Bronchial response to inhaled prostaglandin F*(Y in patients with common or aspirin-sensitive asthma J. Orehek, Marseille,

M.D., P. Gayrard,

M.D., C. Grimaud,

M.D., and J. Charpin,

M.D.

France

The effect of aerosolized prostaglandin F,cu (PGFzcu) on specific airway resistance (SRaw) has been measured in patients with common (n = IO) or aspirin-sensitive asthma (n = 5). In all subjects PGFza caused a dose-related increase in SRaw, but considerable individual dcfberences in sensitivity were observed. The patients with aspirin intolerance did not differ from regular asthmatics in terms of their response to PGF+ Two types of reactions to PGFz(u could be distinguished from their time-course: immediate and short-lasting (3 cases) or delayed and long-lasting (12 cases). Inhalation of a Padrenergic drug rapidly and completely reversed the effect of PGF2a, suggesting that the increase in SRaw was due to bronchospasm. In 7 subjects the inhalation of an anticholinergic drug (SCH 1000) prior to PGFza inhibited to a large extent the effect of the latter, suggesting that the cholinergic system played an important role in the bronchial response to PGF2a. In 9 subjects no correlation was found between the bronchial sensitivity to carbachol and PGF2a.

Several studies’, 2 have been devoted to the relationships existing between prostaglandins and the lung. They have demonstrated that: (1) the lung is able to synthetize and release prostaglandins on various occasions but also to inactivate them rapidly; (2) the prostaglandins exert strong pharmacologic effects on some pulmonary tissues. These facts have led to several hypotheses on the possible role of prostaglandins in both the normal state and also in some respiratory disorders. Thus, it was suggested that prostaglandin F2~ (PGF2a) could play an important role in asthma as asthmatic patients were found to be very sensitive to this agent3 It has also been proposed that asthmatics with aspirin intolerance (aspirin-sensitive asthma) might be less sensitive to PGF20 than regular asthmatics.4 For these reasons we have investigated the bronchial response to PGF,a in a group of asthmatics, including some patients with aspirin intolerance.

From the Laboratoire de Mtiecine Exp&imentale and the Clinique de Pneumophtisiologie de la Faculte’ de MWecine.

Supportedby a grant of the Fond Special desComites Departementaux contre la Tuberculose et les Maladies Respiratoires. Received for publication Dec. 22, 1976. Accepted for publication March 7, 1977. Reprint requests to: Dr. J. Orehek, Clinique de Pneumopthisiologie, HGpital Sainte Marguerite, 13274 Marseille Cedex 2 France.

Vol. 59, No. 6, pp. 414-419

METHODS Subjects Fifteen asthmatics volunteered for the study (Table I). Only Subject 4 was a smoker (10 cigarettes per day). None were receiving long-term steroid therapy, and symptomatic medication was discontinued for at least 24 hr before the tests. They were tested during a symptom-free period. When several tests were performed we took care that the initial values of specific airway resistance (SRaw) were comparable. In some subjects (7, 8, 10, 12, 15), the administration of aspirin and/or other anti-inflammatory drugs which inhibit prostaglandin synthesis“ had provoked severe asthma attacks on several occasions. In addition, Subjects 7, 8, and 12 had nasal polyps.

SRaw measurements

and drugs used

SRaw was determined with a constant volume-body plethysmograph (DR-8 amplifier-recorder; Electronics for Medicine Inc., White Plains, N. Y.). For the measurements the subject panted at a frequency of 2 cycles/set,” and the thoracic gas volume measured simultaneously was close to functional residual capacity. The results were expressed either as absolute (cm Hz0 . set) or percent variations of initial SRaw. We used a solution of PGF,cu (tromethamine salt, Upjohn Laboratories, Kalamazoo, Mich.), which was prepared as follows: 1 mg of the base was dissolved in 0.1 ml of 95% ethanol and added to 0.9 ml of a 0.02% (w/v) solution of sodium carbonate in 0.9% (w/v) saline. Subsequent dilutions were made with saline to obtain the 0.01% (w/v)

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FIG. 1. Effect of the inhalation of aerosolized Maw, ordinate) of patients with common bers identify each subject (see Table I).

response

to inhaled

prostaglandin

Fs

415

PGF,(u (abscissa, doses in pg) on the specific airway conductance (solid lines) or aspirin-sensitive (dotfed lines) asthma. The num-

solution that was used. A solution without PGF,a was made up in the same manner to serve as control. A 0.1% (w/v) solution of carbachol-base (carbaminoylcholine chloride, Merck Laboratories, Darmstadt, West Germany) in saline was also used in some subjects.

Protocols To attempt to estimate the amount of drug inhaled by the patient we buseda technique detailed elsewhere.6 Briefly, the subject inhaled the aerosol (nebulizer, Gauthier, Paris, particle size of 0.1 to 5pg) from a spirometer bell as a fixed volume corresponding to a known quantity of the drug (lpg of PGF,a or 2Opg of carbachol). Inhalations of this volume were repeated until the desired dose was administered and were alternated with SRaw measurements. This procedure probably underestimates the actual amount of drug deposited in the airways. However, this error was considered to be constant throughout the tests. In all subjects we verifed that inhalation of the control solution did not consistently change SRaw. Then, each subject inhaled lkg of PGFzol and SRaw was measured immediately (in the first minute) and then 5, 10, and 15 minutes afterwards. If a change in SRaw was observed, the measures were continued at 5-minute intervals until SRaw had returned to its initial value. When the maximum change of SRaw was less than 100% of its initial value, increasing doses of PGF,(Y (5, 15, and 3Opg) were administered according to the same schedule. The interval between two PGFzcv inhalations was not constant owing to individual variauons in the time required for return of SRaw to baseline (usually 15 to 30 minutes, with extreme values of

10 to 55 minutes). After administration of the last effective dose, if SRaw did not compietely return to baseline within 15 to 20 minutes, 2 puffs of a metered aerosol of salbutamol (2OOpg) were given to the patient, and SRaw was measured 5 minutes after. In 9 subjects (1, 2, 4, 6, 8, 9, 11, 13, and 15), the bronchial response to carbachol was determined on a separate occasion. In contrast to the procedure used with PGF+r, dose-response curves were established in a cumulative manner. The dose of carbachol causing a 100% increase in initial SRaw (D 100, mg) was calculated from the curves to express the sensitivity of each subject to carbachol.6 In 7 subjects (1, 2, 3, 4, 5, 6, 7), the protective effect of an anticholinergic drug,’ SCH 1000 (Boehringer Ingelheim Laboratories, Reims, France) was studied. Two tests were performed in a randomized order at a one-week interval. Fifteen minutes before PGF,(w administration, the subject inhaled 10 puffs of either a metered aerosol containing the placebo or SCH 1000 (1OOpg per puff). The subject was not aware of the nature of the aerosol administered. Statistical calculations were performed using Student’s paired t test.

RESULTS Fig. 1 shows that the inhalation of PGF,a! increased SRaw in all the subjects tested (for each dose of

PGF,(Y the effect shown in the figure is the maximum effect observed). For a given subject, the effect of PGFza was dose-related, but the sensitivity to PGF2(r varied largely among individuals. In addition, Fig. 1 shows that aspirin-sensitive patients did not react in a

416 Orehek et al. TABLE I. Biometrical

Subject

&w (yr)

1

31 17 37 20 35 30 26 27 21

F

55

M M M M M M

2 3 4

5 6 7

8 9

10 II 12 13 14 15

38

29 35 24 33

Sex

J. ALLERGY

and functional

Height (cm)

M M F F F F

I55 173 162

160 158 172 174

170 183 183 167 162

58 56 51 49 70 60 47 52 53

E E E E E

78 72 68 70 55

E

71

of the subjects

Intrinsic (I) or extrinsic (E) asthma*

Weight (kg)

166 159 160

F F

characteristics

E E

E E

CLIN. IMMUNOL. JUNE 1977

Duration of asthma (vr)

(grass pollen) (house dust) (grass pollen) (grass pollen) (house dust) I I (house dust) (house dust, cat dander) (house dust) I I (house dust) (house dust) 1

Initial SRaw (cm Hz0 set)*

Severity of asthmat

6

DlOO carbachol (md§ 1.2

5.5 6.0 5.5 7.0 5.5 6.5 4.5 9.5 6.5

1 11 5 10 5 5 8 2

1

0.34 0.15

0.10 0.38

17

8.5 5.0

1

10.0

2 3 3

8.5 6.0

0.43 0.30 0.45

5.0

0.98

*As evidenced by skin testing. Grade 1 = less than 8 days of dyspneayearly. Grade 2 = less than 60 and more than 8 days of dyspneayearly. Grade 3 = more than 60 days of dyspnea yearly but not every day.

$-Normalvalue up to 6.5 cm H20 . set in our laboratory. §Dose of carbachol causing a 100% increase in initial SRaw.

TABLE II. Effect of successive inhalations of PGF2a and salbutamol on SRaw (cm H,O . set)”

Without

After PGF2a

Control 6.6 kO.4 (4

At the maximum of effect

Immediately before salbutamol

17.4 (+163%) kl.9

11.4

@I

TABLE III. Effect of PGF2a: on SRaw (cm Hz0 . set) without and with SCH 1000”

(+71%) 21.7 (cl

After salbutamol (5 min) 5.8 (-13%) e-o.6 (4

(a)-(b) p < 0.001. (a)-(c) p < 0.01. (c)-(d) p < 0.01. *Mean + SE of 12 subjects; numbers in parentheses indicate the

Control

SCH 1000 After PGF& 14.5

With SCH 1000

Control

After SCH 1000

After PGF&

5.8 kO.3

k-1.1

5.4 k-o.3

4.1 kO.3

5.4 kO.6

(4

@I

(cl

(4

(e)

(a)-(b) p < 0.001. (c)-(d) p < 0.01. (c)-(e) NS. *Mean 2 SE of 7 subjects. tSame dose on both tests.

percent change of SRaw from control. similar manner: 2 subjects of this group were the most sensitive whereas the remaining 3 were the most in-

sensitive subjects of the whole group. Fig. 2 shows that two types of response to PGFza could be distinguished based upon their time-course. Type A responses were immediate (maximal within the first minute) and short-lasting, and were observed in only 3 subjects (3, 8, 15). In contrast, type B responses were delayed (maximal between 5 and 10 minutes) and long-lasting. The return of SRaw to baseline, when demonstrable, was slow with high doses of PGF+. In Subject 12 the effect of PGF,a plateaued for one hour until salbutamol was administered .

Inhalation of the first dose of PGF2a usually caused coughing of the irritative type. Such cough reactions were always immediate and often disappeared with subsequent doses of PGF2a. At the end of the test some subjects experienced one or two “loose” coughs suggesting the presence of secretions in the airways. Salbutamol administration when bronchial obstruction was still present in the 12 subjects with type B reactions returned SRaw to its initial value (Table II). In Subject 14 a complete reversal was observed within one minute of salbutamol administration at the maximum of bronchial obstruction (Fig. 2). In the 9 subjects having inhaled PGF2~ and car-

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response

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prostaglandin

F2a 417

bachol, no significant correlation (r = -0, 17) was found between the sensitivity to these 2 agents (sensitivity to PGF2cz was expressed as the percentage change of SRaw caused by the inhalation of Ipg of PGF,cr and sensitivity to carbachol as D 100, Table I). Inhalation of SCH 1000 prior to PGF,a decreased the initial value of SRaw and inhibited partially or completely the effect of PGF,a (Fig. 3 and Table III). Subject 3, who had a type A response, and Subject 7, who was aspirin-sensitive, did not seem to differ from the other subjects of the group (Fig. 3). PGF*ainduced cough was not prevented by SCH 1000.

DISCUSSION The present results confirm reports that the inhalation of PGF2(r causes a bronchial obstruction in asthmatic patientss3’ 8-11 The doses of PGF2a that were found effective in these studies varied from a few nanograms3 to several hundred micrograms,1° but most of them were in the same range as ours (1 to 3Opg). These variations may probably be attributed to: (1) individual differences in the sensitivity to PGF2~ that were apparent in both our studies and those of Smith, Cuthbert. and Dunlopi and (2) variations in the techniques used for aerosol administration, calculation of inhaled doses, and measurement of effect. In keeping with other observations,14 the bronchial sensitivity to PGF2a did not seem related to clinical features of asthma such as its allergic origin, the duration, or the severity. Moreover, our observation that aspirin-sensitive asthmatics did not differ from patients with regular asthma is in contrast to the postulate of other auth0rs.l As previously reported, 3, ii, I4 the PGF,c-u-induced bronchial obstruction was slow in onset and the maximum effect occurred after several minutes in a majority of the cases studied. In contrast, the immediate and short-lasting response that occurred in 3 out of 15 cases in our study has not been reported previously. Such responses may have previously gone unnoticed owing to their brevity. Bronchial edema and/or secretions could account for the delayed effect of PGF,(Y since these would take some time to appear. The occurrence of “loose” cough in some subjects suggested an involvement of secretions. However, it seems probable that the major factor in airway obstruction was a bronchospasm since the inhalation of salbutamol promptly and completely caused its reversal. Bronchospasm occurring after a variable latency w,as also observed in isolated human bronchi.lJ In vivo it is unlikely that this delayed bronchospasm was due to the release by PGF,cr of bronchoactive substances from bronchial mast cells

0

5

10

15

20

25

30

35

40

45

50

TIME,min. FIG. 2. Time-course of the effect of PGF*u in two asthmatics. In Subject 3 the effect was immediate but shortlasting, whereas in Subject 14 the effect was delayed but prolonged. Note that in both cases the effect was doserelated. For Subject 14 note the effect of salbutamol (200 pg, dotted line).

since disodium cromoglycate did not prevent the effect of PGF+x.~‘~ I4 However, it is possible that the effect of PGF2~ was due, at least in part, to the appearance of a prostaglandin metabolite with strong bronchoconstrictor properties. l6 With either type of response, SCH 1000 prevented it partially or completely. Inhibition of the PGF2a effect by anticholinergic drugs (atropine or SCH 1000) in asthmatics has also been reported,g* 11, i3 although Newball, Keiser, and Lenfant” were unable to prevent the effect of very large doses of ?GFpa with anticholinergic drugs. Since anticholinergic drugs do not inhibit the effect of PGFza on isolated human bronchi,i5 these observations suggest that, in patients with asthma, the bronchial choiinergic nervous system plays an important role in the response to PGF,(Y. How the cholinergic system intervenes in the bronchial response remains unclear. First, PGF2a could act synergistically, as previously demonstrated for histamine,” with the cholinergic tone that impinges on the airways at rest. Inhibition of the resting tone by SCH 1000, as evidenced by the decrease of initial SRaw, could thus decrease the bronchoconstrictor effect of PGF*a. Second, PGF,a could stimulate the cholinergic ganglia as observed in other organs.ix Third, PGF,a could trigger a bronchoconstrictor reflex via the irritant receptorsrg either by stimulating

418

J. ALLERGY

Orehek et al.

CLIN. IMMUNOL. JUNE 1977

60

180

60 0 c" 9 :: $

0

-60 120 60

fi

0

-60 120 60 0 -30

FIG. 3. Effect of PGF*(Y either with (dottedlines) or without (solid lines) prior inhalation of SCH 1000. Individual results of 7 asthmatics identified by the number in the upper right corner. Administration of SCH 1000 is indicated by an arrow. Note the decrease of initial SRaw after SCH 1000.

directly these receptors or indirectly by provoking a bronchospasm. *O In this study PGF,(r appeared to have irritant properties since its inhalation caused coughing. However, the cough reaction was immediate whereas the bronchoconstrictor response was usually delayed, suggesting that it is probably the bronchospasm itself which stimulates the irritant receptors. On the other hand, immediate bronchoconstrictor responses could be due to irritation only, and their brevity supports the hypothesis of a reflex action. Finally the fact that the bronchial effect of PGFza is probably complex (e.g., possible action of a metabolite, stimulation of the cholinergic system) could explain why no correlation was found between the sensitivity to carbachol and to PGF2~. We thank Dr. A. J. Lewis who revised the English of our text. REFERENCES 1. Said, S. I.: The prostaglandins in relation to the lung: Regulators of function, mediators of disease, or therapeutic agents? Bull. Physiopathol. Respir. (Nancy) 10~411, 1974. 2. Charpin, J., and Orehek, J.: Prostaglandines et appareil respiratoire, in 4Oeme Congo&s Fran&s de M&decine, Dakar, 1975, Paris, 1976, Masson & Cie, vol. 1, 206 pp.

3. Mathe, A. A., Hedqvist, P., Holmgren, A., and Svanborg, N.: Bronchial hyperreactivity to prostaglandin F,ol and histamine in patients with asthma, Br. Med. J. 1:193, 1973. 4. Szczeklik, A., Gryglewski, R. J., and Czemiawska-Mysik, G.: Relationship of inhibition of prostaglandin biosynthesis by analgesics to asthma attacks in aspirin-sensitive patients, Br. Med. J. 1:67, 1975. 5. DuBois, A. B., Botelho, S. H., and Comroe, J. H., Jr.: A new method for measuring airway resistance in man using a body plethysmograph: Values in normal subjects and in patients with respiratory disease, 1. Clin. Invest. 35:327, 1956. 6. Grehek, J., Massari, J. P., Gayrard, P., Grimaud, C., and Charpin, J.: Effect of short-term, low-level nitrogen dioxide exposure on bronchial sensitivity of asthmatic patients, J. Clin. Invest. 57:301, 1976. 7. Engelhardt, A., and Klupp, H.: The pharmacology and toxicology of a new tropane alkaloid derivative, Postgrad. Med. J. 51 (suppl. 7):82, 1975. 8. Alinescu, R., Besson, J., and Laval, P.: Etude des reactions des voies aeriennes aux aerosols de prostaglandines (PGF,or) dans l’asthme allergique et la bronchite chronique spastique, Rev. Fr. Mal. Resp. 4(suppl. 1): 11, 1976. 9. Mathe, A. A., and Hedqvist, P.: Effect of prostaglandins F*(Y and EZ on airway conductance in healthy subjects and asthmatic patients, Am. Rev. Respir. Dis. 111:313, 1975. 10. NewbaIl, H. H., Keiser, H. R., and Lenfant, C. J.: Influence of atropine on prostaglandin F,cu induced airway constriction in normals and asthmatics, Fed. Proc. 33:366, 1974. (Abst.) 11. Patel, K. R.: Atropine, sodium cromoglycate, and

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14.

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thymoxamine in PGF*cy-induced bronchoconstriction in extrinsic asthma, Br. Med. 1. 2:360, 1975. Patel, K. R.: Effect of prostaglandin Fza on lung mechanics in extrinsic asthma, Postgrad. Med. J. 52:275, 1976. Alanko, K., and Poppius, H.: Anticholinergic blocking of prostaglandin-induced bronchoconstriction, Br. Med. J. 1:294, 1973. Smith, A. P., Cuthbert, M. F., and Dunlop, L. S.: Effects of inhaled prostaglandins E,, E2 and F,cu on the airway resistance of healthy and asthmatic man, Clin. Sci. Mol. Med. 48:421, 19’15. Sweatman, W. J. F., and Collier, H. 0. J.: Effects of prostaglandins on human bronchial muscle, Nature (Lond.) 217:69, 1968. Dawson, ‘W., Lewis, R. L.., McMahon, R. E., and Sweatman,

Bronchial

17.

18.

19.

20.

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to inhaled

prostaglandin

F$

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W. J. F.: Potent bronchoconstrictor activity of 15.keto prostaglandin Fpa, Nature (Lond.) 250:331, 1974. Douglas, J. S., Helgerson, R. B., and Bouhuys, A.: Interaction of humoral agents and regulation of airway smooth muscle responses (ASMR), Fed. Proc. 31:336, 1972. (Abst.) Tatra, N., and Satoh, S.: Prostaglandin F,a as a potent excitant of the parasympathetic post ganglionic neurons of the dog salivary gland, Life Sci. 13:501, 1973. Widdicombe, J. G.: Reflexes from the lungs in the control of breathing, in Linden, R. J., editor: Recent advances in physiology, London, 1974, J. & A. Churchill, Ltd., vol. I, 467 pp. Sellick, H., and Widdicombe, J. G.: Stimulation of lung irritant receptors by cigarette smoke, carbon dust and histamine aerosol. J. Appl. Physiol. 31:15, 1971.