Rr.s~i~io~

Phr~iolcq~~ ( 19 7X) 32. 79m90

@El sevier North-Holland

CHANGES

OF AIRWAY

Abstract. The present

animals

preparations

isolated of airway

from

control

substrate control

asthma

smooth

and asthmatic

asthmatic

by ED,,, (effective developed

smooth

to histamine.

asthma

abolished

Similarly.

muscle reactivity,

in grams.

removing

showed

a substrate

of

It was found that tracheal a significant significantly

stimulation.

response

by ED,,

stimulation.

and contractility

change

with preparations

and carbachol

contractile

as measured

(ITP) from control

50”,, response).

animals

ASTHMA’

and carbachol

as compared

asthmatic

after histamine

preparations

did not demonstrate

or carbachol

ITP from

tension

bath significantly

animals

airway

dose developing

with experimental

isometric

tracheal

to histamine

tension expressed

muscle to histamine

isolated decreased

The absence

of ITP isolated

from the experimental

to histamine.

of

from both solution

in both control

and

animals.

After tracheal

preparation

was contracted

was tested by isoproterenol(2.43 sensitization)

(Prrru.wi.s

x IO-’

smooth

of airway

muscle smooth

by carbachol.

lower (P < 0.001) ability

significant

isolated

the ability

of airway

M). It was found that ITP from animals

has a significantly

Itt sur~~trr~~. this study demonstrates es of airway reactivity

isometric

On the contrary.

maximal

in the experimental

did not change

IN EXPERIMENTAL

ofisolated

from animals

animals.

to develop

MUSCLE

the response

by maximal

in reactivity ability

SMOOTH

with two types of experimental

of ITP was measured

ITP uas measured

Press

study demonstrates

and animals

Reactivity

Biomedical

impairment

from guinea-pigs

muscle isolated

to relax following

of both contractility

with experimental

from asthmatic

smooth

animals

muscle to relax

with experimental and relaxation

asthma.

asthma

beta stimulation. process-

On the contrary.

was not found

to be different

the than

controls. Airway

smooth

Histamine

muscle

Carbachol Experimental

As frequently pointed out (Nadel, 1967). hyperreactivity of airways The nature of this hyperreactivity Acceptedfor

puhlicalion

8 August

’ This study was supported Grant

Substrate

dependency

asthma

~‘t al., 1965, 1975, 1976; Reed, 1974; Simonsson lung. is an important pattern of the asthmatic is not established, although several hypotheses

1977.

by the National

Institute

HL-17322. 79

of Health,

United

States

Public

Health

Service,

J. F. SOUHRADA

80

were suggested (Bouhuys, 1976; Gold ei trf., 1972a. b; Nadel, 1965, 1975, 1976; Reed, 1974; Richardson et al., 1973). Most often the irritant receptors and the activation of nerve pathways are implicated to explain this phenomenon (Gold rf al., 1972b; Mills and Widdicombe, 1970; Nadel, 1965, 1975; Simonsson et al., 1967). According to hypothesis introduced by Nadel (1965), the constriction of airway smooth muscle occurs as a result of reflex response mediated via vagus. This hypothesis does not imply direct involvement of airway smooth muscle assuming that the antigen-antibody reaction occurs on the surface of mast cells or irritant receptors. Airway smooth muscle isolated from lungs of asthmatic patients, however, demonstrates a significant response to agonists or antigen challenges (Schild ct ul., 1951). A significant degree of hyperplasia and hypertrophy of airway smooth muscle cells was also shown in the asthmatic lung (Dunnill rt al., 1969; Hossain, 1973) facts which could modify airway smooth muscle reactivity and its contractile response. The present study investigated the irr rim reactivity and contractile response of airway smooth muscle isolated from guinea-pigs with experimental asthma. Utilizing the in oitro preparation eliminates direct involvement of irritant receptors, epithelial, mucous and mast cells, and could demonstrate if the reactivity and/or contractility of asthmatic airway smooth muscle itself is changed. The role of substrate in the reactivity and/or contractility of airway smooth muscle isolated from animals with experimental asthma was also studied, since it was demonstrated (Altura and Altura, 1970) that the contractile response of vascular smooth muscle to some agonists is severely inhibited when no substrate is present in the experimental bath. In addition, the present study also investigated the activity of the beta adrenergic system of tracheal preparations, since it was previously suggested that loss ofactivity of beta adrenergic receptors might be an important factor in the pathogenesis of asthma (Szentivanyi, 1968).

Method CHRONIC

EXPERIMENTAL

ASTHMA

Two different experimental models of asthma were used. In the first model a modified method of Stotland and Share (1974) was employed. Twenty male guinea-pigs (Hartley strain) were injected subcutaneously with 1.O mg of egg albumin (grade V, salt-free, crystallized and lyotilized, Sigma Chemical Company, St. Louis, MO.), and suspended in 1.O ml of saline. Then these animals received 1.O ml of ~UC~IIUS pertussis vaccine administered intraperitoneally (E. Lilly, Indianapolis, Ind.) containing approximately 16 billion killed bacilli. Twenty-one control animals were injected with saline. Two weeks were allowed for immunization, and then animals were exposed daily (5 times per week) to inhaled antigen, for a total period of 3 weeks. This procedure consisted of continuous exposure for 45 seconds to aerosolized 19., albumin administered through a nebulizer (USV Corporation) while animals were

ASTHMA

AND AIRWAY

SMOOTH

MUSCLE

81

placed in a special box (Souhrada and Dickey, 1976). The control group received corresponding treatment with aerosolized saline. In the second model the experimental protocol of Stein et al. (1961) was used. Ten male guinea-pigs (Hartley strain) were injected intraperitoneally three times on three alternating days with 0.25 ml of fresh, undiluted egg white. Two weeks were allowed for sensitization, the animals were exposed daily for a period of three weeks to inhaled antigen (Souhrada and Dickey, 1976). As in the previous group, this procedure consisted of a continuous exposure of aerosolized 1 ‘I0 albumin administered through the nebulizer (USV Corporation) for a period of 2 minutes. The control group (nine animals) received corresponding treatment with aerosolized saline. During exposure to aerosolized antigen, the animals were placed in a plastic box (30 x 18 x 25 cm) in the top portion of which a nebulizer was attached.

ISOLATED

TRACHEAL

PREPARATION

Technical details of this method were described in detail. (Souhrada and Dickey, 1976). Guinea-pigs were anesthetized (sodium pentobarbital i.p. 30 mg/kg BW), and tracheas were rapidly excised from larynx to carina. They were then immediately immersed in a warm (37 ‘C) physiological salt solution (PSS) aerated with a gas mixture of 20j:; oxygen, 5 “/, carbon dioxide, and 75 U; nitrogen (PO2 = 9OkO.5 mm Hg, PC@ = 24-11 mm Hg). The physiological salt solution had the following composition (in mmol/L): NaCl 117.5; KC1 5.37; CaCl, 2.52; MgSO, 7.0; H20 0.56; NaH,PO, 1.17; NaHCO, 15.51; glucose 5.50; and sucrose 13.65. In some experiments, those without substrate, a sucrose concentration of 19.15 mmol was used. The preparation was attached to an isometric force transducer (Grass FT 0.03) the output of which was displayed on a Beckman (411) recorder. The values of isometric tension are reported in grams. The initial length of the preparation (L,) was defined to be zero microns and the length at which no appreciable resting tension was recorded. Then each preparation was set at a tension of 0.5 grams and allowed to equilibrate for 75 minutes in oxygenated PSS. After this period, dose-response curves were performed.

DOSE-RESPONSE

CURVES

Essentially, the method of Van Rossum (1963) and Altura and Altura (1970) was used to generate cumulative log dose-response curves. Increasing doses of histamine (histamine dihydrochloride, J. T. Baker Co.) or carbachol (carbamylcholine chloride, Sigma) were administered into the experimental chamber in concentrations from below threshold to supramaximal levels, utilizing micropipettes (Beckman). Solutions of drugs in saline were prepared fresh every day, and concentrations are expressed on a molar basis.

J. F. SOUHRADA

82 RELAXATION

Tracheal

RESPONSE

preparations

beta adrenergic

with experimental (carbamylcholine mental chamber

isolated

receptors. asthma

(Prvtussis

chloride, Sigma), in two consecutive

preparations was expressed administration.

DETERMINATION

from guinea-pigs

When tracheal

OF

DNA

relax in response

preparations

sensitization)

to stimulation

from both controls were contracted

of

and animals

with a carbachol

isoproterenol was administered into the experidoses (2.43 x IOeh M). Relaxation of tracheal

in percent

of isometric

tension

achieved

after carbachol

CONTENT

The upper portion of trachea was rinsed in 0.6 N of perchloric acid, blotted and placed in liquid nitrogen. While frozen, tissue samples were weighed and placed in I ml of 0.6 N perchloric acid and analyzed. DNA was determined by a modified method of Zamenhof rt al. (1964) and Bevan rt uf. (1976), and DNA content was reported in Leg/g of wet weight. All assays were performed in triplicate with a 2”” coefficient of variation. All data are expressed as mean *SE, and the Student’s t-test for independent samples was used to determine the presence of any statistical differences. Analysis of variance was utilized to compare the doseeresponse curves. ED,, values (the dose that produces 50”. of the maximum response) represent geometric means of determination on individual were made on the logarithms

tracheal preparations. of the actual values.

Statistical

evaluations

of ED,,

Results Twenty-one days of repeated exposure of sensitized animals to aerosolized antigen did not significantly affect growth rate. Table 1 shows final body weights, wet, dry and relative weights of tracheal preparations, water content of trachea, and DNA content of trachea. In both experimental groups, larger tracheas as measured by wet and dry weights were seen ; however, this was due to the larger body size of experimental animals. In addition, the DNA content of tracheas from control and experimental groups was not different, which suggests that airway smooth muscle from asthmatic animals did not demonstrate any hypertrophy or hyperplasia. Figure 1 demonstrates histamine cumulative dose-response curves of tracheal preparations isolated from controls and both groups with experimental asthma. The gradual increase in tension of isolated tracheal preparations is proportional to the increasing dose of histamine. It can be seen that in the presence of substrate (5.50 mM of glucose) in PSS, the maximal values of isometric tension achieved in control groups were 7.86 kO.36 g. The absence of substrate in PSS significantly

ASTHMA

AND AIRWAY

TABLE Some characteristics

of tracheal

Final

preparations Tracheal

SMOOTH

83

MUSCLE

I

from controls

and animals

with experimental Relative

preparations ~

body weight Dry

(mg)

(mg)

DNA

wt.

of tracheal

‘I,, of Hz0

Wet

asthma

ng,‘g wet wt

preparations (mg of dry

(g) 360.00*

Controls

9.80

37.20+

1.40

wtikg of b. wt.)

10.20+0.37

70.90*

1.20

12.97iO.57

72.30+- 1.00

28.40&0.70

1.44*0.08

(n = 32) Chronic

asthma

462.3Ok24.10

47.6Oi2.20

28.50*

1.30

sensitization) Chronic

not determined

(egg albumin (n = IO)

asthma

455.20&

18.50

47.7Oi

1.70

13.10&0.62

P < 0.05 (controls

L‘Sasthmatic

72.30k0.84

29.OOi

I.19

1.36&0.08

( pcrtussis

sensitization) Data represent

(n = 20) mean

+SE.

animals).

decreased (P < 0.05) the maximal values of isometric tension of isolated tracheal preparations and was equal to 2.03 + 0.24 g only. Figure 1 also shows that isolated tracheal preparations from animals with both types of experimental asthma have a decreased response to increased doses of histamine, as measured by maximal isometric tension. These differences were statistically significant at P < 0.05. The reactivity of isolated tracheal preparations to histamine as measured by ED,,, (effective dose to achieve 5OY,, of maxima1 developed tension) is summarized in table 2. It can be seen that removing the substrate from the experimental medium did not affect the reactivity per se to the histamine. Secondly, no differences in ED,,,

TABLE EDsn in histamine

cumulative

doseeresponse

presence

curves

2 of isolated

(5.50 mM) and absence

tracheal

of glucose

preparations

in PSS

EDso.M Glucose

Controls

2.18f0.15~ (n = 24)

IO-’

2.81 iO.13 (n = 12)

x 10m5

Chronic

asthma

I

(egg white) Chronic

asthma

(Pertussis) Data represents

_

PSS

mean

+ SE.

II

(5.50 mM)

No glucose 1.47*0.29x

10m5

(n = 18)

2.51 kO.23 x 10m5 (n = 12)

3.80+0.97x

IO-’

(n = 8) 2.51+1.35x (n = IO)

lO-5

(guinea-pig)

in

-

control

----

/;

,’

!’ I’ !’ r’ I’ !’

,’

I’

,’

I’

,’

,I’

4

I’

log dose-response curve of tracheal preparations

6 5 -log M (Histamine)

A=20 n= 16

PSS:

(0)

= no substrate

asthma

7

0 Glucose 0 Sucrose

exp.

R =12 n = 10

-logM

6

n = 20 n = 16

control

lltistaminel

----

of tracbta

5

J,/J--I

present in PSS.

Ilnc);

(0

1=

substrate Vertical barb indlcatc +SE.

asthma (B) (solld

(5.50 mM of glucose) present m

laolated 1‘1~111 control animal, (broken line); t’rom ammals with chrome (egg white

and from animals with chronic (PWIILLG.\ sensltlzatlon)

histamine

I = 6

Glrcost I =11

0 Sucrose

l

exp. asthma

Dose rtsponst curvt to Histamine :

of track

‘Dost rtsptnst cum to Histamine :

asthma (A);

I. Cumulative

sensitization)

FIN.

6

I,,

8.

6. Pertussis

A. Albumin

85

ASTHMA AND AIRWAY SMOOTH MUSCLE

8

-logM

Fig. 2. Cumulattve animals (broken performed

carbachol

line) and animals in presence

log dose

response

with chronic

of substrate

5

6

7

I

Xarbacholl

curve

of tracheal

(Pcrr~r.\.~.\ sensitization)

(5.50 mM of glucose)

preparation asthma

isolated

from

control

(solid line). All experiments

in PSS. Vertical

bars indicate

+SE.

were observed in tracheal preparations from controls and both groups with experimental asthma. This finding suggests that airway smooth muscle isolated from animals with experimental asthma did not demonstrate different reactivity to histamine administration as compared with controls. Figure 2 shows a carbachol cumulative dose-response curve of isolated tracheas in the presence of substrate (5.50 mM glucose) in PSS. In the control experiments, the maximal isometric tension was 7.5 k 0.50 g, as compared with the experimental group

(Pertussis

sensitization)

where

this value

was 5.8f0.60.

This difference

is

statistically significant at P < 0.05. No significant differences between control and asthmatic groups were found in ED,,; in controls this value was equal to 1.69 +0.33 x IO- ’ M, and in the case of tracheal preparations isolated from asthmatic animals, this value was 2.63kO.31 x lo-’ M, To determine relaxation abilities of tracheal preparations, carbachol was administered first into the experimental chamber. This was followed by a significant increase in the isometric tension. As seen in fig. 3, when isoproterenol was administered tracheal preparations from animals with experimental asthma (Pertunis sensitization) exhibited a significantly lower ability (P < 0.001) to relax. Even when repeated doses of isoproterenol were administered 10 minutes later, tracheal preparations isolated from asthmatic animak demonstrated a significantly lower (P < 0.05) ability to relax as compared with controls.

J. F. SOUHRADA

86

90

p-y01

~--P-q.001

80

I= .O 3 g

70

Z g

60 50 40

m

1

i

m

I

2.43~10.~

4.86 x lO-6 Ilsoproterenol)

Fig. 3. A comparison guinea-pigs contract isometric

of the relaxant

with experimental with carbachol, tension

steady-state

followed

achieved tension

asthma

after

of tracheal

beta response

of tracheal

preparations

isolated

(Pwrussis

sensitization).

Tracheal

preparations

by administrations carbachol

of isoproterenol

administration

preparations

observed

was designed

from controls

in two consecutive

doses.

IOO”,,. Bars represent

after isoproterenol

and

were made

administration

to The

a new

?SE.

Discussion A guinea-pig sensitized with egg albumin represents the classical model of experimental asthma. Several weeks after sensitization, a minute amount of inhaled antigen caused severe airway constriction as seen by dyspnea, coughing and general poor being of animals. Functionally this response resembles severe bronchoconstriction seen in patients with bronchial asthma, but it differs from human asthma in several points. First, the antibody is part of another immunoglobulin fraction (IgG); second, a reaction can be evoked by soluble antigen-antibody complexes; and finally, chemical mediators may differ, histamine being quantitatively more important in the guinea-pig than in man (Bouhuys, 1974). On the other hand, it would appear that human bronchi and guinea-pig tracheas demonstrate pharmacologically similar responses (Fleisch and Calkins, 1976). Airway hyperreactivity is one of the most important aspects concerning pathogenesis of bronchial asthma. Despite numerous in oivo studies concerning hyperreactivity of asthmatic lungs (Gold et al., 1972b; Nadel, 1965, 1975; Simonsson et al., 1967), airway smooth muscle reactivity per se has received limited attention. It has been suggested that in addition to neurogenic and humoral factors (Bouhuys, 1974; Nadel, 1965, 1973), hyperreactivity of asthmatic airways may be due to alteration in the Birway smooth muscle itself (Nadel, 1976). If this assumption is correct, the dose-response curve to histamine or carbachol of a tracheal preparation

ASTHMA

AND

AIRWAY

SMOOTH

MUSCLE

87

possessing hyperreactivity should lie significantly to the left of curves obtained from controls. The present study, however, failed to demonstrate increased reactivity of airway smooth muscle isolated from asthmatic guinea-pigs to histamine or carbachol. Quantitatively, the ability of two tested agonists to combine with its membrane receptor is not different in airway smooth muscle of asthmatic animals. As previously shown (Hansen et a/.. 1974), ED,, is a suitable measure of smooth muscle reactivity. and readily reflects changes in the position of doseeresponse curves. On the other hand, this study demonstrated that the contractility of airway smooth muscle isolated from asthmatic animals is severely impaired. The term ‘contractility’ is used to refer to the force generating ability of the muscle to contract when it is fully activated (Altura and Altura. 1970; Hansen et al., 1974). A decrease of intrinsic ability to develop isometric tension after agonist administration (both histamine and carbachol) was seen in both models of experimental asthma. In this aspect, the experimental asthma as caused by Perrussis sensitization and which probably induced a partial beta blockade in target tissues (Reed, 1967; Szentivanyi, 1968), does not seem to be qualitatively different from the experimental group sensitized with egg white only. During histamine or carbachol dose-response curves, it can be assumed that activation of membrane receptors is proportional to developed tension. Thus one possible explanation for a significant decrease in maximal developed tension after agonist administration might be that repeated antigenantibody reaction interferes in some way with the action of agonist at the receptor side. This, however, does not seem to be the case. considering normal reactivity of airway smooth muscle isolated from asthmatic animals as measured by ED,,. Secondly, a consequent change in cyclic nucleotides observed in tissue of sensitized animals (Krzanowski et al., 1976; Polson et al., 1974) could modify tissue metabolism and probably interferes with excitation-contraction processes of airway smooth muscle. Removing substrate from the experimental medium significantly abolished contractility of tracheal preparations isolated from both control and experimental animals. In histamine dose-response curves without substrate, EDSo was not significantly changed as compared with those with substrate present in PSS, which suggests that the absence of substrate does not affect the airway smooth muscle reactivity to histamine. These findings correlate well with the author’s recent data (unpublished observation) which suggested that glucose metabolism of airway smooth muscle is an important factor maintaining the normal ability of smooth muscle to develop isometric tension. Finally, these studies show that tracheal preparations isolated from asthmatic animals have decreased ability to relax, following beta stimulation with isoproterenol. This finding seems to correlate well with the assumption that asthmatic airway smooth muscle indeed has impaired contractile machinery. In addition, it seems probable that this can also reflect partial beta blockade of adrenergic receptors, hypothesis introduced by Szentivanyi (1968).

88

J. I.. SOUHRADA

Available data concerning reactivity and contractility of airway smooth muscle in abnormal lungs is lacking. Simonsson et al. (1970) isolated airway smooth muscle from patients with chronic bronchitis. A five-fold increase in sensitivity (reactivity) to carbachol. response

and a lOO-fold increase

seen in a normal

to bradykinin

lung. The credibility

was found

as compared

of this data may be argued,

to the

however,

due to the fact that the mucosa of bronchi was scraped away from the muscular layer, a fact which could modify the performance of smooth muscle cells. There is an apparent analogy between presented data and data received with vascular smooth muscle isolated from animals with systemic hypertension. Both reactivity and contractility of isolated vessels from hypertensive animals after agonist stimulation was decreased (Hansen et al., 1974; Spector et al., 1969). The relevance of this data to human bronchial asthma could be questioned, since no airway smooth muscle hypertrophy was detected in the present experimental model. This is probably due to relatively short exposure of animals to repeated antigen administration, time probably being insufficient to stimulate development of airway hypertrophy. On the other hand, it is a clinical experience that the airway hyperreactivity can develop and disappear in a relatively short time (Empey et c/I., 1976). These findings do not support the assumption that airway smooth muscle per se is responsible or is a significant component of airway hyperreactivity in the asthmatic lung. However, they are compatible with the ‘reflex’ theory of airway hyperreactivity in bronchial asthma (Mills and Widdicombe, 1970; Nadel, 1965, 1975; Simonsson rt al., 1967) implying that the hyperreactive response of irritant receptors and/or nerve pathways together with consequent mediator release are factors responsible for clinically observed airway hyperreactivity in asthmatic lungs.

Acknowledgements

The technical assistance of Ms. J. Loader and Ms. G. Kaub clerical assistance of Ms. Georgia Sear is greatly appreciated.

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Rr.s~i~io~ Phr~iolcq~~ ( 19 7X) 32. 79m90 @El sevier North-Holland CHANGES OF AIRWAY Abstract. The present animals preparations isolated of ai...
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