Mechanisms of bronchial hyperreactivity in healthy persons

MECHANISMS OF BRONCHIAL HYPERREACTIVITY
IN HEALTHY PERSONS

V.N.Solopov, S.B.Dogadkina
Medical center ‘Pulmonologist’, Moscow, Russia

KEY WORDS

Bronchial hyperresponsiveness. Microcirculation. Sinus arrhythmia. Nebulized distilled water test.

ABSTRACT

The interrelation between the bronchial hyperresponsiveness, degree of sinus arrhythmia and the state of the microcirculatory bed was studied in 64 teenagers — 38 males and 26 females aged 15-16 years. The examination program consisted of the evaluation of the microcirculatory bed state,expression of the respiratory (sinus) arrhythmia and pulmonary function (PF) investigation with bronchoprovocation nebulized distilled water test.
Photomicrographs of the microcirculatory bed were taken on a intravital slit bulboconjunctive microscope with a camera attachment. Morphometric measurments were performed on negative pictures by means of the graduated photomagnifier with an object-micrometer scale.
The degree of the sinus arrhythmia was evaluated by the ECG second standard deviation after recording of 15 cardiac complexes PQRST. For each person all the intervals R-R were measured and Means ± SD were calculated. The degree of the sinus arrhythmia was expressed by the coefficient of variation (CV):

SD
CV = ——- x 100%
Mean

The PF investigation and evaluation of the bronchial hyperresponsiveness using the nebulized distilled water test were carried out by means of the computer spirometer as follows: 1) initial evaluation of the PF indices; 2) 3 min inhalation of a distilled water aerosol by means of the highly productive (4 ml/min) ultrasonic nebulizer with particle size less than 5 mm.; 3) repeated evaluation of the PF indices. The bronchoprovocation test was considered to be positive in cases, when one of the PF indices decreased by more than 10% of predicted values and it was associated with all the indices decreasing.
It was found that bronchial hyperresponsiveness is closely connected with microcirculatory bed state and the degree of sinus arrhythmia.

INTRODUCTION

One of the characteristic feature of bronchial asthma pathogenesis determined inadequate response to various factors (execise, hyperventilation, forced respiration, fog, cold air etc.) is bronchial hyperresponsiveness /1, 2/. Primary hyperresponsiveness (without bronchial inflammation or allergy) in number of cases can play the key role in asthma development / 2 /. Since any constitutional and inherent mechanisms determine the primary bronchial hyperresponsiveness appearance /1, 2/ it is of interest to carry out a deeper study with regard to prevention of asthma development and progression.
As it is known the most probable mechanisms of hyperresponsiveness are being considered any intrinsic, parasympathetic or sympathetic disorders as well as increased delivery of different bronchoconstrictor agents (inflammatory mediators, different peptides, allergenes etc.) /1, 2/ causing bronchial mucosa inflammation. On the other hand all the inflammatory processes are closely connected with microcirculation disturbances increasing capillar permeability and causing bronchial mucosa edema /1/. With this in mind we consider that it is of theoretical interest to study the interrelation of certain physiological mechanisms and their contribution in the primary hyperresponsiveness phenomenon. One of the method using for estimation of non-specific bronchial reactivity in asthmatics is inhalation test with distilled water /3/. We decided to use nebulized distilled water test in healthy persons and to find any relationship between bronchial hyperresponsiveness, state of the microcirculatory bed and expression of parasympathetic (vagal) activity manifesting by the phenomenon of the respiratory (sinus) arrhythmia /4/.

SUBJECTS AND METHODS

We examined 64 teenagers aged 15-16 years (38 males and 26 females), non-smokers, occupying physical culture on common program with no history of respiratory or cardiovascular diseases. All the subjects were investigated in the morning hours. The examination program consisted of the evaluation of the microcirculatory bed state, expression of the respiratory (sinus) arrhythmia and pulmonary function (PF) investigation with bronchoprovocation nebulized distilled water test.
Photomicrographs of the microcirculatory bed were taken on an intravital slit bulboconjunctive microscope with a camera attachment using the analogous Kodak black & white film with a resolution 300 lines/mm. The original micrographs were taken in each person two times. Morphometric measurments were performed on negative pictures by means of the graduated photomagnifier with an object-micrometer scale.
The degree of the sinus arrhythmia was evaluated by recording of the ECG second standard deviation as follows: in resting respiration 15 cardiac complexes PQRST were recorded. Then for each person all the intervals R-R were measured and Means ± SD were calculated. The degree of the sinus arrhythmia was expressed by the calculating of the coefficient of variation (CV):

SD
CV = —— x 100%
Mean

The PF investigation and evaluation of the bronchial hyperresponsiveness using the nebulized distilled water test were carried out by means of the computer spirometer (Vitalograph-Compact) as follows:
1) initial evaluation of the PF indices:Vmax 25%, Vmax 50% and Vmax 75% — maximum expiratory flow at 25, 50 and 75%, respectively, of forced vital capacity;
2) 3 min inhalation of a distilled water aerosol by means of the highly productive (4 ml/min) ultrasonic nebulizer with particle size less than 5 m.;
3) repeated evaluation of the PF indices.
All the PF indices were expressed as a percent of predicted values / 5 /. The bronchoprovocation test was considered to be positive in cases, when one of the PF indices decreased by more than 10% of predicted values and it was associated with all the indices decreasing.
Thus the examination program included measuring the following parameters:
1) AI and AII — diameter of arterioles of the first and second divisi ons (mm);
2) CV — coefficient of variation (in per cent) as a degree of sinus ar rhythmia expression;
3) Vmax 25%, Vmax 50% and Vmax 75% — maximum expiratory flow, respectively 25, 50 and 75% of forced vital capacity;
4) ReVmax 25%, ReVmax 50% and ReVmax 75% — bronchial response («+» — increase; «-» — decrease) to inhalation nebulized distilled water test.
Statistical analysis of the obtained results was performed by applying the methods of variation statistic and correlation analysis. The large standard deviations and abnormal distribution determined the use of nonparametric methods: Wilkoxon’s unpaired test and Spearman’s correlation analysis.

RESULTS

According to the results of bronchoprovocation test with nebulized distilled water all the subjects were divided into two groups (table 1).

Table 1. The results of subjects’ investigation
(X ± SEM)

*W — Wilkoxon’s test (* — p<0.05, ** — p<0.01) the 1st group vs. the 2nd group.

The first group comprised 22 persons with bronchial hyperreactivity resulted in decreasing of flow-volume curve indices. In 7 out of these 22 teenagers we found slight clinical symptoms of bronchoconstriction: cough and wheezes revealed by auscultation. In one youth aged 15 years after 3 min inhalation we observed an appearance of acute expiratory dyspnea which was arrested by the inhalation of one dose (0.2 mg) of fenoterol. His PF indices dynamics was the follows: a) initially — Vmax 25% = 101%, Vmax 50% = 109% , Vmax 75% = 99%; b) on the background of bronchoprovocation test — Vmax 25% = 60%, Vmax 50% = 54%, Vmax 75% = 41%; c)20 min after fenoterol inhalation — Vmax 25% = 102%, Vmax 50% = 108% and Vmax 75% = 99% of predicted values.
The second group comprised 42 individuals without realible bronchial response (more than 10% of predicted values) to inhalation of nebulized distilled water. As it is seen from the results of table 1, there was not significant difference between the both groups as compared with initial PF and microcirculatory bed state indices. Of interest is the fact that the degree of sinus arrhythmia in teenagers with bronchial hyperresponsiveness was significantly lower than in subjects without realible response to inhalation of nebulized distilled water.
The correlation analysis of the data referring to the first group (table 2) has revealed the presence of a direct relationship between the initial maximum expiratory flow indices — Vmax 50%, Vmax 75% and the diameter of arterioles of the first and the second division. A direct relationship has been also revealed between the microcirculatory bed state (AI, AII) and the severity of bronchial response to nebulized distilled water inhalation (DVmax 25% and DVmax 50%). In the first group of subjects under study an inverse relationship between the value of bronchoconstrictive response to the provocation with nebulized distilled water (DVmax 50%, DVmax 75%) and the degree of sinus arrhythmia was also found.
In the second group of teenagers — with the lack of bronchial hyperresponsiveness — such interrelations was not found.

Table 2. The results of correlation analysis in teenagers with bronchial hyperresponsiveness

1 — correlation test; 2 — value of probability.

The correlation analysis revealed only the presence of an inverse relationship between the maximum expiratory flow — Vmax 25% and the degree of sinus arrhythmia (r = -0.340, p < 0.05). Thus the obtained results show that the bronchial hyperresponsiveness in healthy persons is closely connected with the microcirculatory bed state and the degree of sinus arrhythmia.

DISCUSSION

Our explanation of the obtained data will be based on the affirmation that the PF indices Vmax 25%, Vmax 50% and Vmax 75% reflect correspondingly the airway conductance of the large, medium and small bronchi.
Firstly one can see from the obtained data a different interrelation between the PF indices or bronchial response to nebulized distilled water and the degree of sinus arrhythmia (table 2). An inverse relationship between the value of bronchoconstrictive response of middle and small bronchi (DVmax 50%, DVmax 75%) to bronchoprovocation test and the degree of sinus arrhythmia in the first group can be explained as an effect of vagal influences against the background of the unfavourable environmental agents action. And an inverse relationship between the airflow conductance of large bronchi and sinus arrhythmia degree in the second group reflects probably a natural interdependence of vagal activity with bronchial tree tone. Therefore, vagal influence is manifested quite differently in subjects with bronchial hyperresponsiveness and without it. In the former case it consists in exaggeration of bronchoconstrictive response to the unfavourable environmental agents, while in the latter — it reflects a regulatory action on the large bronchi tone.
The fact that a degree of sinus arrhythmia within the first group has been found to be significantly lower than that in the second group (table 1) may be explained as follows: in pathogenesis of bronchial hyperresponsiveness not absolute but relative predomenance of parasympathic (vagal) activity as a result of diminished sympathic (adrenergic) influences is of primary importance. And since the state of the microcirculation bed (particular its arteriolar link) is mostly determined by adrenergic activity, interrelationship between the microcirculatory bed state (diameter of arterioles of the first and the second division — AI, AII) and bronchial hyperresponsiveness is quite clear: adrenergic activity decreasing results in increse of microvascular permeability and swelling of the bronchial mucosa which is observed as a direct influence on the initial maximum expiratory flow indices — Vmax 50%, Vmax 75% as well as on the severity of bronchoconstrictive response to nebulized distilled water inhalation (DVmax 25% and DVmax 50%) (table 2).
Thus the use of inhalation test with nebulized distilled water permits on the one hand to select the subjects with bronchial hyperresponsiveness representing probably high risk group for asthma contracting. On the other hand the presence of relationship between the bronchoconstrictive response to nebulazed distilled water and microcirculation bed state contributes to a need for preventive measures elaboration in these group during the epidemics of respiratory acute diseases because acute inflammation and mucosa edema due to microvessel dilation and plasma exudation combined with an inadequate response to unfavourable inviromental agents can lead to forming of bronchial obstruction and then to development of the disease.

ACKNOWLEDGMENTS:

The authors would like to express their gratitude to «VITALOGRAPH Ltd» for supplying spirometer, used in carrying out this investigation. The authors are very grateful personally to signor Piero Jacomoni from «MONNALISA S.r.l» (Italy) for his support of the medical center «Pulmonologist» (Moscow) with personal computer.

REFERENCES

1. Cross CE: Pathogenic Mechanisms in Asthma; in Gershwin ME (ed): Bronchial Asthma. Principles of Diagnosis and Treatment. Grune & Stratton. New York. 1981, pp. 53-71.
2. Pauwels R, Snashall PD. A Practical Approach to Asthma. CBA Publishing Services. Printed by Adlard & Son Ltd. Dorking. 1986, pp. 19- 32.
3. Dal Negro R, Allegra L.: Distributional Methods and Invasive and Noninvasive Gas Analysis in Asthma; in Allegra L, Braga PC, Dal Negro R (eds): Methods in Asthmology. Springer-Verlag. Berlin, Heidelberg. 1993, pp. 126-155.
4. Porges SW: Vagal mediation of respiratory sinus arrhythmia. Implications for drug delivery. Ann N Y Acad Sci 1991; 618: 57-66.
5. Knudson KJ, Slatin C, Lebowitz MD, Bunrows B: The maximal expiratory flow-volume curve. Normal standards, variability and effects of age. Am Rev Respir Dis 1976; 113: 587-600.

Translated from the book:
V.N. Solopov. Asthma and Asthmatic, Moscow, 1992

Dr. V.N. Solopov
28 Lenskaya str.129327, PO BOX 23, Moscow, Russia