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1 REVIEW ARTICLE Korean J Clin Lab Sci. 2015, 47(3): pissn eissn Korean J Clin Lab Sci. Vol. 47, No. 3, Sep Inflammation and Insufficient or Disordered Sleep Suk Jun Lee 1 and Jinkwan Kim 2 1 Department of Biomedical Laboratory Science, College of Health Science, Cheongju University, Cheongju 28497, Korea 2 Department of Biomedical Laboratory Science, College of Health Science, Jungwon University, Goesan 28024, Korea 염증반응과수면장애 이석준 1, 김진관 2 1 청주대학교보건의료대학임상병리학과, 2 중원대학교의료보건대학임상병리학과 Sleep is not only an essential physiological function, but also serves important roles in promoting growth, maturation, and overall health of humans. There is increasing interest regarding the impact of sleep and its disorders on the regulation of inflammatory processes and end-organ morbidities, particularly in the context of metabolic and cardiovascular diseases (CVD) and their complications. Obstructive sleep apnea syndrome (OSAS) is an increasingly common health problem in children. In the last decade, the emergence of increasing obesity rates has further led to remarkable increases in the prevalence of OSAS, along with more prominent neurocognitive, behavioral, cardiovascular and metabolic morbidities. Although the underlying mechanisms leading to OSAS-induced morbidities are likely multifactorial and remain to be fully elucidated, activation of inflammatory pathways by OSAS has emerged as an important pathophysiological component of the end-organ injury associated with this disorder. To this effect, it would appear that OSAS could be viewed as a chronic, low-grade inflammatory disorder. Furthermore, the concurrent presence of obesity and OSAS poses a theoretically increased risk of OSAS-related complications. In this study, we will critically review the current state of research regarding the impact of insufficient and disrupted sleep and OSAS on the immune processes and inflammatory pathways that underlie childhood OSAS as a distinctive systemic inflammatory condition in children, and will explore potential interactions between OSAS and obesity. Keywords: Obstructive sleep apnea, Obesity, Insufficient sleep, Inflammation Corresponding author: Jinkwan Kim Department of Biomedical Laboratory Science, College of Health Science, Jungwon University, Goesan 28024, Korea Tel: jkkim@jwu.ac.kr This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright 2015 The Korean Society for Clinical Laboratory Science. All rights reserved. Received: May 26, 2015 Revised 1 st : June 11, 2015 Revised 2 nd : June 13, 2015 Accepted: June 14, 2015 서론수면현상은모든동물뿐아니라인간에있어없어서는안될중요한현상이며비록정확한수면의목적과기능은다소명확하지않지만수면박탈 (Sleep deprivation), 수면장애 (Sleep disorder), 수면시간 (Sleep duration) 과다양한질병의연관성에대한활발한연구가최근 30여년동안진행되어오고있다. 현대사회의급격한발달과기술의발달, 문명의발달과더불어지난반세기동안인간개개인의생활양식뿐아니라가족구성원및생활형태가급격히 변화해오고있으며따라서이러한변화는수면습관뿐아니라수면시간에큰변화를유발하고있다. 흥미로운것은이러한수면위생또는수면습관의급격한변화와더불어소아뿐아니라성인에서도급격한비만인구의증가를가져오고있다는것이다 (Ievers-Landis 와 Redline, 2007; Must 와 Parisi, 2009). 이러한비만유병률의증가는수면시간의감소와동반되어나타남으로써인간수면의질적또는양적저하와비만인구의증가에대한잠재적인연관성에대한추측과관심이증가되고있다 (Horne, 2008; Cappuccio 등 2008). 따라서이러한수면수면시간의감소와수

2 98 Suk Jun Lee and Jinkwan Kim. Slee and Inflammation 면장애는심혈관계의기능적측면뿐아니라호르몬의분비주기, 인슐린의분비, 체내각기관의인슐린민감성의변화등을살펴볼때중요한공중보건의문제가될것으로판단된다. 인체의대사항상성에대한수면부족의영향에대한연구는현재성인의경우시카고대학의 Van Cauter 그룹에의해서활발히진행되고있다 (Van Cauter 등, 2008). 이전의연구결과를살펴보면, 실험적으로인위적인수면제한을시행할경우수면제한은배고픔의증가를유발하는신경호르몬인렙틴 (leptin) 의조절장애를유발하고또한당뇨의위험을증가시키는체내내당능 (glucose tolerance) 의변화를유발하는것으로보고하고있다. 또한소아에서의집단연구결과에서는수면시간이체중증가와대사장애의위험을증가시기는중요한결정요인으로보고하고있고, 소아에서의수면시간의감소는수면환경, 수업시간의시작, 메스미디어, 부모의수면습관등에의하여영향을미치는것으로보고하고있다. 또한가족의수면습관이소아의수면습관에큰영향을미치는것으로보고하고있다 (Spruyt 와 Molfese, 2011; Chassin 등, 2005). 예를들면미국에서의연구보고에의하면주중에식구들과저녁식사를 5회이상하는가족들의미취학아동들은 10시간이상의충분한수면시간을가지고있고, 텔레비전이나미디어시청이하루에 2시간미만이었으며, 이러한아동들은이러한생활습관을가지지못한가족들에비해 40% 낮은비만율을보여주고있어입시과열로세계적으로최저의수면시간을기록하고있는국내소아 / 청소년을살펴볼때시사하는바가크다할것이다 (Anderson 와 Whitaker, 2010). 따라서수면시간과규칙적인수면습관은대사증후군과심혈관계질환의위험을증가시킬뿐아니라비만을유발하는중요한요인이될것으로사료된다. 염증 (Inflammation) 은신체의다양한위해상황에서감염또는조직의항상성을유지하기위하여생존할수있는필수적인면역반응이다 (Medzhitov, 2010). 염증과정은세포또는조직에서다양한염증반응의부산물을발생시킬수있으므로조직의일시적인기능감소를유발할수있고, 또한직접적인질병의병인에기여할수있다. 이전의연구결과에의하면수면의질적또는양적저하를대표하는수면부족또는수면방해는염증경로의활성화와연관성이있는것으로보고하고있다. 수면박탈은감염을극복할수있는능력이나자기방어기전에중요한역효과를유발, 염증반응의강도와특성에변화를유발하는것으로보고하고있다 (Benca 등, 1989; Rechtschaffen 와 Bergmann, 2001). 또한수면무호흡증의생리적특성으로나타나는수면분열 (Sleep fragmentation) 또한유의한염증반응의활성화를유발하는것으로보고하고있다 (Gozal, 2009; Farre 등, 2008). 수면무호흡증 (Obstructive Sleep Apnea: OSA) 은수면중의 반복적인상기도반복적인폐쇄로나타나며이로인한상기도의저항의증가로코골이, 체내반복적인저산소 (intermittent hypoxia) 와고탄산혈증 (Hypercapnia) 이발생하며또한주기적인각성 (frequent arousals) 으로인하여수면분열을유발한다. 이러한수면중의생리적변화는반복적인저산소-재산소화 (hypoxia-reoxygenation) 로인한활성산소 (Reactive oxygen species, ROS) 의증가와전신염증반응 (Systemic inflammation) 을유발하는것으로알려져있으며궁극적으로죽상경화증 (Atherosclerosis), 대사질환 (Metabolic disorder) 의위험증가와인지능력장애 (Cognitive dysfunction) 등의다양한질병의발생위험률을증가시키는것으로보고되고있다 (Farre 등, 2008). 이러한수면무호흡증으로인한질병발생의위험은성인에서뿐아니라소아에서도다양한역학연구와환자-대조군연구에서심혈관계질환 (Cardiovascular disease), 뇌혈관질환 (Cerebrovascular disease) 의위험도를증가시키고신경인지능력의저하와행동장애유발과매우밀접한관련이있는것으로현재까지보고되고있다 (Suzuki 등, 2006; Gozal, 2007; Lavie, 2009; Pack, 2009). 더불어소아수면무호흡증의치료가지연된다면인지기능의저하로인한학업성적의저하와밀접한관계가있는것으로보고되고있어사회적문제로인식되고있다. 따라서본종설에서는수면부족 / 수면질환으로인한염증경로의활성화로인한다양한질환과의연관성에대한최근의연구결과에대하여살펴보고자한다. 본론 1. 수면과염증반응 (Sleep and Inflammatory Response) 인간의수면현상은우리몸의중요한방어기전인면역체계와깊은상호연관성이있는것으로알려져있으며, 특히면역계의기능을조절할뿐아니라면역체계활성화와염증성사이토카인의분비와조절에영향을미치는것으로알려져있다. 그러나이러한수면현상이직접적으로또는선택적으로면역계에영향을미치는지에대한다양한연구결과가보고되고있지만여전히논쟁의여지가있다. 염증성경로의다양성에도불구하고염증은신체의항상성유지하기위하여여러가지해로운상황 (harmful conditions) 이나조건에적응하기위한반응으로인간에게는필수적이다 (Medzhitov, 2010). 염증은이러한신체의이로운또는해로운측면들로서따라서설명될수있을것이다. 그동안면역조절의중요한인자인사이토카인은감염에대한숙주반응의효과와역할에대하여집중적으로연구되어왔지만생리적으로수면현상에대한염증반응의잠재적조절자 (potential modulator) 로서의역할에대해서는아직많이알려져있지않고, 이에대한연구가최근에몇몇그룹을중심으

3 Korean J Clin Lab Sci. Vol. 47, No. 3, Sep 로관심이증가되어오고있다 (Opp, 2009). 급성기의염증반응은감염또는손상에대한면역 cascade 의빠른초기활성화로설명할수있다. 선천적면역계의주요한구성성분의하나인TLRs (toll like receptors) 은자기와비자기의분자패턴을인식하는패턴인식수용체 class로서조직에존재하는대식세포에서발현되거나프로스타글란딘 (prostaglandins) 뿐아니라염증성사이토카인 (e.g. TNF-, IL-1, IL-6) 과케모카인 (CCL2와 CXCL8) 생산을유도한다 (Medzhitov, 2010; Pecchi, 2009). 이들경로들은전통적으로세균세포막의외부지질다당질 (lipopolysaccharide, LPS) 에의하여활성화되는것으로알려져있다. 하지만수면박탈 (sleep deprivation) 그자체로 TLR 경로가자극되며, 사이토카인생산을유도하는것으로알려져있다. 최근의연구에서는수면결핍된사람에게서 TLR-4의 LPS에의한활성화가정상군에비해더큰것으로보고하고있다 (Irwin, 2006). NF- B는염증성경로의활성화와조절에관여하는중요한전사인자로서다양한사이토카인과염증성마커의분비에관여하는 200여개이상의유전자의전사에관여하는중요전사인자이다 (Brasier, 2006; Perkins, 2007). NF- B 결합도메인은 adenosine A1 수용체, cyclooxygenase-2 (Cox-2) 와 nitric oxide synthase (NOS) 와같은수면관련물질의유전자의프로모터부위에서발견되었다 (Krueger 등, 2001). 따라서수면박탈 (Sleep deprivation) 시에수면조절과연관한뇌의특정부위의 NF- B의활성과전위를유도하고 (Brandt 등, 2004; Kuo 등, 2010), 국소적인염증반응의활성화를나타낸다 (Irwin 등, 2008). 동물또는사람대상의연구에서 IL-1, IL-1, IL-2, IL-4, IL-6, IL-8, I-10, IL-13, IL-15, IL-18, TNF-, TNF-, IFN-, IFN-, IFN- and macrophage inhibitory protein 1b와같은다양한사이토카인과케모카인이수면과관련이있는것으로보고하고있다 (Vgontzas 등, 2006). 이가운데가장활발히연구되고있는염증성사이토카인은 IL-1 and TNF- 이다 (Takahashi 등, 1999; Vgontzas 등, 1997). 비록대부분의사이토카인이말초면역계에서발견되었지만몇몇사이토카인과수용체들은중추신경계에서발견되고뇌의특정부위또는특정세포에국한되어존재하는것으로알려져있다 (Allan & Rothwell, 2001). 중추신경계는미주신경의자극을유발하는사이토카인을통하거나또는뇌실주변기관내의사이토카인활성을통하여말초로부터중추신경계로사이토카인의능동수송을통하여말초면역계의활성을감지한다 (Dantzer 등, 2008). 그러나사이토카인은 de novo에서또한합성될수있고신경세포와신경아교세포에의하여중추신경계에서분비된다 (Marz 등, 1998). 동물모델에서 IL-1 과 TNF- 의투여는비렘수면 (non-rem sleep) 의증가를보고하고있고, IL-1 and TNF- 의억제는정상적으로수면 박탈후에발생하는수면회복 (sleep rebound) 과자연적인수면현상을억제하는것으로보고하고있다 (Krueger, 2008). 따라서이두가지사이토카인은 TNF 수용체 (TNFRF) 와 IL-1 수용체분절 (IL-1RF) 을이용하는것으로보여지며수면현상에상호의존적인것으로보고하고있다 (Takahashi 등, 1999). TNF-α 의수치는수면무호흡증환자에서뿐아니라류마티스관절염에보이는과도한졸리움과피로와연관이있는것으로보고하고있다 (Vgontzas 등, 1997; Franklin, 1999). 수면과면역계와관련한또다른중요사이토카인은 IL-6이다. 이전연구에선사람에게전신성감염과관련한수치에도달할만한 IL-6의투여후 6.5시간후에주관적인피로와유의한관계를보였으며이때급성염증단백질인 CRP 수치의증가가나타나는것으로보고하고있다. 또한렘수면의유의한감소와수면전반부에서깊은수면이감소하고수면후반부에서는증가하는것으로보고하고있다 (Spath-Schwalbe 등, 1998). 하지만다른종류의염증성사이토카인은 IL-6 투여후에증가하지않아 IL-6가수면구조 (sleep pattern) 변화와유의한관계가있을것으로생각하고있다. 비록염증과수면부족또는수면방해의연관성에대한관심이증가되고있지만실험법의민감도, 개인차, 기저염증정도, 스트레스, 육체활동등다양한요인이염증마커의측정을위한 sampling 시에고려되어야한다. Pro-inflammatory cytokine 과숙주면역기능, 수면-각성주기 (sleep-wakefulness cycle) 사이의연관성을볼때, 수면시간의감소와유사한수면방해는비만과수면무호흡증의질병발생과면역경로의활성화틀통한염증성반응과정이매우밀접한연관성이있으므로중요한역할을하는것으로추정되고있다. 2. 수면결핍, 염증과비만 (Fig. 1) 비만은현재소아, 성인모두에서예상수명을감소시킬뿐아니라질병의이환율과사망률의위험을증가시키는전세계적인공중보건문제로인식되고있다 (Poirier 등, 2006). 특히소아에서의비만유병률이미국과유럽등의서구선진국에서증가하고있어심각한공중보건의문제로대두되고있다 (Ogden 등, 2006). 비만으로인한신체의변화는생리적교란뿐아니라비만그자체로전신성만성저염증 (low-grade systemic inflammation) 을성인, 소아모두에서유발하는것으로보고하고있다 (Ford, 2003). 미국의국립건강영향조사의연구보고에의하면체질량지수는염증마커 C-반응단백질 (C-reactive protein) 을증가시키는주요예측인자로서보고되고있고, 이러한연관성은나이성별, 인종과상관없이나타나는것으로보고하고있다 (Ford, 2003). 비만 (Obesity) 은대사물질의변화뿐아니라결합조직, 지방세포와혈관내피세포, 지방전구세포, T 림프구와대식세포를포함하

4 100 Suk Jun Lee and Jinkwan Kim. Slee and Inflammation Fig. 1. Interaction of sleep disorder and obesity in activating inflammatory processes leading to increased risk of CVD. 고있는기질세포분획 (stromal vascular fraction, SVF) 으로구성된지방조직의축적변화를유발한다. 비만은특히간과골격근을포함한조직들에서대사변화를유발하는데, 비만은간에서지방저장과밀접한연관성을가지고있어지방간질환에대한주요위험요인으로보고되고있다 (Ouchi 등, 2011). 따라서비알코올성지방간질환의발생과비만은밀접한연관성을가지고있으며간에서저장된지방의양은지방산의흡수, 내인성지방산의합성, 중성지방의합성, 지방산의산화와중성지방의배출의균형에의하여결정되는데이들각각의대사과정의변화는간에서지방의저장의정도에영향을미칠수있다 (Farrell와 Larter, 2006). 지방조직은 adipokine 이라불리는케모카인을분비하며염증과대사에중요한영향을미치는것으로알려져있다. Resitin, 아디포넥틴, 렙틴, MCP-1은면역조절기능을나타내는지방조직에서분비되는단백질이며, 아디포카인의분비와생산은비만으로변화하고전염증반응의증가와죽종형성과밀접한연관성이있는것으로보고하고있다 (Yu 와 Ginsberg, 2005). 반면 MCP-1과 restin과다른전염증사이토카인 (Proinflammatory cytokines) 들은비만에의해증가하지만항염증단백질인 adiponectin 은감소하는것으로보고되고있다 (Kadowaki와 Yamauchi, 2005). 현재까지내장지방의축적과비만세포비대는지방조직의염증반응을더증가시키는것으로보고하고있지만 (Matsuzawa, 2006), 비만환자에서지방조직의전염증성상태를발생시키는정확한경로는여전히확실하지않다. 최근에이에대한대식세포의역할에대한관심이증대되고있다. 지방세포-침투대식세포 (Adipocyte infiltrated Macrophages, ATMs) 는지방조직의기질세포분획 (SVF) 의일부분으로서 MCP-1, TNF-, and IL-6를포함한다양한전염증단백질의생산과분비에중요한역할을하는것으로알려져있으며지방세포에서인슐린 저항성의증가와대식세포의침윤 (Macrophage infiltration) 과깊은연관성이있는것으로보고하고있다 (Suganami와 Ogawa, 2010). 더불어지방세포의기질세포분획의 T세포군과염증반응효과의균형 / 불균형은지방세포의증식과인슐린저항성과밀접한연관성이있는것으로보고하고있어흥미로운결과가아닐수없다 (Feuerer 등, 2009). 체중조절, 인슐린민감성, 지방세포항상성에대한수면의효과는현재집중적으로연구되고있는과제로비만과대사과정에일주기리듬과관련된유전자가중요한역할을하는것으로최근보고되고있다 (Marcheva 등, 2010). 식욕을조절호르몬의변화로인한칼로리섭취의변화에대한다양한기전연구들이이루어지고있다 (Van Cauter 등, 2008). 예를들면수면제한 (Sleep restriction) 은 leptin의수치를감소시키지만 ghrelin과같은 orexigenic peptides의분비를증가시키는것으로알려져있다 (Leproult와 Van Cauter, 2010). Leptin은에너지의섭취, 소비를조절할뿐아니라염증조절에중요한역할을한다 (Lago 등, 2008). 앞서언급하였듯이수면결핍 (sleep loss) 과수면방해 (sleep disturbance) 는소아와성인에서비만과관련이있고낮은수준의전신성만성염증상태를유발한다. 무작위교차임상연구결과를살펴보면수면제한 (sleep restriction) 은 leptin의감소와 Ghrelin의증가를나타내며이와같은변화는식욕을증가시키고인슐린저항성을증가시켜지방의축적과탄수화물대사를감소시키는것으로보고하고있다 (Spiegel 등 2004). 수면시간의감소에대한생리적반응에대한몇몇연구결과에서는수면시간과소아에서의과체중과비만의위험도를증가시키는것으로보고하고있고 (Chaput 등, 2006), 특히수면시간의감소는취학전아동에서의비만의위험률을증가시키는것으로보고하고있다 (Jiang 등, 2009). 요약해보면수면은아동

5 Korean J Clin Lab Sci. Vol. 47, No. 3, Sep 기에서비만의예방과치료를바꿀수있는요인으로나타나고있지만, 수면시간자체보다수면현상과관련된다른요인또한중요한역할을할수있을것으로추정하고있다. 더불어최근의소아연구에서취침시간의변화가수면시간감소와더불어중요한비만의독립적인위험요인으로보고하고있다 (Spruyt 등, 2011). 객관적으로측정된수면시간과취침시간의변화는공복시인슐린의변화, 저밀도지질단백질, 고민감 CRP 수치와밀접한관계가있는것으로보고하고있다. 이들결과들을종합해볼때가족구성원이나일반대중에게적당량의수면시간과규칙적인수면습관을위한교육프로그램등은특히아동에게서대사성기능장애나심혈관기능장애를감소시킬뿐아니라비만율을감소시킬수있는중요한전략이될수있을것으로사료된다. 3. 수면무호흡증으로인한심혈관계질환의이환률 (Fig. 2) 수면무호흡증은수면중의주기적인상기도의폐쇄로발생하며이로인한반복적인저산소 (Intermittent hypoxia) 와흉부내음압 (Intrathoraxic negative pressure) 의증가로인하여반복적인각성을유발하여이러한현상은교감신경의활성화를유발하여혈압의증가를발생시킨다. 수면무호흡증은교감신경계의항진을유발하여궁극적인혈관내피기능저하를유발하여성인과소아에서궁극적인심혈관계질병의위험을증가시킨다 (Farre 등, 2008). 수면무호흡증으로인한심혈관기능장애에대한정확한기전은아직밝혀져있지않지만핵심기전으로는활성산소 (ROS, reactive oxygen species) 의증가와염증반응의활성화가중요한역할을하는것으로알려져있다 (Gozal, 2009). 수면무호흡증은지방조직이 나염증세포로부터 IL-1, IL-6, TNF- 와같은사이토카인과다양한 adipokines들의증가를통하여죽상경화증의발생 (atherosclerosis) 을촉진하는것으로알려져있다 (Lavie, 2009). 또한 NADPH 산화효소뿐아니라 ROS와 RNS (Reactive nitrogen species) 등의형성과분비는특히혈관내피세포와같은 end-organ 의세포손상을유발하는것으로알려져있다. 이와같은염증의증가는간에서급성염증단백질인 CRP의분비를촉진시키고, 산화적스트레스의증가를동반하여실질적인혈관내피기능저하를유발하고, 직간접적인산화질소 (Nitric oxide) 의활성을감소시키는것으로알려져있다 (Hein 등, 2009; Valleggi, 2010). 이와같은일련의모든현상은세포부착분자 (adehison molecule) 의증가와염증병소의증가, 단핵구의거품세포 (foam cells) 로의변환을유발하고혈관내피세포의사멸을증가시키고혈소판등의혈액응고인자를활성화시킨다 (Gozal, 2009). 다양한전염증사이토카인, 케모카인과부착인자들이수면무호흡증환자에서증가된것을보고하고있고효과적인수면무호흡증의치료후에이들수치가감소하는것으로보고하고있다. 그러나모든연구결과에서이와같은결과를보고하는것이아닌몇몇연구결과에서는이와같은변화를증명하지못한연구결과를보고하고있고, 그원인으로는성인수면무호흡증에서 IL-6 의증가가수면무호흡증의위험요인인비만과더밀접한관계가있는것으로보고하고있다 (Vgontzas, 1997; Yokoe 등, 2003). 그러나클리블렌드가족연구에서는 IL-6는수면무호흡증의중증도와독립적인연관성이있는것으로보고하고있고 (Mehra 등, 2006), Gozal 등의환자-대조군연구결과역시 4 9 세의소아수면무호흡환자에서나이, 성별, 인종과체질량지수를 Fig. 2. Schematic diagram underlying inflammatory pathways associated with obesity and obstructive sleep apnea syndrome that may lead to increased CVD risk.

6 102 Suk Jun Lee and Jinkwan Kim. Slee and Inflammation 짝짓기한대조군에비해 IL-6증가, IL-10 감소를보고하고있으며편도절제술 (adenotonsillectomy) 을시행하여수면무호흡증의치료 4 6 개월후에정상수치로돌아간결과를보고하고있다 (Gozal 등, 2008). TNF- 와수면무호흡증과의연관성연구는더흥미로운결과를보고하고있다. 현재전염증사이토카인은혈관내피 (vascular endothelium) 의백혈구부착을야기하는세포부착분자 (cellular adhesion molecules) 의발현에의한죽상경화와밀접한관련이있는것으로알려져있다 (Kritchevsky 등, 2005). 몇몇환자-대조군연구에서 TNF- 수치는폐쇄성수면무호흡환자에서비만과독립적으로연관성이있으며효과적인지속적양압기치료 (continuous positive airway pressure, CPAP) 후에유의한감소를보고하고있다 (McNicholas, 2009). 그러나모든환자에서이러한 TNF- 의수치가상승되었다는결과를보이지않는데그이유중의하나로서 TNF- 유전자의유전자다형성의변이에의한결과로설명하고있다 (McNicholas, 2009). T 세포와단핵구는잠재적인 TNF- 와전염증사이토카인의증가를유발하는것으로보고하고있다. Gozal 등의연구결과에의하면단핵구는수면무호흡증에서염증반응을유발하는주요한타겟세포가될것으로제안하고있으며, 그들은저산소모델을이용한동물실험에서단핵구의활성화는혈관벽에서평활근의유의한증식을유발하고, 혈관벽안의손상된혈관내피세포로대식세포가이동됨으로써거품세포를형성하는복잡한생물학적인케스케이드가시작되는것으로알려져있다 (Gozal 와 Kheirandish-Gozal, 2008). 단핵구의동원 (monocyte recruitment) 에대한연구결과와같은맥락으로 Dyugovskaya 등은성인수면무호흡증환자에서 T-세포의존성염증반응의활성을보고하고있다 (Dyugovskaya 등, 2005). 이와같은연구결과를살펴볼때반복적인저산소혈증은 T 림프구의활성화를통하여특이사이토카인의분비를유도하고, 이러한사이토카인의네트워크의신호는죽변형성과관련한대식세포의반응과매우흡사할것으로생각되고있다. 수면무호흡환자에서 CD4+ 와 CD8+ T세포의표현형의변화는 Th1 사이토카인으로부터 Th2 사이토카인생산으로이동을보고하고있고, IL-10 발현이수면무호흡증의중증도와역상관관계를나타내는반면 TNF-α 은수면무호흡의중증도와순상관관계를나타내는것으로보고하고있고, 더불어수면무호흡증환자로부터얻어진 CD8+ T 세포 TNF-α 와 soluble CD40 리간드의증가를보고하고있다. 흥미로운것은이와같은염증반응의항진은수면무호흡증의치료인지속적양압기치료후에정상으로되돌아가는것으로보고하고있다 (Dyugovskaya 등, 2005). 또다른염증성마커로알려진 C-반응단백질 (C-reactive protein, CRP) 은주로 IL-6에의하여간에서생산되는급성기단백질 로서알려져있을뿐아니라혈청농도는염증반응의정도를반영하는주요지표로또한죽상경화의위험을평가하는단백질로알려져있다 (Ridker 등, 2000). C-반응단백질은죽상경화병소부위, 특히혈관내막층에서더특이적으로발견되며이곳에서단핵구와단핵구기원대식세포와지질단백질과함께국소화 (localization) 된것으로알려져있다 (Lusis, 2000). 이러한국소화는 C-반응단백질이죽상경화과정에직접적인관여를하는것으로알려져있다. 성인과소아수면무호흡환자모두에서 C-반응단백질이증가하고, 치료후에 C-반응단백질이실제로감소하는것으로보고되고있다 (Li 등, 2008; Kheirandish-Gozal 등, 2006). 그러나다른모든연구에서이러한 C-반응단백질과수면무호흡증의중증도사이의연관성에대하여확증된것은아니다 (Guilleminault 등, 2004). 그이유가운데하나는 C 반응단백질과비만과의강한연관성으로인하여 (Visser 등, 1999), 수면무호흡증의강력한위험요인인비만이염증마커인 C-반응단백질과수면무호흡증의중증도에대하여혼란변수 (Confounding factor) 로작용하고있어독립적인연관성에대한추가적인연구가계속필요할것으로사료된다 (McNicholas, 2009). 결론앞서본문에서기술한수면, 면역계, 염증사이의밀접한관계를살펴볼때어떠한원인으로든수면장애또는수면방해는염증반응을시작하거나악화시킬수있는것은놀랄만한일이아니다. 비록수면장애또는다양한수면문제들과만성염증성상태사이의인과관계는완전히규명되지않았지만, 수면부족이나수면장애는다양한만성염증성질환의표현형을조절하는중요한요인으로보아야할필요가있다. 따라서비만과수면무호흡증모두심혈관계질환을비롯한만성질환의이환을증가시키고염증성반응경로를활성화시킨다는측면에서보다추가적이고세밀한연구가진행되어야할것이다. 수면장애나수면부족은특히 TLR과 NF- B 를통하여중계되는전염증성신호경로 (Pro-inflammatory signaling pathways) 들을활성화시키고, 다양한아디포카인을유도하여, 죽상경화의위험을증가시키는것으로보고되고있다. 따라서이러한과정이생의초기즉소아또는청소년기에발생한다면심혈관계질환의이환시기를앞당기거나이로인한각종만성질환의이환을증가시키는심각한공중보건의문제가될것으로예상되며성인에있어서역시심혈관질환등과같은만성질환과의깊은연관성을살펴볼때보다적극적인치료전략과효과적인공중보건정책이마련되어야할것으로사료된다.

7 Korean J Clin Lab Sci. Vol. 47, No. 3, Sep 요약 수면현상은인간의삶의 1/3을차지하는중요한생리적현상으로인간의수면은신체의기능을유지하기위한중요한생리적기능뿐아니라수면을통한휴식을통하여신체건강을유지하고성장을유지하는중요한역할을한다. 최근의급격한산업화와정보화로인하여급격한사회생활구조의변화를유발하여성인뿐아니라소아에서도평균수면시간의감소와다양한스트레스환경으로인한수면의질적저하로인한다양한수면문제가사회적문제로대두되고있다. 단순히수면부족또는수면의질적저하뿐아니라수면장애, 특히폐쇄성수면무호흡증은심혈관질환뿐아니라비만, 대사증후군, 심혈관질환, 뇌혈관질환등의다양한만성질병의발생과깊은연관성이있는것으로보고하고있다. 특히이러한만성질환을유발하는핵심기전으로염증반응이관여하고있는것으로알려져있으며, 따라서수면현상과다양한수면장애에대한관심이급격히증가하고있는실정이다. 비록수면무호흡증으로인한이러한질병의이환에대한기전은다양한요인이복합적으로작용하는것으로알려져있지만핵심기전으로알려진염증반응의활성화가병태생리학적으로중요한역할을하는것으로추측하고있다. 따라서최근수면무호흡증을낮은수준의만성염증질환으로인식되고있으며, 더불어비만과수면무호흡증으로인한연관된질병의이환을더욱증가시키는것으로보고되고있다. 따라서본종설에는수면의질적또는양적저하뿐아니라폐쇄성수면무호흡증으로인한염증성반응의활성화가인간의신체면역과정미치는영향을중심으로최근의연구결과및수면무호흡증과비만의잠재적상호작용에대하여서술하고자한다 Acknowledgements: None Funding: None Conflict of Interest: None References 1. Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration. Nat Rev Neurosci. 2001, 2: Anderson SE, Whitaker RC. Household routines and obesity in US preschool-aged children. Pediatrics. 2010, 125: Benca RM, Kushida CA, Everson CA, et al. Sleep deprivation in the rat: VII. Immune function. Sleep. 1989, 12: Brandt JA, Churchill L, Rehman A, et al. Sleep deprivation increases the activation of nuclear factor kappa B in lateral hypothalamic cells. Brain Res. 2004, 1004: Brasier AR. The NF-kappaB regulatory network. Cardiovasc Toxicol. 2006, 6: Cappuccio FP, Taggart FM, Kandala NB, et al. Meta-analysis of short sleep duration and obesity in children and adults. Sleep. 2008, 31: Chassin L, Presson CC, Rose J, et al. Parenting style and smoking-specific parenting practices as predictors of adolescent smoking onset. J Pediatr Psychol. 2005, 30: Chaput JP, Brunet M, Tremblay A. Relationship between short sleeping hours and childhood overweight/obesity: results from the 'Quebec en Forme' Project. Int J Obes (Lond). 2006, 30: Dantzer R, O'Connor JC, Freund GG, et al. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008, 9: Dyugovskaya L, Lavie P, Hirsh M, et al. Activated CD8+ T-lymphocytes in obstructive sleep apnoea. Eur Respir J. 2005, 25: Farre R, Montserrat JM, Navajas D. Morbidity due to obstructive sleep apnea: insights from animal models. Curr Opin Pulm Med. 2008, 14: Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006; 43:S99-S Feuerer M, Herrero L, Cipolletta D, et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med. 2009, 15: Ford ES. C-reactive protein concentration and cardiovascular disease risk factors in children: findings from the National Health and Nutrition Examination Survey Circulation. 2003, 108: Franklin CM. Clinical experience with soluble TNF p75 receptor in rheumatoid arthritis. Semin Arthritis Rheum. 1999, 29: Gozal D. Sleep, sleep disorders and inflammation in children. Sleep Med. 2009, Supple 1:S Gozal D, Serpero LD, Sans Capdevila O, et al. Systemic inflammation in non-obese children with obstructive sleep apnea. Sleep Med. 2008, 9: Gozal D, Kheirandish-Gozal L. Cardiovascular morbidity in obstructive sleep apnea: oxidative stress, inflammation, and much more. Am J Respir Crit Care Med. 2008, 177: Guilleminault C, Kirisoglu C, Ohayon MM. C-reactive protein and sleep-disordered breathing. Sleep. 2004, 27: Horne J. Short sleep is a questionable risk factor for obesity and related disorders: statistical versus clinical significance. Biol Psychol. 2008, 77: Hein TW, Singh U, Vasquez-Vivar J, et al. Human C-reactive protein induces endothelial dysfunction and uncoupling of enos in vivo. Atherosclerosis. 2009, 206: Ievers-Landis CE, Redline S. Pediatric sleep apnea: implications of the epidemic of childhood overweight. Am J Respir Crit Care Med. 2007, 175: Irwin MR, Wang M, Campomayor CO, et al. Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch Intern Med. 2006, 166: Irwin MR, Wang M, Ribeiro D, et al. Sleep loss activates cellular inflammatory signaling. Biol Psychiatry. 2008, 64: Jiang F, Zhu S, Yan C, et al. Sleep and obesity in preschool children. J Pediatr. 2009, 154:

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