Role of different prostaglandins in asthma

Name:eman abd elraouf ahmedyoussif

Immunology department

The contentEvidence that prostaglandins cause inflammation

Mechanism of action

conclusions

references

introduction

Bronchial asthma is a disease characterised by an increased

responsiveness of the trachea and bronchi to various stimuli,

associated with reversible narrowing of the airways. A rise in

immunoglobulin E (IgE) can be demonstrated in individuals who

develop an attack of asthma on exposure to an allergen. Histamine,

SRS-A and kinins from the basophils and mast cells which are

abundant in the ungs, are liberated as a result of reaction

between allergen and cell fixed lgE.But in some individuals

it is not possib e to detect the specific allergen and increased

IgE levels in the plasma, indicating that IgE may not be the solemediator of asthma. Further, adrenergic drugs, which are commonlyused in asthma, are known to enhance cellular cyclic AMP levels andthus may inhibit or block the release of histamine, SRS-A and Kinins.However, adrenergic drugs are not always helpful in asthma. Thebeta-adrenergic theorproposes that in asthmatics there is a partialblockade of beta-receptors of the sympathetic nervous system throughwhich the beta-adrenergic drugs are known to act .

But thistheory does not explain why individuals who are not allergic to

analgesics develop an attack of asthma on exposure to analgesics1 ike aspirin, indomethacin etc., which are known to have no effect

on beta-receptors .This shows that other mechanisms may beplaying an important role in the pathogenesis of asthma. Our

recent finding that prostaglandin E(PGE) levels are low in bronchialasthmatics during an attack ,including those in whom the attack

id due to the ingestion of analgesics shows that possibly theprostaglandin system is involved in the pathogenesis of asthma.

Steroids, Analgesics, sympathetic nervous system and PGs

It is well known that PGE’s (PGEl and PGEP) are potent

bronchodilators invivo and in vitro. whereas PGF compounds are

broncho constrictor in nature(b) Prostaglandins are also known

to influence the adenylcyclase-cyclic AMP system of various types

of cells .Corticosteroids, which are employed in the treatment

of asthma are also known to modify the PG system .Treatment

of rats with PGEl and PGE2 suppresses antigen induced release of

SRS-A, which is mediated by IgE antibody .Thus it is likely

that prostaglandins have anti-allergic activity. Further, persons

who show idiosyncrasy to aspirin -like drugs is not of immunologic

type but has been shown to be due to the suppression of PG

generation in tissues of the patients .In addition PGs are

also known to regulate adrenaline and nor -’ adrenaline secretion

and thus may have a modulating effect on the beta-receptors

and the sympathetic system,

Prostaglandins in bronchial asthma.

It is possible that an exposure to bronchospastic stimuli such as a

allergens, exercise or infection may produce a fall in the PGE level

in the target cells of lungs (basophils and mast cells). This drop

in the PGE level may result in reduction in the activity of the

adenyl cyclase-cyclic AMP system, leading to the liberation of

histamine, SRS-A etc.from the target cells. This assumption is

strengthened by the observation that a fall in the PGE content of

mast cells leads to their degranulation .A fall in the levels

of the natural bronchodilator, PGE, may make the bronchial

Prostacyclin (PG12)a newly discovered member of the PG family, is

knownto have vasodilator and bronchodilator properties .PG12

is considered as a circulating hormone being released from

lungs into the circulating blood with potent platelet antiaggregating

activity (t8,lg). PG12 is synthesized mainly by the

vessel walls of several species including man ,It enhances

platelet cyclic AMP levels probably by stimulating adenyl cyclase

activity .PC12 synthesis has been shown to be regulated by PGE2

in rat liver endothelial cells and presumably a similar regulatory

mechanism might be operating in the lungs also, Low doses of aspirin

selectively affect platelet cycle-oxygenase but less avidly the vessel

wall cycle-oxygenase system .Since analgesic induced asthma can

occur after the ingestion of a single tablet of aspirin (.325 mgm)

it can be asumed that PGE synthesis is inhibited (5) whereas PGI

synthesis may be less affected. As PGE can regulate PGl2 synthesis

a primary role for PGE and PGF is indicated in asthma though a

supportive role for PGl2 cannot be ruled out,

Evidence that prostaglandins cause asthma

PLASMA PROSTAGLANDIN ACTIVITIES IN SOMEIMMUNO-INFLAMMATORY DISEASES

The role of prostaglandins (PGs) in the regulation of

immune and inflammatory responses has been investigated

by many workers (Bourne, 1974; Pelus and

Strausser, 1977).

The presence of increased PG activity in human

inflammation has been firmly established, and that

increased PG activity is a feature not only of the

integument, but also of deep tissue, is suggested by

the presence of PG activity in synovial fluid of

patients with rheumatoid arthritis (Ellattar, 1978).

Infectious processes and host defences against infection

have also been found to be connected with

dramatic changes in PG activities (Osheroff et al.,

1975; Plescia et al., 1975).

MATERIALS AND METHODS

A group of 30 asthmatic persons, ranging between

18-70yr, with spirometrically determined bronchospasm

were used. The forced expiratory volume in the first second

FEVI~ o showed values of less than 71~ in the whole group,

with an average of 50~; of these, 15 patients were free from

parasitic infestations and 15 were suffering from schistosomiasis

beside the bronchospasm. The schistosomal nature

of the condition was confined by positive urine and/or

positive stool examination for schistosomal ova. Both urine

and stool showed the presence of schistosomal ova, i.e. the

patients suffered from mixed schistosomiasis mansoni and

hematobium.

.

A group of 15 schistosomal patients of the same agegroup but not suffering from bronchospasm, with FEV~more than 80~o, were also examined.A group of 15 clinically normal subjects were taken ascontrols. The patients did not receive any treatment for atleast 15 days before the investigation was performed.Peripheral venous blood was collected from all subjects inthe early morning for PG determination. Plasma was separatedfrom the freshly collected blood and PGs were extractedaccording to the method of Unger et al. (1971). Theextracted PGs were estimated, using gas liquid chromatographicmethods according to Rosello and Gelpi(1978). The statistical analysis of the results was done usingthe Student's T-test according to Bailey (1959)

RESULTS

The plasma levels of PGF2~ and PGE in the

different groups investigated and the statistical analysis

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Prostaglandins and asthma: The use of blood components for metabolic studies

The prostaglandins (PGs) are a class of naturally occurring acidic lipidsof highly potent biologic activities.l Of the three biologically important PGs,PGFs and PGEs are actively metabolized in the lung2 whereas PGAs escape degradationby the lung. PGF,, is the major PG found in the lung of severalspecies, including man.3 PGF,, is a potent bronchoconstrictor in contrast toPGE’s which relax tracheobranchial smooth muscle.4-7 Asthmatic individualshave been shown to possess much higher sensitivity to the bronchoconstrictoractionof PGF,, than nonasthmatic subjects. +I0 In addition, PGF,, has been shownto be released from sensitized guinea pig lung following antigenic challenge,where antigenic release of PGE has not been detected by specific radioimmunoassay.”Immunoglobulin E-mediated histamine release in vitro from human leukocytesand lung fragments has been shown to be modified by PGE’s andPGF’s.~~

MATERIALS AND METHODSLeukocytes were suspended in

, Sigma Chemical Co., St. Louis, Missouri; 1.2 x 10-i M sodium chloride; 5.0 x 10-3 Mpotassium chloride; 6.0 x 10-k M calcium chloride; 1.0 x 10-a M magnesium chloride; 0.03%human serum albumin) and antigenic release and fluorometric assay of histamine wereperformed according to a method slightly modified from the one described by May.14 Thefinal leukocyte counts ranged from 3 to 4 x lOa/ml.The blood used for the assay of plasma and serum PGF was cooled in ice mater immediatelyafter being drawn from the central cubital vein. The plasma was obtained bycentrifuging heparinized blood at 1,200 g at a temperature between 0 and 4” C for 10 min.Serum was separated from the cells by allowing the nonheparinized blood to coagulate, at37” C for 30 min. All the samples were stored in silieonized glass or polystyrene tubesbelow -20’ C prior to the assay. The group of patients studied consisted of equal number ofmales and females 14 years of age or older. They had mild to no wheezing, no aspirin hypersensitivity,and positive skin tests to environmental allergens. They intermittently had sympathomimeticor xanthine drugs, but had no medication for 48 hr and no aspirin, indomethacin,or steroids for 1 wk before the morning of blood collection. Healthy males and femalesapproximately in equal numbers, over 15 years of age without a history of allergy, were thesources for the normal blood. PGF was measured by radioimmunoassay as described byCaldwell and associates.15 Anti-PGF,, antibody was obtained commercially (Clinical Assays,Inc., Cambridge, Mass.) as well as by immunizing rabbits .

RESULTSSpontaneous PGF release

The cell suspensions were incubated at 37O C for up to 40 min. The suspensions

were cooled in ice water after varying periods of incubation. PGF released

during the incubation was measured with the supernatants obtained by centrifuging

the suspension at 150 g for 8 min at a temperature between 0 and 4’ C. The

cells of both nonasthmatic and asthmatic individuals were found to release PGF

Antigenic histamine release and release of PGF

Table I shows the effect of optimal antigenic challenge on PGF levels measured

in the supernatant after 40 min of incubation at 37“ C. The antigen was

used in concentrations identical to those in a separate series of experiments which

observed the release of more than 50% of cellular histamine. Except for one patient,

D. R., who had more than 10 times as much PGF release as control on antigenic

challenge, none of the patients showed a statistically significant difference .

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CONCLUSIONSThe concept presented here envisages that the levels of PGE and PGF are

balanced in the lungs (4,5,22) which contains the Complete system for

PG synthesis and metabolism (23) and that this balance is upset on

exposure to bronchospastic stimuli. Further it is hypothesized that

corticosteroids, which are used in the management of asthma, exert

their beneficial effect by virtue of their influence on the PG system

(8). Since PGE bypasses the beta-receptor in stimulating the adenyl

cyclase (24) the therapeutic potential for PGE in asthma should be

promising, in persons who are non responsive to beta-adrenergic drugs.

As PGs are known to be involved in mast cell degranulation (12) and

nor - adrenaline secretion (lo), possibly an interaction exists between

the histamanic, beta-adrenergic and PG receptors.

Mechanism of different prostaglandins in asthma

referenceshttp://ac.els-cdn.com/0306987779901002/1-s2.0-0306987779901002-main.pdf?_tid=f3567c64-8393-11e4-88a3-

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