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  • 學位論文

肥胖與氣喘研究

The Study on Obesity and Asthma

指導教授 : 吳美環
共同指導教授 : 謝武勳

摘要


肥胖與氣喘是近年來兩個日益增長的健康問題,尤其是隨著肥胖逐漸變成全球流行的問題,因而肥胖成為一個重大的公共衛生問題。肥胖對於呼吸系統有一些影響,但影響層面有多少?是否為主要危險因素?目前仍然是有爭議的,尤其是像呼吸氣道高反應性或氣喘。然而,這類的問題在近年來受到相當的矚目,也被認為是重大的健康議題。因此博士研究的主題想要探討肥胖與氣喘之間的關聯性與相互作用,並闡述了其各自的角色,並了解可能的機制,尤其是發炎反應在這中間的作用。因此,本博士研究建立了兩項重要的研究方向。 第一個研究方向是利用流行病學研究,分析大規模青少年的調查資料,以進一步了解肥胖對於氣喘的影響,這是一群一般兒童族群的橫斷面研究。兒童氣喘的發生率逐年在增加,先前的研究發現這個可能與肥胖問題(可用身體質量指數Body Mass Index (BMI)過高來做參考)或早產(可用低出生體重來做參考)問題有一定的關聯。因此流行病學研究希望測試這些與體重有關聯的假說,我們假定低出生體重的兒童長大成超重和肥胖青少年時,發生氣喘的風險更大。 本項研究收集台灣在1995-1996年所參與篩檢氣喘疾病的75,871名初中學生。出生體重和出生估計週數是由台灣的出生登記資料檔獲得。運用邏輯迴歸分析(Logistic regression)和簡單回歸分析排除干擾因子的影響。研究發現氣喘盛行率較高的族群是出現在出生體重低於3000公克和青少年時BMI較高的兒童身上。更重要的是兼有兩者時,發生氣喘的機率最高。低出生體重兒的氣喘診斷,不管是經由醫師直接診斷(Physican Diagnosis, 簡稱PD)或是來自醫療問卷(Medical Questionaire, 簡稱MQ),其與正常體重兒的相較之下的勝算比(Odd ratio),在下列的族群都明顯升高,男孩超重(PD:1.41; MQ:1.25)和肥胖(PD:1.38; MQ:1.47 );以及女童超重(PD:1.63; MQ:1.30)和肥胖(PD:1.44; MQ:1.32)(P <0.05)。此研究證實低出生體重兒容易罹患氣喘,而超重與肥胖讓風險大大提高。而針對男女生性別不同,其風險也不一樣。所以這項流行病學研究結果可以推論,如果注意週產期照顧與營養體重控制的方法,來減少低體重兒後續出現的肥胖問題,這樣可能會降低氣喘的盛行率。針對這個關聯,以及背後可能的機制,我們希望進一步用動物實驗來釐清。 所以第二個研究方向是利用肥胖動物模式來了解其發生呼吸氣道高反應性的狀況及機轉。ob/ob基因型肥胖小鼠本身缺乏瘦素(leptin)(一種飽足感激素),此時吸入臭氧(Ozone)所誘發的氣喘反應會增加。而擁有長型瘦素受體(OB-Rb)對飽足感的需求是必須的;缺乏這種受體的db /db基因型小鼠基本上就會產生肥胖。 在本研究中,我們將野生型和db / db基因型小鼠暴露在空氣或臭氧(2 ppm)3小時。再以小型動物肺功能的強迫振盪技術,測量暴露於空氣後呼吸氣道的反應性,發現db / db小鼠反應大於野生型小鼠。臭氧誘發肺阻力及呼吸氣道反應性也在db / db小鼠大幅增加。BALF eotaxin, IL-6 KC,和MIP-2等發炎因子在小鼠吸入臭氧暴露後4小時有增加,並在24小時左右消退,而蛋白質和嗜中性球在24小時仍維持增加。對於這幾項發炎因子的研究結果,吸入臭氧的效果在db / db小鼠的效果是顯著高於野生型小鼠的。這和先前發表的文獻中研究關於ob / ob小鼠所獲得的結果是相似的,唯一主要的差別是在於吸入臭氧誘發的嗜中性白血球和MIP-2對於ob / ob小鼠和野生型小鼠的影響是一樣的,沒有什麼不同,而對於db / db小鼠則反應明顯上升。同時在db / db小鼠,吸入臭氧會引起肺部IL-1 beta和TNF-alpha mRNA表現,但ob / ob小鼠不會有這樣的表現。db / db小鼠的特色是缺乏長型瘦素受體(OB-Rb),而造成在db / db小鼠的血清中,瘦素是大量增加的,至於短型瘦素受體(OB-Ra)在肺部mRNA裡的表現,db / db小鼠與和野生型小鼠是類似的。這些研究結果證實了肥胖小鼠有先天的呼吸氣道高反應性,並且吸入臭氧會增加肺部的呼吸氣道反應性。由於ob / ob小鼠(缺乏瘦素) 和db / db小鼠(缺乏OB-Rb的,但不缺乏OB-Ra)在這些研究結果上的差異,說明了大量的瘦素還是會通過對於OB-Ra的作用,調控肺部對於吸入臭氧的呼吸氣道反應性,增加了發生氣喘的機會。 所以從兩個研究分析重點來看,流行病學研究看到了肥胖會增加氣喘發生的機率,而這個影響是在低體重兒有加速數體重增加變胖的情況下最明顯。而動物實驗更進一步以瘦素受體缺乏的肥胖老鼠,發現其產生呼吸道收縮高反應性的現象,以及其後引起發炎的腫瘤壞死因子TNF-alpha所參與的角色。這些研究幫忙指出[肥胖性氣喘]的獨特性,也需要更多研究針對其疾病特色,以及如何預防與治療有更好的對策。

關鍵字

肥胖 氣喘

並列摘要


Obesity and asthma has been two increasing health issues that are more and more important as the global epidemic of obesity became a major public health problem. Whether obesity is a major risk factor in certain respiratory diseases is still controversial, such as in airway hyperresponsiveness or asthma. However, its contributory role in related diseases has gain more focus recently. Therefore, we would like to explore the interactions between obesity and asthma, and elaborate the weight of its role, and possibly their mechanism. Therefore this thesis established the whole project to include two specific arms. The first arm is a cross sectional study on a large population survey in children to clarify the role of obesity on asthma on a huge population, that is relatively healthy children. Childhood asthma, a growing health concern, has been associated with low birth weight and elevated body mass indices (BMIs). This study tested the hypothesis that overweight and obese adolescents with a history of low birth-weight are at even greater risk of developing asthma. A cohort of 75,871 junior high school students was screened for asthma during 1995 Oct-1996 Mar in Taiwan. Birth weight and estimated gestational age were obtained from the birth registry. Logistic regression and simple regression analyses were adjusted for confounding variables. Asthma was more prevalent in those with birth weights below 3,000 g and higher adolescent BMIs. Furthermore, those with both characteristics were consistently most likely to have asthma. Whether the asthma diagnosis among low birth weight subjects was assigned by physicians (PD) or medical questionnaire (MQ), the odd ratios were elevated for both overweight (PD: 1.41; MQ: 1.25) and obese (PD: 1.38; MQ: 1.47) boys as well as overweight (PD: 1.63; MQ: 1.30) and obese (PD: 1.44; MQ: 1.32) girls (P < 0.05). Low birth weight predisposes one to develop asthma and excess body mass amplifies the risk. A sex difference was observed. This study suggests prenatal care and nutrition counseling may reduce asthma prevalence. The second arm is a basic research study, utilizing an animal model to explore the relationship between obesity and airway hyperresponsiveness, and whether inflammation plays any specific role in their relationship. Epidemiological studies indicate the incidence of asthma is increased in obese and over-weight humans. Responses to ozone (O3), an asthma trigger, are increased in obese (ob/ob) mice lacking the satiety hormone leptin. The long form of leptin receptor (Ob-Rb) is required for satiety; mice lacking this receptor (db/db mice) are also substantially obese. Here, wild type and db/db mice were exposed to air or O3 (2 ppm) for 3 h. Airway responsiveness, measured by the forced oscillation technique, was greater in db/db than wild type mice after air exposure. O3-induced increases in pulmonary resistance and airway responsiveness were also greater in db/db mice. BALF eotaxin, IL-6, KC, and MIP-2 increased 4 h after O3 exposure and subsided by 24 h, whereas protein and neutrophils continued to increase through 24 h. For each outcome, the effect of O3 was significantly greater in db/db than wild type mice. Previously published results obtained in ob/ob mice were similar except for O3-induced neutrophils and MIP-2, which were not different from wild type mice. O3 also induced pulmonary IL-1beta and TNF-alpha mRNA expression in db/db but not ob/ob mice. Leptin was increased in serum of db/db mice, and pulmonary mRNA expression of short form of leptin receptor (Ob-Ra) was similar in db/db and wild type mice. These data confirm obese mice have innate airway hyperresponsiveness and increased pulmonary responses to O3. Differences between ob/ob mice, which lack leptin, and db/db mice, which lack Ob-Rb but not Ob-Ra, suggest leptin, acting through Ob-Ra, can modify some pulmonary responses to O3. As for summary, two specific study arms show important information for clarifying the relationship between obesity and asthma. Epidemiologic study reveals that obese increases the risk of asthma, and this effect is more prominent when the body weight gain increase to overweight and obese at teenage since being born as low birth weight babies. Animal experiments further elaborates that db/db obese mice lacking the leptin receptor, which produces exaggerated airway hyper-responsiveness constriction, and its mechanism has involved tumor necrosis factor TNF-alpha as an inflammation role. These results provide us more clues about the characteristics of obese-induced asthma, and need further more research to settle down specific preventive and treatment modalities for this type of asthma.

並列關鍵字

obesity asthma

參考文獻


Hsieh W-S, Wu H-C, Jeng S-F, Liao H-F, Su Y-N, Lin S-J, Hsieh C-J, Chen P-C. Nationwide singleton birth weight percentiles by gestational age in Taiwan, 1998-2002. Acta Paediatr Taiwan 2006;47: 25-33.
Aaron SD, Fergusson D, Dent R, Chen Y, Vandemheen KL, Dales RE. Effect of weight reduction on respiratory function and airway reactivity in obese women. Chest 2004;125: 2046-2052.
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被引用紀錄


李少騰(2012)。不同程度肥胖童之心肺適能與身體活動量關係之研究〔碩士論文,國立屏東科技大學〕。華藝線上圖書館。https://doi.org/10.6346%2fNPUST.2012.00028
楊馥菱(2016)。先天性心臟病學童之能量平衡相關行為、健康體位及相關因素探討〔碩士論文,國立臺灣大學〕。華藝線上圖書館。https://doi.org/10.6342%2fNTU201603694

延伸閱讀


  • 白家銘、徐世達(2008)。肥胖與氣喘臺灣兒童過敏氣喘及免疫學會學會通訊9(4),24-26。https://doi.org/10.7025%2fHEJ.200812.0024
  • 張景明、張金堅(2015)。肥胖與癌症臺灣醫界58(12),10-14。https://www.airitilibrary.com/Article/Detail?DocID=17263603-201512-201512210019-201512210019-10-14
  • 張景明、張金堅(2016)。肥胖與癌症中華民國內膜異位症婦女協會會刊23(3&4),10-14。https://doi.org/10.6498%2fEA.2016.23(03%2f04).3
  • 劉佩青(2014)。The Association between Obesity and Asthma in Children〔博士論文,國立臺灣大學〕。華藝線上圖書館。https://doi.org/10.6342%2fNTU.2014.02144
  • 洪嘉蔚、吳維峯(2008)。Pediatric Asthma and ObesityActa Paediatrica Taiwanica49(S),11-17。https://doi.org/10.7097%2fAPT.200811.0011

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