45 Effects of a -linolenic acid on asthma and changes in lilids

Effects of a -linolenic acid-rich supplementation on leukotriene generation by leucocytes in pa­ tients with asthma associated with lipometabolism

Makoto Okamoto, Fumihiro Mitsunobu, Kozo Ashida, Yasuhiro Hosaki, Hirofumi Tsugeno, Norikazu· Nishida, Tadashi Yokoi, Shingo Takata, Yoshiro Tanizaki, and

Mitsune Tanimoto 1)

Department of Medicine, Misasa Medical Branch, and

I )Second Department of Medicine, Okayama University Medical School, Tottori, Japan

Abstract: Dietary sources of a -linolenic acid, such as perilla seed oil, may have the capacity to inhibit the generation of leukotrienes (LTs) by leucocytes in patients with asthma, as has been reported with the consumption of other long - chain n - 3 fatty a-cids. The factors affecting the suppression of leukotriene (LT) C4 generation by leucocytes were examined by comparing the clinical features of patients with asthma who had been given dietary perilla seed oil (n - 3 fatty acids). Group A consisted of patients in whom the leucocyte generation of dietary perilla seed oil LTC4 was sup­ pressed by this procedure. Group B consisted of those in whom LTC4 generation was not suppressed. LTC4 generation by leucocytes significantly decreased in group A for two (P<0.05) and four weeks (P

study groups after four weeks of dietary supplementation. The effects of dietary supplementation with perilla seed oil to patients with asthma by suppressing the generation of LTC4 is associated with clinical features such as res­ piratory function and lipometabolism.

key word : a -linolenic acid, leukotrieneC4, bronchial asthma, lipometabolism

histamines and LTC4 participate in the onset Introduction mechanism of atopic asthma, whereas only LTC4 participates in the onset of non-atopic 9 Asthma is a chronic inflammatory disease of asthma ). Leukotrienes are generated from the airways, that is characterized by recurrent arachidonic acid (AA), which is released from episodes of wheezing, breathlessness, chest tight­ membrane phospholipids during cell activation ness, cough variable airflow obstruction (often through the 5-lipoxygenase pathwaylO). Leuko­ reversible either spontaneously or with treat­ trienes B4 and C4 are generated from AA de­ ment) and bronchial hyperresponsiveness 1) • rived from linoleic acid (LA) (n-6 fatty acid), The airways of patients with asthma have in­ and LTB5 and LTC5 are generated from creased numbers of both inflammatory cells and eicosapentaenoic acid (EPA) derived from a­ their products compared with normal individuals 2). linolenic acid (a -LNA) (n -3 fatty acid) through Airflow obstruction associated with asthma con­ in the same 5-lipoxygenase pathway. sists of airway wall swelling, elevated luminal Polyunsaturated fatty acids (PUFA) of the n-3 secretion, increased presence of inflammatory series (EPA and docosahexaenoic acid-DlfA) cells in the airway wall, and muscle contraction 3) • suppress the production of LTs by antagonistic Numerous chemical mediators including leuko­ metabolism, which occurs at the level of LT trienes (LTs) released in the airways can elicit hydrolase through the 5-lipoxygenase pathway. an allergic reaction. Four series LTs (LTC4, At this level, PUFA may exert an effect by al­ LTD4 and LTE4) increase postcapillary permea­ tering LT generation by leucocytes. Anti-inflam­ bility , and are potent stimulators of airway matory effects of PUFA have been demonstrated smooth muscle cells that mediate airway inflam­ in patients with chronic inflammatory diseases mation through their involvement in vasocon­ such as rheumatoid arthritis, psoriasis and ll 16 striction and mucus secretion 4). LTC4 and D4 chronic inflammatory bowel disease - ). Several can stimulate the contraction of smaller airways studies have suggested beneficial effects of EPA 18 22 of pulmonary parenchymal tissue 5) and the or fish oil on asthma - ), whereas others have 23 24 smooth muscle of the lobar and segmental bron­ demonstrated no such effects • ). chi in vitro 4). Leukotrienes are present in the Our previous studies showed that dietary sup­ blood, bronchial alveolar lavage fluid and urine plementation with perilla seed oil, a vegetable of asthmatics and are produced by cells that oil rich in a -LNA, inhibits the generation of 6 25 mediate airway inflammation in asthma ). The LTs by leucocytes ). In the present study, we principal 5-lipoxygenase product of human examined the factors that affect the suppressive 7l eosinophils and mast cells 8) is LTC4. effects of perilla seed oil supplementation on the Our previous studies demonstrated that generation of LTC4 by leucocytes in patients 47 Effects of a -linolenic acid on asthma and changes in lilids with asthma. degree of suppression of generation of LTC4 by leucocytes after four weeks of dietary supple­ Subjects and Methods mentation with perilla seed oil. Patients in whom LTC4 generation was suppressed by sup­ Twenty six patients (16 females and 10 males) plementation were classified as "Diet Inhibition" with mild asthma were admitted to our hospital (group A), and those in whom no suppression for treatment (mean age, 61. 0 year; range 30 was evident, were classified as "No Inhibition" -84 year). Their mean serum IgE level at admis­ (group B). sion was 771. 6U/ml (range 21.1 to 9780U/ Group A included 11 females and 4 males ml) .Thirteen patients were atopic and thirteen with a mean age of 64.3 years (range 44 to 84 patients were non-atopic, and the mean dura­ years). Group B included 5 females and 6 tion of asthma for both groups was 8.7 years. males with a mean age of 56. 5 years (range 30 Asthma was evaluated according to the crite­ to 73 years). ria of the International Consensus of Diagnosis The concentrations of serum total cholesterol, 26 and Management of Asthma ). All patients dem­ triglyceride, high density lipoprotein (HDL) -cho­ onstrated a reversible airway response, as indi­ lesterol and phospholipid were assayed using an 27 JO cated by a 15% or greater increase in forced enzymatic method - ). Low density lipoprotein expiratory volume in one second (FEVl. o) after (LDL) -cholesterol concentration was calculated inhaled bronchodilator use. The study was ap­ from the following formula: [(serum total chol proved by the Institutional Human Investigation esteroI) - (HDL-cholesteroI) -0.2X (triglyceride) ]

Committee at our hospital. Informed consent to (Friedwald's convert) 31), and (3 -lipoprotein was participate in the study was obtained from all p assayed by turbidimetry. Serum IgE levels were atients. At the time of the study, all patients estimated by the radioimmunosorbent test (RIST). were undergoing regular treatment with long­ Pulmonary function tests, forced vital capacity acting oral theophylline, inhaled (3 Z adrenergic (FVC) , forced expiratory volume in one second agonists and glucocorticosteroid (beclometha­ (FEVI.O ) and V25 were performed using a sone dipropionate : BDP). The mean dose of in- Chestac 33 (Chest Co. Tokyo, Japan) linked to a haled BDP was 305.8 p. / day. computer while the patients were at an attack­ The patients consumed 10-20g of perilla seed free state. oil (rich in a -LNA) per day as salad dressing The generation of LTC4 by peripheral leuc­ 9 3Z and/or mayonnaise instead of other oils for 4 ocytes was assessed as described . ). Cells were weeks. The mean dose of consumed perilla separated by counterflow centrifugation elutria­ seed oil was 14. 65 ± 1. 41g/day. Other dietary tion using a JE 6B rotor (Beckman Co., Geneva, 3Z components were not changed, and the amount Switzerland) [33], as described ,34). The number of oil used in the diet and supplemented diet of cells was then adjusted to 5X10 6 /ml in Tris was recorded throughout the study period. ACM (composition: 1ml of O.lmoVICaz+, 0.5 Peak expiratory flow (PEF) during the early mor­ ml of O. 1mol/l M~· and 98.5ml Tris A buffer; ning and evening was recorded using a peak­ Trizma preset crystal, pH 7. 7 ; Sigma Chemical flow meter (Assess: Health Scan Products Inc., Co., St. Louis, Mo, USA). The Ca ionophore Cedar Grove, NJ, USA). A23187 (1 p. g) was added to the cell suspension The patients were classified according to the and incubated for 15 min at 37°C. Leukotriene Effects of a -linolenic acid on asthma and changes in lilids 48

C4 was quantified by HPLC as described by Morning PEF values were significantly lower 35 Lam et al ). Leukotrienes were extracted using in group A than in group B during the study a CI8 Seppak (Waters Associates, Milford, MA) period (P

All data are expressed as means ±SEM. Stu­ before after two weeks after four weeks dent's t-test was used for paired analysis. 259.3±113.9~·' Groups were compared by the one-way analysis Group A 241.3±134.9....' 271.3±105.1·... GroupB 366.7±163.0····, 366.7±146.6·" 388.9±138.6··h ofvariance(ANOVA) andp<0.05 was considered significant. Analyses were perfonned using Stat­ Group A: LTC4 generation suppressed by diet ary supplementation wit h perIIa seed 01. Group B: no suppression of LTC4 by supplementation. View 5. 0 (Abacus Concepts, Inc., Berkeley, CA). Each value represents t he mean±SEM for 15 subjects(group A) and 11 sUbjects(group B) a.b,c,d,e,f,g and h ,P

Results The FVC, FEVI.O and V'l!5 values were signifi­ cantly lower in group A than in group B prior Group A leucocytes generated significantly to dietary supplementation. The FVC and FE less LTC4 after two and four weeks of supple­ VI.O values increased significantly in group A fol­ mentation with perilla seed oil (P

180 Dietary supplementation 160 before after four weeks 140

FVC(L) group A 2.31 ±O.50~· 2.43±O.40" 1"0 .. b c i 100 ---- 1------group B 3.39±1.16 3.43±1.30 80 !j d df FEV",(L) group A 1.45±O.4S .. 1.66±O.51 60 .. group B 2.68±O.98· 2.62±1.07' 40

zo V2s(l/secl group A O.43±O.34' 0.51 ±0.47

Fig 1. Dietary supplementation(weeks) group B O.97±O.62' O.86±O.61

Figure 1. Changes in LTC4 generation in two study groups. LTC4 generation de­ GRqtA: LTC4 generatkm suppr8SS8d by dilII: my supplementation wft h J*Iaseed 01. creased significantly after two and four weeks of perilla seed oil supplementation in Group B: no suppression of LTC4 by auppJiomentatfon. group A (e-e). In contrast. LTC4 generation increased significantly after fOUf Each YUle f8preseRts t he meen±SEM tor 15 aub)ltcls(group A) and 11 subjects(groupB). weeks of supplementation in group B(•...•). Levels of LTC4 significantly differed .. b,c,d, e, f,andg,P

esterol, WL-Cholesterol and phosphlipid were during an allergic reaction. Leukotrienes C4, D4 significantly higher in group A than in group B and E4 are implicated in the pathogenesis of al­ prior to dietary supplementation (P

dietary au pplementatlon and fish oil on asthma are controversial. Some before after four weeks 17 22 investigators have suggested beneficial effects ' ),

Total cholesterol(mg/dl) group A 216.5 ±39.5 u 198.0±45.9- whereas others have reported little effecfl' 24) • group B 191.0±20.9' 179.9±31.8 Our preliminary examinations suggested two Trlglycerlde(rng/dl) group A 65.2±25.e c 62.4±13.1' asthmatic populations with respect to suppres­ c group B 90.9±41.3 80.e±20.1 d sion of LTC4 generation by the n-3 fatty acids HDL-Cholesterol(rng/dl) group A 70.1 ±22.S· 65.6±22.1 in perilla seed oil. We therefore compared the group B 54.7±16.S· 51.8±26.0 clinical features of patients in whom LTC4 gen­ LDL-Cholesterol(mg/dl) group A 145.8±36.7'01 135.9±22.2 f,t, eration by leucocytes was suppressed (group A) groupB 121.3±15.,'J 108.2±20.0IlJ or not (group B) by perilla seed oil suppleme­ Il-Llpoproteln(m g/dl) group A 426.8±71.2 419.7±76.8 groupS 410.1 ±48.1 386.0±63.0 ntation . Dietary supplementation with perilla

Phosphollpld(mg/dij group A 250.8±19.2'" 218.4 ±35.0 I seed oil for two and four weeks significantly group B 199.5 ±23.8· 194.0±28.9 suppressed LTC4 generation by leucocytes in

Group A: LTC4 generation was aupprNHd by dietary 1'1 pplementation. group A. In contrast, LTC4 generation in group Group B: noauppresslon of LTC4 generation by perlllaaHd an. E8Ch vaJue represents the mun ±SEMfor 15 lubJectl(group A) and 11 • ubJectl(oroup B). B increased significantly after four weeks of a, b,c, d, .,1, ", h, I, J .-1d k,P

portant role in the late asthmatic reaction (IA rameters-PEF, FVC, FEVl.O and V2s -compared R). Large quantities of these mediators are syn­ with· group B, suggesting that group A subjects thesized and/or released by inflammatory cells had a clinically more severe state of asthma Effects of a -linolenic acid on asthma and changes in lilids 50 than group B. The FVC and FEVl.o values were can be developed for patients with asthma. significantly improved only in group A after four weeks of perilla seed oil supplementation. This References indicates that LTC4 affects respiratory function in group A. PEF values increased in both two 1. Guidelines for the diagnosis, management groups during the study. This was thought tobe of asthma : Expert Panel Report n. Bethesd caused by the other therapy (drugs and respira­ a, MD . National Institutes of Health NIH tory rehabilitation) accompanied with diet therapy. publication No. 97 - 4051, 1997. Recent dietary trends in lapan include increas­ 2. Holgate S: Mediator and cytokine mecha­ ing consumption of saturated fatty acids and n-6 nisms in asthma. Thorax, 48 : 103 -109, 1993. PUFAs, whereas that of low n-3 PUFAs was 3. Kaliner M, Eggleston PA, Mathews KP : 38 decreased ). The present results showed signifi­ Rhinitis and asthma. lAMA, 258: 2851­ cantly higher levels of serum total-cholesterol, 2871, 1987. HDL-Cholesterol, LDL-Cholesterol and phos­ 4. Dahlen SE, Hedquvist P, Hammarstrom S, pholipid and a significantly lower level of serum Samuelsson B: Leukotrienes are potent triglyceride in group A than in group B prior to constrictors of human bronchi. Nature, 288: dietary supplementation, suggesting that group 484 - 486, 1980. A patients consumed diets that were rich in n-6 5. Chagnon M, Gentile 1, Gladu M, Sirois P: fatty acids prior to the beginning of this study. The mechanism of action of leukotrienes A4, Other reports suggest that PUFA diets-incl­ C4 and D4 on human lung parenchyma in 39 48 uding a -LNA-decrease serum lipids - ). Some vitro. Lung, 163: 55 - 62, 1985. researchers have demonstrated that perilla oil 6. Henderson WR lr : Role of leukotrienes in supplementation decreases serum lipids in rat­ asthma. Ann Allergy, 72: 272 - 278, 1994;.

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脂質代謝に関連 した気管支嘱息患者における白血 取 2 過後 (P<0.05),4 週後 (P<0.05) に白血 球ロイコ トリエン産生能に対するα-リノレン酸 球I:T C4 産生能が低下 した｡逆に B 群では摂取 4

食の効果 週後有意に増加 した (P<0.05) 0 2 群間で食事 摂取 4 遡後に白血球I:TC4 産生能に有意差がみ ら 岡本 誠,光延文裕,芦EEl耕三,保崎泰弘, れた (P<0.05) ｡ ピークフロー値 (PEF) ､努力 柘野浩史,西田典数,横井 正,高田真吾, 性肺活量 (FVC)､ 1秒量 (FEVl) といった呼吸

谷崎勝朗,谷本光音 1) 機能はA 群において食事摂取 4 週後に有意に上昇 した (P<0.05) ｡食事摂取前の PEF ､ FVC ､FE 岡山大学医学部附属病院三朝分院内科､ v l､V 25は A 群,B 群の 2 群間で有意差がみ られ 1)岡山大学医学部第二内科 た｡A 群において血清総コレステロール､低比重 リポ蛋白 (LDL) コレステロール､ リン脂質は食 エゴマ油のような α- リノレン酸食が他の n-3 事摂取 4 週後に有意に低下 した｡食事摂取前の血 系不飽和脂肪酸食において報告 されてきた様に嘱 清総コレステロール､中性脂肪､高比重 リポ蛋白 息患者の白血球 ロイコ トリエン (I:Ts) 産生能を コレステロール､LDL コレステロール､リン脂質 抑制すると考えられる｡そこでエゴマ油 (n-3 系 において 2 群間に有意差がみられた｡血清中性脂 脂肪酸)を摂取 した気管支嘱息患者の臨床所見を 肪､1♪L コレステロールは食事摂取 4 遇後 2 群間 比較することによって白血球 ロイコ トリエン に有意差がみ られた｡気管支職息患者のある群へ (LT)C4 の抑制に影響する因子を検討 したoA のエゴマ油食はLTC4 産生能を抑制 し､それには 群はエゴマ油摂取により白血球lTC4 の産生能が 呼吸機能や脂質代謝 といった臨床因子が関連 して 抑制 された群であり､B 群は白血球IJTC4 の産生 いると考えられた｡ 能が抑制 されなかった群である｡A 群では食事摂