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1 SMN SURGICAL METABOLISM AND NUTRITION Vol. 1, No. 1, December 2010 REVIEW ARTICLE 면역지원영양소 이재길 연세대학교의과대학외과학교실 Immuno-supportive Elements Jae Gil Lee, M.D., Ph.D. Department of Surgery, Yonsei University College of Medicine, Seoul, Korea Immunonutrients can modulate the immune system after infection, surgery, and trauma. They can modulate inflammation and oxidative stress and help to maintain immune function, thus having beneficial effects on the body when used properly. This article reviews immunosupportive macronutrients, such as glutamine, arginine, and ω-3 fatty acids. (SMN 2010;1:21-25) Key Words: Nutritional support, Immunonutrients, Immunonutriton 서론 우리몸은외상이나감염, 수술등에의해손상이가해지면정상적으로면역체계가활성화되면서사이토카인이분비되고활성산소및염증에관여하는여러물질들이활성화되어염증반응이일어난다. 이와더불어염증반응후에는항염증물질이분비되면서면역이억제되는항염증반응증후군 (compensatory anti-inflammatory response syndrome, CARS) 이나타나게된다. 과도한염증반응은체내과도한이화상태를유발하며, 반대로과도한항염증반응은면역을억제하여감염에대한저항성을떨어뜨리게한다.(1-3) 따라서과도한염증반응과항염증반응을억제하여체내항상성을최대한유지하는것이손상에의한이화반응을최소화하고, 감염에대한위험성을낮출수있다. 염증반응과항염증반응을줄이기위한많은노력들이시도되고있으며, 이중영양소를이용하여염증반응과면역반응을조절하기위한방법으로면역영양의개념이시작되었다.(3-7) 면역을담당하는세포의활성화에영향을주어면역반응을조절할수있는영양소를면역지원영양소 (immuno-supportive nutrition) 또는면역영양소 (immuno-nutrients) 라고하며, 이를위한영양지원을면역영양 (immunonutrition) 이라한다. 이러한면역영양을통해체내면역체계를조절하여환자의상태를호전시킬수있는것으로제시되고있다 (Fig. 1). 본영양소들은세포중개면역반응에주로관여하는것으로알려져있고, 최근들어임상적으로활발히사용되고있으며, 이에대한연구가지속되고있다. 본글에서는면역지원영양소의종류와그기전, 임상적유용성에대해알아보고자한다. 책임저자 : 이재길, 서울시서대문구성산로 , 연세대학교의과대학외과학교실, 중환자관리및외상 Tel: , Fax: jakii@yuhs.ac 21 Fig. 1. The roles of immunonutrition.

2 22 Surgical Metabolism and Nutrition Vol. 1 No. 1, 2010 Table 1. Possible immunonutrients and action mechanisms Glutamine Nutrient for immune cells (T-cells) Improve gut barrier function (major fuel of the enterocytes) Precursor of glutathione (most important endogenous radical scavenger) Arginine Precursor for nitric oxide (blood flow mediator) Involved in nucleotide synthesis and ATP generation Enhances T lymphocyte numbers and function (proliferation) Stimulates growth hormone production Nucleotides Precursors of RNA and DNA Improve T lymphocytes functions, antibody responses ω-3 fatty acids Produce anti-inflammatory eicosanoides and cytokines Produce anti-inflammatory resolving Reverse immunosuppression Antioxidant vitamins Maintain antioxidant defence Prevent oxidative stress and lipid peroxidation Trace elements Major component of the antioxidant enzymes (Zinc, cooper, selenium) Maintain antioxidant defence Branched-chain amino acids Precursor of glutamine Improve immune function N-acetyl cysteine Glutathione synthesis - enhance T lymphocytes, cell mediated immune function 본론 1. 면역지원영양소의종류 면역지원영양소로많은물질들이제시되고있으나 (Table 1), 실제로임상적인유용성이입증된것은많지않다. 따라서주로논란이되고있고, 임상적인연구결과들이많은아르기닌 (arginine), 글루타민 (glutamine), ω-3 지방산에대해간략히정리해보고자한다. 1) 글루타민 : 글루타민은세포질에서가장풍부한아미노산으로 T 림프구, 장점막세포, 폐내피세포및심근세포의주된에너지원으로작용한다. 스트레스나병적인상태가되면횡문근이분해되면서공급되는아미노산의약 70% 정도는글루타민이차지한다. 손상이발생하면많은세포들, 특히세포분열이활발히일어나는세포들에서글루타민의소모가많아지면서체내글루타민양은감소하게된다. 따라서평소에는필수아미노산이아니지만, 손상이나스트레스상황에서는필수적으로공급해주어야하는아미노산이다. 글루타민은체내에서강력한활성산소제거제 (scavenger) 로작용하는글루타치온을합성하는전구체로항산화작용에중요한역할을한다. 또한장점막세포의에너지원으로사용되어장점막의위축을방지하고, 장내세균의전치 (translocation) 를억제하여소화관에의한감염을방지하여, 추가적인감염및패혈증이발생하는것을방지한다. 글루타민은림프구의에너지원으로사용되며, 림프구의활성및기능을유지시키고, 열쇼크단백 (heat shock protein, HSP) 의발현을촉진하여염증성사이토카인의분비를억제하는등항염증작용과면역지원효 Table 2. Possible effects of glutamine Trauma patients Burn patients Surgical patients Critical patients Effects of glutamine Higher HLA-DR expression Reduced insulin resistance Lower cytokine production Lower mortality Reduced length of stay Improved nitrogen balace Less infectious complications Less insulin requirement Lower mortality (?) 과를가지고있다. 글루타민은수술후환자나중환자에서감소되어있으며, 글루타민의감소는환자의결과로밀접한관련성을가지고있어, 감소된환자는감염의위험성이증가되고사망률이높은것으로알려져있다. Novak 등 (8) 은중환자에서글루타민의정맥내투여는감염성합병증을감소시키며, 입원기간을단축시키고, 사망률을낮출수있는것으로보고하였으나, 수술후환자에서는사망률과의연관성은없는것으로보고하였다. Avenell(9) 은글루타민에대한메타분석을통해글루타민을공급한환자들에서사망률이감소되는경향이있는것으로보고하였다. 글루타민의공급은중환자및외과환자에서감염성질환의합병증과입원기간을줄일수있으며, 사망률을감소시킬수도있는것으로알려져있으나, 현재에도연구가지속적으로이루어지고있으며, 큰효과가없다는보고들도있어, 좀더많은연구가있어야할것이다. 글루타민의효과에대해서는 Table

3 이재길 : 면역지원영양소 23 2에정리하였다. 2) 아르기닌 (Arginine): 아르기닌은필수아미노산은아니지만스트레스나손상후에는체내사용량이증가하여쉽게결핍되는아미노산으로, 글루타민과더불어조건적인필수아미노산으로분류된다. 프롤린과글루타메이트 (glutamate), polyamine의전구체가되고, 암모니아의해독에사용되며, 산화질소 (nitric oxide) 의전구체이다. 활성산소의생성을감소시키는작용이있으며, T 림프구의수와기능을활성화시켜면역을증강시키는역할을한다. 그러나반대로유도성산화질소합성효소 (inducible NO synthase, inos) 의생성을촉진하여미세순환장애를일으켜장기부전을유발할수있다. 수술이나외상환자에서아르기닌의보충은감염의위험성을줄이고, 인공호흡기간과중환자실입원기간및재원기간을줄일수있는것으로보고되었으나, 중환자에서는별다른이득은없으며 inos의과발현에의한장기부전을발생시키는등해로운결과를보일수있다.(10-12) 3) ω-3 fatty acids: 지방제제는적은양으로고에너지를공급할수있어정맥영양시흔히사용된다. 지방용해성비타민의운반체역할을하며, 세포막의인지질을구성하는중요한요소이다. 세포막에포함된아라키돈산 (archidonic acid) 은 cyclooxygenase (COX) 와 lipooxygenase (LOX) 에대사되어트롬복산, 프로스타글란딘, 류코트리엔을합성하며, 이합성체들은염증반응을유발하는전구물질로작용하여사이토카인분비를촉진하게된다. ω-3 지방산은생선에많으며, docosahexaenoic acid (DHA) 와 eicosapentanoic acid (EPA) 등이있다. 아라키돈산과는달리, DHA와 EPA는 COX-2와 5-LOX에의해항염증효과가있는 resolvin과염증반응을다소약하게일으키는프로스타글란딘합성을유도하여, 항염증작용을가지며면역반응을조절할수있는것으로알려져있다 (Fig. 2). 복부수술환자에서 ω-3 지방산을정맥내로투여한경우에인공호흡기간과재원기간이더짧고사망률도낮다고보고되었다.(13) 또한급성폐손상환자또는급성호흡부전증후군환자에서경구 / 정맥내 ω-3 지방산투여는인공호흡기간을단축시키고, 생존율을높이는등긍정적인효과가있는것으로알려져있다. 2. 면역영양지침지금까지캐나다그룹, 유럽경장정맥영양학회 (Europenal Society of Parenteral and Enteral Nutrition, ESPEN), 미국중환자의학회-영양학회에서영양지원에대한지침을발표하였다. 이중 ESPEN 지침을간략히소개하고, 다른학회와비교해보았다 (Table 3).(14-19) 1) 유럽경장정맥학회지침 (1) 경장영양 1 복부악성종양으로대수술을시행받거나중증외상환자에서는영양위험과관계없이면역조절영양소 ( 아르기닌, ω- 3 지방산, nucleotide) 를포함하여경장영양을우선적으로고려한다. 2 다음환자에서는면역조절영양소 ( 아르기닌, ω-3 지방 Fig. 2. Action mechanisms of ω-3 fatty acids. DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; COX = cyclooxygenase; LOX = lipooxygenase; PG = prostaglandin; TX = thromboxane; LT = leukotriens.

4 24 Surgical Metabolism and Nutrition Vol. 1 No. 1, 2010 Table 3. Comparison of current guidelines about immuno-supportive elements Canadian ESPEN SCCM/ASPEN Arginine Do not use in critical ill pts Enteral Enteral Major GI surgery Major GI surgery Sever trauma Trauma/sepsis Mild sepsis MV Glutamine Enteral Enteral Enteral (EN) Burn/truama Burn/trauma Burn/trauma Parenteral Parenteral Parenteral Critically ill pts with PN Critically ill pts with PN Critically ill pts with PN ω-3 fatty acids ARDS pts Enteral Enteral (EN) GI surgery/trauma ARDS/ALI Mild sepsis/ards Caution in severe sepsis Parenteral Critically ill pts with PN Nucleotides Enteral Enteral Major GI surgery Major GI surgery Sever trauma Trauma/sepsis Mild sepsis MV ESPEN = European Society of Parenteral and Enteral Nutriton; SCCM = Society of Critical Care Medicine; ASPEN = American Society of Parenteral and Enteral Nutrition; GI = gastrointestinal; MV = mechanical ventilation; pts = patients; PN = parenteral nutrition; ARDS = acute respiratory distress syndrome; ALI = acute lung injury. 산, nucleotide) 를포함한경장영양이더우수한효과를보인다. * 상부위장관수술환자, 경증의패혈증 (APACHE II<15), 외상환자, 급성호흡부전증환자 (ω-3 지방산과항산화제가포함된식이 ) * 중증패혈증환자는해가될수있으므로추천하지않음. 3 글루타민은화상및외상환자에서경장영양시보충해주어야한다. 단, 수술후또는중환자에서는환자군이다양하여충분한결과를보이지못하고있다. (2) 정맥영양 1 지방제제에 EPA와 DHA를첨가한경우세포막과염증반응에좋은효과를보이며, 생선지방이풍부한지방제제는중환자에서재원기간을줄일수있다. 2 중환자에서정맥영양의적응증이된다면, 아미노산제제는 L-글루타민으로 g/kg/day ( g/kg/day, alanyl-glutamine dipeptide) 를포함하여야한다. 3 외과중환자에서적절한정맥영양제는 ω-3 지방산을포함하고있어야한다. 결론 최근들어면역지원영양에대한관심이많아지면서다양한제품들이개발되고임상에응용되고있으나, 향후에도지속적인임상연구와데이터가필요한상태이다. 영양지원을통해공급되는각각의면역영양소들은아직도연구중에있으므로, 임상적용시각각의장단점과적응증에대한숙지가필요하다. REFERENCES 1. Adib-Conquy M, Cavaillon JM. Compensatory anti-inflammatory response syndrome. Thromb Haemost 2009;101: Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest 1997;112: Calder PC. Immunonutrition in surgical and critically ill patients. Br J Nutr 2007;98(Suppl 1):S Cerantola Y, Hübner M, Grass F, Demartines N, Schäfer M. Immunonutrition in gastrointestinal surgery. Br J Surg 2011; 98: Marik PE, Zaloga GP. Immunonutrition in critically ill patients: a systematic review and analysis of the literature. Intensive Care Med 2008;34: Mizock BA. Immunonutrition and critical illness: an update. Nutrition 2010;26: Xu J, Yunshi Z, Li R. Immunonutrition in surgical patients. Curr Drug Targets 2009;10: Novak F, Heyland DK, Avenell A, Drover JW, Su X. Glutamine supplementation in serious illness: a systematic review of the evidence. Crit Care Med 2002;30: Avenell A. Glutamine in critical care: current evidence from systematic reviews. Proc Nutr Soc 2006;65: Suchner U, Heyland DK, Peter K. Immune-modulatory actions of arginine in the critically ill. Br J Nutr 2002;87(Suppl 1): S Zhou M, Martindale RG. Arginine in the critical care setting. J Nutr 2007;137(6 Suppl 2):S Jones NE, Heyland DK. Pharmaconutrition: a new emerging paradigm. Curr Opin Gastroenterol 2008;24: Mayer K, Seeger W. Fish oil in critical illness. Curr Opin Clin Nutr Metab Care 2008;11: Braga M, Ljungqvist O, Soeters P, Fearon K, Weimann A, Bozzetti F, et al. ESPEN Guidelines on Parenteral Nutrition: surgery. Clin Nutr 2009;28: Heyland DK, Dhaliwal R, Drover JW, Gramlich L, Dodek P; Canadian Critical Care Clinical Practice Guidelines Committee. Canadian clinical practice guidelines for nutrition support in

5 이재길 : 면역지원영양소 25 mechanically ventilated, critically ill adult patients. JPEN J Parenter Enteral Nutr 2003;27: Kreymann KG, Berger MM, Deutz NE, Hiesmayr M, Jolliet P, Kazandjiev G, et al. ESPEN guidelines on enteral nutrition: intensive care. Clin Nutr 2006;25: McClave SA, Martindale RG, Vanek VW, McCarthy M, Roberts P, Taylor B, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically Ill patient: society of critical care medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr 2009;33: Singer P, Berger MM, Van den Berghe G, Biolo G, Calder P, Forbes A, et al. ESPEN guidelines on parenteral nutrition: intensive care. Clin Nutr 2009;28: Weimann A, Braga M, Harsanyi L, Laviano A, Ljungqvist O, Soeters P, et al. ESPEN guidelines on enteral nutrition: surgery including organ transplantation. Clin Nutr 2006;25:

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untitled SMN SURGICAL METABOLISM AND NUTRITION Vol. 6, No. 2, December, 2015 pissn 2233-5765, eissn 2465-8383 http://dx.doi.org/10.18858/smn.2015.6.2.17 REVIEW ARTICLE 경장영양액의분류및적용 이재길 연세대학교의과대학외과학교실 General Categorization