research institute

The contentIntroduction

Causes

Amine mediators

Lipid mediators

Cytokines and asthma

Focus on IL-13 role

Asthma and cancer

pathophysiology

treatment

What’s the relation between asthma and lung cancer?

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

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.

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.

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.

D. Mediator Effects

Inflammatory mediators produce many effects in the airways, including bronchoconstriction, 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 predominantly 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)

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 .

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.

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

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

Role in asthmaMeasurement 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.

Lipid-Derived Mediators

ProstanoidsProstanoids 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

Prostanoids have effects

on the release of

inflammatory mediators

from inflammatory cells

.

Cytokines and asthma

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

Asthma and cancer

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

References:http://www.theasthmacenter.org/index.php/disease_information/skin_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&rslt=&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

://http. . /www sciencedirect com sci/ / / 108112061ence article pii S

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