Naunyn-Schmiedeberg's

Naunyn-Schmiedeberg's Arch. Pharmacol. 297, S 99 - S 101 (1977)

Archivesof Pharmacology 9 by SpringerWerlag 1977

Participation of Prostaglandins in Pathogenesis of Aspirin-Sensitive Asthma ANDRZEJ

SZCZEKLIK, RYSZARD

J. G R Y G L E W S K I ,

and G R A Z Y N A

CZERNIAWSKA-MYSIK

Departments of Allergy and Clinical Immunology, and Pharmacology, Copernicus Academy of Medicine, 31-066 Cracow, 8 Skawinska, Poland SUMMARY:

Recent evidence

suggests that the

induction of bronchoconstriction

in as-

pirin-sensitive patients by analgesics

of

oral challenge tests in which 13 different is

due to the inhibiton of PG biosynthesis their respiratory tract.

This statement is based on the results

in

PGEs might play

non-steroidal anti-inflammatory

drugs were

administered to 90 patients with aspirinsensitive asthma

(Szczeklik et al., 1975;

the main defensive role in the bronchi of

Szczeklik et al., 1976). The results re-

aspirin-sensitive

vealed that in addition to indomethacin

asthmatics.

Removal of

this potent bronchodilator by PG syntheta-

and mefenamic acid, which were already re-

se inhibitors

ported by other authors,

leaves the effects of spas-

mogens unopposed,

and possibly promotes

the release of histamine

from its stores.

several non-stero-

idal anti-inflammatory With different chemical structure)drugs were able to induce bronchospasm in aspirin-sensitive

KEY W O R D S :

asthma,

Prostaglandins,

bronchial

tics. These included:

aspirin

fen,

ibuprofen,

phenylbutazone. Among patients with bronchial asthma there is a group which can be distinguished clinical grounds rate aspirin.

since they do not tole-

In these patients

asthmaticattacks

on

severe

diclofenac,

asthmafenopro-

napro•

All these drugs markedly

inhibited prostaglandin biosynthesis microsomes

and

in

of bovine seminal vesicles,

rabbit kidney and rabbit brain. 2. Drugs which did not in hibit PG synthe-

occur within minutes to

hours following ingestion os aspirin.

flufenamate,

This

type of asthma has been estimated as va-

tase in vitro

(IC50~ 1.000 ~M) did not in-

duce any change in lung function of the aspirin-sensitive patients.

The drugs were

rying from 4 to 20 per cent among adult following: asthmatics.

The pathogenesis

of this

disorder has remained unknown.

salicyl~de,

benzydamine, chloro-

quine and dextropropo~phene.

In few aspirin-

Allergic sensitive patients these drugs were admi-

mechanism has been excluded by extensive immunological studies.

We propose that in

the sensitive patients

induction of asthma-

nistered over a period of a week in a dose of 5 tablets a day without any untoward reaction.

tic attacks by aspirin-like drugs is due 3. There is a good correlation between the to inhibition of prostaglandin biosyntheability of the drugs to induce bronchoconsis. The evidence can be summarized as follows:

striction in the sensitive patients and the inhibitory potency on prostaglandin

i. Only the drugs which inhibit prostaglandin biosynthesis

synthesis in vivo

(Szczeklik et al., 1975;

Szczeklik et al.,

1976). Thus,

in vitro induce bronchothe stron-

constriction in the sensitive patients. gest inhibitor,

indomethacin,

was also the

S 100 most powerful bronchoconstrictor in the

the ~-adrenergic one. Such a concept is in

clinical setting.

agreement with clinical observations sug-

phenylbutazone,

On the other hand,

as expected,

showed the

gesting that the importance of various me-

lowest degree of the activity in the

diators is not the same ~in different types

patients.

of asthma

4. Each aspirin-sensitive patient is cha-

Removal of endogenous PGE by PG syntheta-

racterized by an individual pattern of

se inhibitors deprives the respiratory

sensitivity

tract of a potent bronchodilator,

(Szczeklik et al., 1976).

(Szczeklik et al., to be published).

and

Thus, patients sensitive to low doses of

leaves the effects of endogenous broncho-

aspirin also respond to low doses of in-

constrictor unopposed.

domethacin,

of PGE might promote the histamine release.

fenoprofen and ibuprofen, while

Furthermore,

lack

those who develop obstruction to airflow

In vitro, PGEs stabilize membranes of ma-

only following relatively high doses of

stocytes, inhibit their degranulation,

aspirin also need high doses of other

and block the release of histamine

drugs to respond with bronchoconstriction.

tenstein,

These results can be explained by ~hhibi-

fore, opens the way to histamine action,

tion o~ the bronchial prostaglandin syn-

to which patients with aspirin-induced

thetase. They also indicate that the degree

asthma are highly sensitive

of enzymic inhibition which is sufficient

al., to be published).

to precipitate bronchoconstriction

be of clinical importance.

is an

individual hallmark of each patient.

(Lich-

1973). Removal of PGE, there-

(Szczeklik et

This mechanism may Arroyave et al.

(1976) reported that a significant rise

5. The enzymic system generating PGE in

in plasma histamine occurs in aspirin-

nasal polyp pieces of aspirin-sensitive

sensitive asthmatics following aspirin

patients has an increased susceptibility

oral challenge.

to the inhibitory action of aspirin

remained unchanged in aspirin-non-sensi-

(Szczeklik et al., to be published).

Plasma histamine levels

These

tive asthmatics and healthy subjects. We

observations appear relevant to the patho-

observed that the obstruction of airflow

genesis of the disorder discussed,

since

following aspirin ingestion can b e s i g n i -

chronic nasal congestion and

ficantly attenuated in sensitive patients

rhinorrhea,

nasal polyps are among the prominent

by the pretreatment with disodium cromo-

symptoms of the development of aspirin-

glycate.

sensitivity in the asthmatics.

of 240 mg on two consecutive days pre-

The in-

This drug inhaled in a daily dose

creased susceptibility to inhibitory a~ion

ceeding the aspirin challenge and admi-

of aspirin appears not to be restricted

nistered additionally i m m e d i a t e l y b e f o r e

to

nasal mucosa, but may also occur in

the challenge, protected completely 3 sen-

other parts of the respiratory tract,.

sitive patients against aspirin-induced

namely in bronchi.

bronchoconstriction and markedly diminished

The question which

remains to be answered is: Why does the

the bronchospastic reaction in 3 others.

inhibition of PG biosynthesis bring

Disodium cromoglycate has no bronchodila-

bronchoconstriction?

about

Our general concept

is that PGEs along with the

~ad:renergic

system play the main defensive role in

ting properties, but inhibits the release of histamine and possibly of other spasmogens from mastocytes.

These results indi-

bronchial asthma. However, aspirin-sen~

cate that several secondary mechanism may

sitive patients differ from other asthma-

be involved in the final pathway leading

tics as well as from healthy subjects by

to bronchial obturation in the sensitive

relying more on the PGEs mechanism than on

patients. We believe, however, that the results point to PGs as the modulators of

S 101

primary importance in pathogenesis of aspirin-sensitive asthma. ACKNOWLEDGEMENT This study was supported by NIH Special Foreign Currency Agreement USA N ~ 05-082 N, and by Wellcome Trust. REFERENCES Arroyave, C.M., Stevenson, D.D., Bhatt, K.N., Tan, E.M.: Oral challenge in asthmatic patients: a study of plasma mediators (abstr.) J. Allergy Clin. Immunol. 57, 206 (1976) Lichtenstein, L.M.: The control of IgE-mediated histamine release, in: Asthma, eds. by K.F. Austen and L.M. Lichtenstein, Academic Press, New York-London, 1973, p. 91 Szczeklik, A., Gryglewski, R.J., Czerniawska-Mysik, G.: Relationship of inhibition of prostaglandin biosynthesis by analgesics to asghma attacks in aspirin-sensitive patients. Br. Med. J. &, 67-69 (1975). Szczeklik, A., Gryglewski, R.J., Czerniawska-Mysik, G., Zmuda, A.: Aspirininduced asthma: Hypersensitivity to Fenoprofen and Ibuprofen in relation to their inhibitory action on prostaglandin generation by different microsomal preparations. J. Allergy Clin. Immunol. 58, 10-18 (1976)