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REVIEWS Study of Therapeutic Mechanism of Acupuncture in Treating Bronchial Asthma LI Ji ( ~

~ ) and DONG Jing-cheng ( ~ ; 1 ~ )

It has been considered by modern medicine that bronchial asthma is a chronic airway allergic inflammation (AAI) which is the major factor that induces reversible airway ventilating disturbance and bronchial hyper-responsiveness (BHR) in asthmatic patients, as well as a correlation between the delayed-phase onset of asthma and AAI is more significant than immediate-phase onset of asthma in its pathogenesis. Anti-inflammatory therapy as a fundamental principle of treatment for bronchial asthma has been brought forward during the interval phase so that a large number of antiAAI drugs to significantly enhance the curative effect such as inhalant corticoid, disodium cromoglycate, and leukotriene receptors antagonist, etc., has been rapidly developed. Additionally, traditional Chinese medicine (TCM) and integration of TCM and western medicine (WM) therapies, including acupuncture, are gradually taken into account by the medical circle as a characteristic in our country for treatment of bronchial asthma. It is worthy of being pointed out that the curative effect of acupuncture and moxibustion in treating asthma is evident, and that its therapeutic mechanism has to a certain extent, been found along with the recent deep-going acupunctural research. EFFECT OF ACUPUNCTURE ON INFLAMMATORY CELLS

Eosinophil is one of the key cells which causes AAI, BHR and delayed-onset asthma response, and drugs for treating asthma such as corticosteroid, aminophyllin and sodium

cromoglycate, etc., during the time of remittence to asthmatic symptom, can reduce the count of peripheral eosinophil while at the same time relieve asthma. Acupuncture, likewise, can reduce the count of eosinophil. YANG Yong-qing, et al. r discovered that direct and differential counts of eosinophil in peripheral blood were revealed to be lower in 20 allergic asthma patients after acupuncture therapy and other acupunctural treatments, such as, acupoint injection of drugs r , suppurative moxibustion~3), moxibustion-plasterr all induced similar results. These results showed that using acupuncture and moxibustion to control allergic asthma onset possessed positive therapeutic effect, that it also can promote eosinophil apoptosis, and its therapeutic mechanisms for treating asthma had potential relationship to its anti-AAI effect via inhibition of airway inflammatory cells which release inflammatory factors. ANTAGONISM OF ACUPUNCTURE ON INFLAMMATORY MEDIA

Sulphur-peptide leukotriene almost represents all biological activity of slow reaction substance (SRS-A), which is a strong contractile factor of bronchial smooth muscle [leukotriene I)4 ( LTD4 ) and leukotriene C4 (LTC4) yield the strongest effect], as well as The Affiliated Huashan Hospital of Shanghai Medical Universiy, Shanghai (200040) Correspondence to: LI Ji, M . D . , 12 # Mid-Urumehi Road, Huashan

Hospital, Shanghai 200040;Teh 0 2 1 - 6248999 Ext. 6592; Fax: 021 - 64283265 ; E-rr~l: leeji68(~163, net

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one of the important inflammatory media to cause asthma attacks. WANG Ju, et al. (s.6), observed the effect of acupuncture on LTD4 and LTC4 in treating asthmatic patients by using leucocyte adhesion inhibition test ( L A I ) , the results of which indicated a significant variation of LTD4 vs LAI: the conversion of positive to negative LAI being 73 % ; and the same results were observed in another group of a variation of LTC4 vs LAI. It was reported by Sternfeld (7) that the production of LTC4 in asthmatic patients can be reduced by acupuncture, which means that the inhibitory effect of acupuncture on the production of inflammatory mediums LTD4 and LTC4 may be one of the essential mechanisms to obtain certain efficacy of acupuncture therapy in bronchial asthma. In addition, acupuncture can reduce the elevated concentration of serum histamine in asthma patients during its attacks (8) . SUN Gui-xia discovered the declining of serum histamine contents ( P < 0.05) of asthma patients in clinical study of 141 patients treated by acupuncture (9) , indicating that acupuncture has anti-inflammatory and anti-asthmatic function. EFFECT OF ACUPUNCTURE ON IMMUNE CELLS

AAI occurrence is closely related to serum IgE, whose synthesis and inactivation is regulated by T lymphocytes; under the stimulation of antigen, the enhancing of T lymphocytes' function in synthesizing interleukin, etc. is a key factor in leading to the occurrence of allergic reaction. Therefore, it is significantly important that the variations of serum antigen such as specific IgE, IgG, IL-4 and lymphocytic transformation, and the changes of the function for lymphocyte subpopulation (CD3 + , CD4 + , CD8 § ), brought about by acupuncture in treating asthma patients be observed. It was reported (~~ that serum total IgE of asthma patients treated with acupuncture was lowered for 54 % ( P < 0.01 ) than that of those untreated; and the same was true

with moxibustion. This result showed that acupuncture and moxibustion therapy in asthma patients could inhibit the immediate-type of allergic reaction in view of IgE intervening in antigen release from mastocyte as well as delayed-type allergic reaction in view of IgE intervening iti antigen release from eosinophil. LU Ying (12} , using moxibustion-plaster to study immunological parameters of asthma, discovered that the changes of IgG and IgM in asthfna patients were significant before and after ~tctlpuncture treatment, and conceived that improvement of patients' symptoms may be due to IgG increment in organism so as to reinforce immune function of asthma patients. Li De~yan(13) , found that there was no influence on serum IgE levels by suppurative-moxibustion therapy through the study with autocontrolled ~ethods, and also believed that the effect won by the therapy on asthma was not eorrelated with serum IgE levels. It was pointed out that the symptomatic improvement in asthma patients was due to changes in count of specific IgE antigen combined with target cell surface, not due to that of serum IgE (m . Therefore, the result of above-mentioned research is not convincing, and there should be more study on the effects of acupuncture with antigen of target cell surface and the changes of specific IgE level. YANG Yong-qing et al(1~ . discovered that in the peripheral blood of asthma patients treated with acupuncture, IL-2R + activating T lymphocyte counts was obviously abated ( P < 0. 001 ), while all the T lymphocyte subpopulation (CD3 +, CD4 +, CD8 § ) were elevated compared with before acupuncture treatment. H U Zhi-guang (is) found that acupuncture therapy was able to increase the lowered CDs* counts so as to reduce the elevated CD4 +/CDs + ratio and IL-4 ( P < 0. 0 1 ) . HONG Hai-guo ( m e t al. found the same result by means of observation on the effects of suppurative~moxibustion on CD3 + , CD4 § counts in asthma patients. It was indicated that acupuncture possessed an extensively anti-allergic

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effect and could enhance immunological function. The rise of serum specific IgE of asthma patients may be due to insufficient CD8 + counts and excessive CD4 +/CD8 + ratio. Allergicreaction can be controlled in asthma patients via the regulatory effect of acupuncture and moxibustion on T lymphocytes subpopulation so as to lower the serum specific IgE counts. REGULATORY EFFECT OF ACUPUNCTURE ON cAMP AND cGMP CONTENTS

It is assumed by modern medicine that an increase of intracellular cGMP contents would accelerate the release of bioactive substance and then stimulate vagus receptor of bronchial submucosa, which would induce bronchial constriction, thus leading to asthma attacks; while intracellular cAMP stabilized the membrane potential of bronchial smooth muscle and blocked the release of bioactive substance, which would lead to bronchial dilatation, thus preventing asthma attacks. It is presumed generally bronchial dilative effect would be produced when the increase of cAMP or decrease of cGMP takes place, consequently elevating the cAMP/cGMP ratio. In the study of the acupunctural effect on cAMP and cGMP contents in pulmonary tissue and plasma in experimented allergic asthma guinea-pig, it was found that cAMP contents in pulmonary tissue and plasma of asthmatic guinea-pig were lower than that of normal subjects ( P < 0.05), their cGMP contents in pulmonary bronchial tissue were higher than that of normal subjects, though plasma cGMP contents did not obviously change; but cAMP contents in pulmonary bronchial tissue and plasma were synchronously elevated ( P < 0.05) in asthmatic guinea-pigs treated by electro-acupuncture(ls'17) . It is postulated that the therapeutic effect of electro-acupuncture in asthma is due to intracellular cAMP contents of smooth muscle maintained at a normal level via its regulation of cAMP/cGMP ratio. From this the consistency of acupuncture' s regulating direction is in-

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ferred, thus indicating that acupuncture's regulating cyclic nucleotide level is a benign link at the holistic regulations. Moreover, clinical studies showed that acupuncture, acupoint-injection, moxibustion and laser-moxibustion can all raise plasma cAMP levels and cAMP/cGMP ratio of asthmatic patients (n'18) . Hence, it is significant that the changes of plasma cyclic-nucleotide levels are clinically determined in asthmatic patients treated by acupuncture and moxibustion. Yet the changes of their tissue cyclic-nucleotide level needs to be further studied. REGULATORY EFFECT OF ACUPUNCTURE ON II-ADRENERGIC RECEPTOR

13-adrenergic blockade theory puts forward that a 13-receptor hypofunction induced tension elevation of bronchial smooth muscle, and the extent of the decrease of 13-receptor is correlated to the impairment of respiratory function (19) After long-term application of 132-receptor agonist to treat asthma clinically, the responsiveness of airway 132-receptor against its agonist was lowered, which is called 132-receptor down-regulation, hence producing resistance to drugs in asthma patients. JIN Yuan-jiu(2~ adopted an experimental methods of receptor function to observe the relaxation effect of lung-trachea strips in asthmatic guinea-pigs on isoprenaline, and the result showed that in the lung-trachea strips of asthmatic guinea-pigs the affinity of 13-receptor to its agonist isoprenaline became lower than that of normal control, and electro-acupuncture therapy in asthma animal can restore this affinity to normal levels, but produces no effect in normal animal. LI Tao (21) et al. reported that the number of 13-receptor in model group are lowered by 38 % ( P < 0.01 ) than that in normal group, that acupuncture therapy in asthmatics can restore the number of 13receptor to normal levels, but produces no el-

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fect in normal animals, and also the number of [3-receptor in pulmonary tissue of guinea-pig has an obvious trend to decrease with the increase of asthma attack frequency, which was found by a study on maximum-combining amount of guinea-pig ~-receptor combining 3Hdihydroalprenolol. Moreover, CHEN Ling <2~ reported the experiment of using auricular-acupoints to study 13-receptor of asthmatic guineapig lung tissue and the result is the same as above. It suggested that acupuncture regulates the numbers of ~-receptor in asthmatic guineapigs lung tissue to a certain extent, which turns a down-regulation into up-regulation, and can lower 13-receptors' resistance to its agonist.

ACUPUNCTURE'S REGULATION OF HYPOTHALAMUS-PITUITARYADRENAL CORTEX AXIS (HPA-axis) SHEN Zi-yinC23~et al. assumed that asthmatic patients, who were diagnosed by TCM as Kidney Yang deficiency syndrome, had mild potential HPA-axis hypofunction, especially, those who were administrated with corticosteroid for a long-term had their HPA-axis function suppressed and adrenal cortex atrophied; but regulation on functions of HPA-axis system could elevate excitation of HPA-axis (which was inhibited by exogenous hormone), protect adrenal cortex, as well as enhance the long-term effects of asthma, helping the patients to withdraw corticosteroid. In clinical study, FENG Jian-guo ~24~, discovered that after treatment of acute attacks of asthmatics with acupuncture, asthma patients had their immediate serum-cortisol level raised, which was, also insignificantly different from that of two weeks after acupuncture. Acupuncture therapy in asthma patients could markedly improve adrenal cortex function in the study of hormone-dependent patients with severe symptoms ~25) . HE Zi-yang ~ls~ , used laser-moxibustion theray in asthma through the observation in his random controlled trial and found that serum-cortisol level was lower in asthma patients than that in healthy people ( P <

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0 . 0 1 ) , especially in those who were diagnosed as Kidney deficiency it was the lowest. Compared with Lung, Spleen deficiency group, the difference was significant ( P < 0.01 ). Additionally, it was also found that serum-cortisol levels were promptly increased in asthma patients treated by laser-moxibustion in Sanyinjiao (SP6) and the urinary 17-hydroxyl corticosterone as well as urine 17-ketone corticosterone levels were raised, too ( P < 0.01 ) r In experimental study on electro-acupuncture stimulation at acupoint Zusanli (ST36) in rats to prevent adrenal cortex hypofunction and atrophy, it was discovered that the weight of adrenal gland were significantly heavier in the tested group than that in the control group, and that in zona fasciculate and zona reticularis the nuclear density of adrenal cortex were smaller than that of the control group (27,zs) , which indicated that in zona fasciculate and reticularis the nucleus v o l u m e were relatively larger in the tested group. Therefore, it is assumed that electro-acupuncture exerts antagonism to the influence of negative feedback of dexamethasone vs HPA-axis, which prevented exogenous ~3-receptor adrenal cortex hormone from adrenal cortex atrophy or alleviate it, thus protecting animals' adrenal cortex function. ZHAO Xiang-jie's studies (29) also elucidated that acupuncture could efficiently antagonize negative feedback action of exogenous hormone vs HPA axis and stimulated the adrenal cortex suppression. Moreover, acupuncture could increase adrenocorticotrophin ( A C T H ) activity in peripheral blood. A great deal of studies revealed that acupuncture exerts an obvious regulation on ACTH secretion. Although acupuncture and moxibustion themselves cannot support any exogenous substances, with respect to its therapy in asthma patients, especially in the hormone-dependent ones, it can influence HPAaxis function and elevate HPA-axis excitation. Nevertheless it still lacks multi-factors analysis in the study of the regulatory effects of acupuncture .on HPA-axis, which remains to be

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further studied. IMPROVING EFFECTS OF ACUPUNCTURE ON PULMONARY FUNCTION

The pathophysiologic feature of asthma in ventilatory aspects is a reversible rise of airway resistance, particularly in expiration phase, and indexes of expiratory flow concerning asthma attacks such as one second forced expiratory volume (FEV1), the percentage ratio of one second forced expiratory volume to vital capacity ( F E V 1 / F V C % ) , maximum metaphase expiratory flow rate ( M M F R ) etc., were all remarkably decreased. Therefore, whether acupuncture and moxibustion could influence these indexes or not would be a proof whether it could play a role in improving airway reversible resistance. It has been reported previously in 1961 regarding the study of acupuncture's improving pulmonary function that acupuncture therapy could reduce airway resistance in asthma patients (3~ . ZHANG Xiaoping, et al. discovered in 1981 that pulmonary ventilation volume in asthma patients were markedly increased by consecutively acupuncturing at Feishu (BL13) for one week and the effect remained for a period of time after ceasing the therapy (m . Recently, ZHANG Ya-xi, et al. (32) discovered after more studies of acupuncturing Feishu that FEV1, maximum expiratory flow rate - volume curves ( M E F V ) including peak value of expiratory flow rate, 75 %, 50 %, 25 % of vital capacity of peak expiratory flow rate (VpEAK, VTs, Vs0, V2~ ) were all evidently changed after acupuncture, and there was a time-effect relationship: the therapeutic effect appeared 20 min after retaining needle, it was the strongest at the 40th min, and declined at the 60th rain; they also discovered that passage function of tracheole were markedly improved by acupuncture. Similarly it was found that VC, FEVi] F V C % , MEFV, MMFR, and other indexes were all markedly raised in laser-moxibustiontreated asthma patients (~8~. In the study on

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acupuncture in asthma patients, various degrees of changes in the indexes such as FEV1/ F V C % , MEFV, VTs, Vs0, V2s, etc., except for VC, were found by SUN Lan-ying(3) . Acupuncture and moxibustion therapy in asthma aspects in clinical and experimental studies has acquired many achievements, but on the whole, there was more study on clinical effect of acupuncture and moxibustion, and few on its therapeutic mechanism. It is believed that along with modem medicine understanding in the pathogenesis of asthma onset, the study on therapeutic mechanism of acupuncture and moxibustion in asthma would make a new breakthrongh. It is a fundamental premise that whether acupuncture and moxibustion can cure and prevent asthma attacks is decided by the clear understanding whether the mechanism of acupuncture and moxibustion in treating asthma is mainly its anti-inflammatory effect, or anti-asthmatic effects, or any other effect. Besides, the effect of acupuncture and moxibustion' s facilitating withdrawl of corticosteroid (i. e. whether its regulation of HPA-axis could remain effective for a long-term) has to be confirmed, too. A resolution of these problems requires a rational design of clinical and laboratory study. With respect to methodology in clinical trial, randomized double blind controlled trial is equally required in making an investigation on acupuncture and moxibustion. Through its review of the study of therapeutic mechanism of acupuncture and moxibustion on asthma, this paper elucidates that the acupuncture and moxibustion exerts its effects on asthma are due to involvement of regulation through multi-links, multi-levels as well as dual-directions, etc. But the study on all these therapeutic mechanism has to be improved in research level, for instance, we have to carry out research at the cell-molecular level. REFERENCES 1. YANG YQ, CHEN HP, W A N G RZ et al. The effect of acupuncture therapy in asthma patients on activated lyre-

9 74 ' phocyte and eosinophil in peripheral blood. Shanghai J of Acupunc and Moxibus 1995 ; 1 4 ( 2 ) : 5 8 - 59. 2. YE ST. Observation on curative effects of injection of immune drugs at acupoint on mites in treating allergic asthma. CJITWM 1987;7(8):486 - 488. 3. SUN LY. Analysis and observation on multiple indexes of treating asthma with moxibustion-plaster at three hottest periods. Shanghai J of Acupunc and Moxibus 1987 ; 6 (3) :3 --4.

4. YAN H. Suppurative-moxibustion therapy for 299 cases with bronchial asthma. Shanghai J of TCM and Pharmacology 1981;(5) :29 - 31. 5. WANG J, PAN Z. Study of the therapeutic effect of acupuncture on leukotriene medium in bronchial asthma patients. J of Shenyang Med Univer 1993 ; (7) : 1 - 2. 6. WANG J, PAN Z, LI SY. The influence of acupuncture on bronchial asthma and leukotriene medium I)4. Chin J of Acupunc and Moxibus 1996; 16(12) : 6 4 8 - 649. 7. Sternfeld M. The role of acupuncture in asthma changes in airways dynamics and LTC4 induced LAI. Am J Clin Med 1989 ; 17(3 - 4) : 129 - 131. 8. ZHANG YP. Research on therapeutic mechanism of acupuncture and moxibustion. Hefei : Anhui Science and Technology Publishing House, 1983: 59. 9. SUN GX. The clinical observation on acupuncture therapy for 141 cases with bronchial asthma. J of Clin Acupunc and Moxibus 1994;10(2) : 13 - 15. 10. YANG YQ, CHEN HP. Study on the effect of acupuncture and moxibustion on SlgA immune function in allergic asthma patients. Chin J of Acupunc Research 1995 ;20(2) : 68 - 70. 11. HONG HG, YAN H. The influence of suppurative-moxibustion on immunological function of bronchial asthma patients. Shanghai J of Acupunc and Moxibus 1993 ; 12(2) : 59 - 60. 12. LU Y. Clinical observation on the curative effect of moxibustion-plaster at three hottest periods for treatment of 189 asthmatic cases. J of Anhui TCM Collage 1991 ; 10(3) : 38. 13. LI DY. Observation on the influence of suppurative-moxibustion on serum IgE of bronchial asthma patients. Hunan J of TCM 1989;5(3):50. 14. Peng ZK. Quantitative IgE and IgG subclass responses during and after long-term ragweed immunotherapy. J Allergy Clin Immunol 1992 ;89(2) :519 - 523. 15. HU ZG. The influence of acupuncture on T lymphocyte subpopulation and IL-4 of bronchial asthma patients. Chin J of Acupunc and Moxibus 1999;19(2):111. 16. JIN YJ, BI S. The influence of acupuncture on cAMP and cGMP contents in lung tissue of asthmatic guinea-pigs. J of Yanbian Med Univer 1 9 9 0 ; ( 2 ) : 8 9 - 91. 17. LAI XS. The influence of acupuncture on cyclic-nucleotide level in plasma and pulmonary bronchial tissue of experimentally allergic asthma guinea-pig. J of Clin Acupunc and Moxibus 1997 ;13(3) :24 - 25. 18. HE ZY. Research on the mechanism of laser-moxibustion

CJIM2001;7(1):69-74 therapy in bronchial asthma. Chin J of Acupunc and Moxibus 1996; 1 6 ( 1 1 ) : 7 - 10. 19. Brooks SM. Relationship between numbers of ~-adrenergic receptor in lymphocytes and disease severity in asthma. J Allergy Clin Immunol 1979 ;63(6) :401 - 405. 20.JIN YJ. The influence of comparison between response of lung-trachea strips of asthma guinea-pigs on isoprenaline and acupuncture on its lung-trachea strips. J of Yanbian Med Univer 1990; (1) : 1 - 4. 21. LI T, BI S, LU BZ. Quantitative alteration of ~-adrenergic receptor in pulmonary tissue of experimentally asthmatic guinea-pigs and influence of acupuncture stimulating its adrenergic receptor. J of Pathophysiology 1985;1 (3) :22 27. 22. CHEN L. The influence of auricular acupoint on ~-receptor in lung tissue of experimentally asthmatic guinea-pigs. Chin J of Acupunc Research 1996 ;21(1) : 56 - 59. 23. SHEN ZY, HU GR, SHI SZ, et al. Prevention from seasonal attacks of bronchial asthma by herbs for warm Yang tablet and research on its therapeutic mechanism. CJITWM 1986;6(1) :17 - 19. 24. FENG JG. The effect of acupuncture on cortisol contents of plasma in treating bronchial asthma patients. Zhejiang J of TCM 1982 ;17(1) :16 - 17. 25. Ocaslo~a HH (Translated by WANG You-jin). The role of endocrine system in the process of acupuncturing. J of Foreign Med" Tradi Chin Med and Pharma Fascicle 1983 ; (2) : 1. 26. Lian Nan. The effect of stimulation at acupoint Sanyinjiao (SP6) on corticosteroid levels and the implications for treating kidney yang deficiency. Amer J of Acupuncture 1995; 23(2) : 183 - 184. 27. WU WK, HOU C. Morphological study on electro-acupuncture stimulation at acupoint on Zusanli (ST36) in rats for prevention from adrenal cortex atrophy. J of TCM 1988;29(2) : 98 - 100. 28. WU WK, HOU C. Research on electro-acupuncture stimulation at acupoint on Zusanli (ST36) in rats for prevention from adrenal cortex hypofunction. J of TCM 1989 ;30(3): 27 - 29. 29. ZHAO XJ. The effect of acupuncture on injection of dexamethasone to central 5-HT and adrenal cortex system in rats. Chin J of Acupunc and Moxibus 1995 ; 15 (1) : 28 30. 30. SA TS. The effect of acupuncture therapy in bronchial asthma on airway resistance. Chin J of Internal Med 1961 ; 9(5) :272 - 274. 31. ZHANG XP. The regulatory effect of acupuncture and moxibustion on respiratory function. J of New TCM 1981 ; (10) :21 - 23. 32. ZHANG YX, CHEN YM, YU HY. The study on improvement of time-effect relationship of pulmonary function by acupuncture stimulation at acupoint Feishu (BL13). Chin J of Acupunc and Moxibus 1997;(10):581 - 5 8 2 . (Received October 20,2000)