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1 pissn: eissn: (4): , December ORIGINAL ARTICLE 소아천식군과영유아천명군에서혈청내가용성 ST2 상승의의의 추미애, 이형직, 이은주, 홍석진, 박혜진, 이계향, 정혜리 대구가톨릭대학교의과대학소아과학교실 Increased serum soluble ST2 in asthmatic children and recurrent early wheezers Mi Ae Chu, Hyung Jik Lee, Eun Joo Lee, Suk Jin Hong, Hye Jin Park, Kye Hyang Lee, Hai Lee Chung Department of Pediatrics, Catholic University of Daegu School of Medicine, Daegu, Korea Purpose: Soluble ST2 (sst2) has been reported to regulate Th2 response. In this study, serum levels of sst2 and other cytokines were measured in recurrent early wheezers and asthmatic children. We aimed to investigate if there are any differences or similarities in Th1 or Th2 response between those two patient groups. Methods: Fifty-nine patients admitted with exacerbation of wheezing or asthma were enrolled. Two patient groups were defined: children with atopic asthma ( 6 years, n = 21) and recurrent early wheezers ( 2 years, n = 38). Recurrent early wheezers were divided based on their atopic status: 19 were atopic and 19 were nonatopic. sst2, interleukin (IL) 33, IL-5, and interferon (IFN)-γ were measured in serum samples collected on admission. Cytokine levels in both patient groups were compared with their age-matched controls and evaluated the relationship with blood eosinophils, serum IgE levels, and also with the severity of symptom. Results: sst2 and IL-5 were significantly increased both in asthmatic children (P = 0.02, P = 0.004) and recurrent early wheezers (P= 0.01, P= 0.001) compared to their age-matched controls. IL-5 was significantly higher in atopic wheezers compared with nonatopic wheezers (P = 0.04). Severity score showed a positive correlation with sst2 and IFN-γ in asthmatic children, but only with IFN-γ in early wheezers. There was an inverse correlation between sst2 and blood eosinophil counts both in asthmatic children and atopic recurrent wheezers. Conclusion: Our study suggests that sst2 might regulate allergic inflammation by suppressing eosinophilia and play an important role in pathophysiology of acute exacerbation of wheezing or asthma both in asthmatic children and early wheezers. (Allergy Asthma Respir Dis 2013;1: ) Keywords: ST2, Cytokine, Asthma, Child 서론 ST2는 interleukin (IL) 1 수용체계열에속하며, 세포막에존재하는 ST2L, 가용성으로혈청에서검출되는 soluble ST2 (sst2), 그리고주로위장관에분포한다고알려진 ST2V 등 3가지 isoform이보고되어있다. 1) 이들중 Th2 림프구의세포막에존재하는 ST2L과그리간드인 IL-33의결합은 IL-4, IL-5, IL-13 등 Th2 사이토카인들 의표현을증대시켜호산구성염증반응과 IgE의생성증가를유도하는것으로알려져있다. 2-4) 혈청내에존재하는 sst2의역할에대해서는아직확실하지않은부분이많으나 IL-33과경쟁적으로결합하여 Th2 면역반응을억제하는 decoy 수용체로서작용하여알레르기성염증반응의조절에중요한역할을하는것으로생각되고있으며 4-6) 실제로이전연구들에서급성천식악화상태의환자들에서증가되어있는현상이관찰된바있다. 7,8) Correspondence to: Hai Lee Chung Department of Pediatrics, Catholic University of Daegu School of Medicine, 33 Duryugongwon-ro 17-gil, Nam-gu, Daegu , Korea Tel: , Fax: , hlchung@cu.ac.kr Received: August 2, 2013 Revised: September 8, 2013 Accepted: September 8, The Korean Academy of Pediatric Allergy and Respiratory Disease The Korean Academy of Asthma, Allergy and Clinical Immunology This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (

2 추미애외 소아천식군과영유아천명군에서 sst2 상승의의의 많은소아천식환자들이영유아기에처음천명을경험하며호흡기의잦은바이러스감염과관련된이시기의반복되는천명은이후소아천식의발생과중요한관련성을가지는것으로알려져있다. 이에저자들은아토피천식을가진학동기소아들과반복적인천명증상을가진영유아들에서관찰되는면역반응에어떤공통점이나차이가있는지조사해보고자하였다. 본연구에서는급성천식악화또는천명증상의재발로인해입원하였던두환자군, 즉, 6세이상의아토피소아천식군과 2세이하의반복적인천명군을선정하였다. 이들두군의입원당시의혈청에서 sst2와 IL-33을측정하였고, 또한 Th1 및 Th2 면역반응의표지자인 IL-5와 interferon (IFN)-γ 를함께측정하였다. 이들측정치들이두환자군과동일한연령의두대조군측정치들과각각비교하여차이가있는지조사하였으며환자군에서관찰되는임상양상과의관련성도조사하였다. 또한 3세이하의반복적인천명군은아토피유무에따라다시두군으로나누어양군간에이들사이토카인반응의차이를보이는지비교하였다대상및방법 1. 대상대상환자군은두군으로, 급성천식악화로인해입원하였던 6 세이상의아토피소아천식군 (n= 21) 과 3회이상천명의병력을가지고있으면서급성천명증상의재발로인해입원하였던 2세이하의반복적인천명군 (n= 38) 으로정의하였다. 2세이하의반복적인천명군은아토피유무에따라다시아토피군 (n=19) 과비아토피군 (n=19) 으로분류하였다. 소아천식군에는이전에시행하였던메타콜린유발시험에서 16 mg/ml 이하의 PC 20 값이관찰되었거나, 기관지확장제에대한 12% 이상의 forced expiratory volume in 1 second 증가가관찰되어천식으로진단받은 6세이상의소아들이포함되었다. 천식악화와관련된상기도질환의증상이동반되었던경우는대상군에서제외되었다. 반복적인천명군에포함된 2세이하소아들은모두재태연령 38 주이후에출생한만삭아들이었고만성폐질환, 선천성심장병을비롯한다른선천성질환을가지고있는경우는제외하였다. 소아천식군에서와달리이군에포함된소아들에서급성천명의재발은대부분선행하는상기도감염증상을동반하였다. 두환자군모두에서입원전 4주이내에전신스테로이드제가처방된경우는대상군에서제외되었다. 아토피는최소한 1개이상의알레르겐에대해 0.35 ku/l 이상의특이 IgE 항체를가지고있거나 (ImmunoCAP, Phadia, Uppsala, Sweden), 알레르기피부시험 (skin prick test) 에서 1개이상의양성반응을보였거나 (Allergopharma, Reinbeck, Germany), 연령에비 해높은혈청 IgE (> 평균치 +2 standard deviation) 를나타낸경우로정의하였다. 9) 알레르기피부시험의경우히스타민에대해 3 mm 이상, 음성대조액에대해음성반응을보이면서알레르겐에대한팽진의크기가히스타민에대한팽진크기이상인경우를 (allergen/histamine ratio 1) 양성으로판정하였다. 입원중호흡기증상의심한정도는증상점수 (severity score) 로나타내었다. 입원중산소흡입을하지않은상태에서산소포화도 92% 이하, 빈호흡, 흉부함몰소견, 1주일이상의입원기간등을심한증상으로정하고각각을 1점으로하여이들증상들이관찰되지않았던경우를 0점으로하고 0에서 4까지의증상점수를산정하였다. 반복적인천명군은퇴원이후 1년동안의임상경과를조사하여천명성질환의재발유무를확인하였다. 소아들이본병원을방문하였던의무기록을검토하여확인하였고 1년동안병원을방문한기록이없었던소아들에서는보호자에게전화를하여조사하였다. 두환자군과동일한연령대의두대조군을각각 15명씩선정하였으며, 이들은경미한외과적수술을위해입원하였던소아들로서입원당시호흡기감염이나다른감염의증상이없었고알레르기질환이나다른염증성질환의병력을가지지않은경우로정하였다. 본연구는대구가톨릭대학병원임상심사위원회 (Institutional Review Board) 의심의를받아보호자동의하에수행되었다. 2. 방법 sst2, IL-33, IL-5 및 IFN-γ의측정을위하여입원당시대상환자군들과대조군에서채혈후혈청을분리하여분석전까지영하 70 C에보관하였고이들사이토카인의측정은 Quantikine colorometric sandwich enzyme-linked immunosorbent assay (ELISA) kits들을이용하여이루어졌다 : sst2 및 IFN-γ (R&D, Minneapolis, MN, USA), IL-33 (Enzo Life Sciences Inc., Farmingdale, NY, USA), IL-5 (Abcam, Cambridge, UK). ELISA 측정의하한치는 sst2는 5 pg/ml, IFN-γ은 8 pg/ml, IL-33은 1.7 pg/ml, 그리고 IL-5는 1.7 pg/ml이었다. 2세이하반복적천명군소아들에서는입원당시채취한비인두분비물에서급성천명증상의재발과관련된호흡기바이러스감염을확인하기위하여 multiplex reverse transcription-polymerase chain reaction (Real-Q RV Detection KIT, BioSewoom, Seoul, Korea) 을이용하였다. 3. 통계분석통계분석은 IBM SPSS ver (IBM Co., Armonk, NY, USA) 를이용하였다. 각각의사이토카인측정치들은평균과표준편차를이용하여표시하였다. 두군간비교에서는각군에서의측정치가정규분포를보이지않는경우가있어서그결과의비교에는 Mann- Whitney U test를이용하였으며양군간빈도의비교에서는 Fisher 315

3 Chu MA, et al. Increased sst2 in recurrent early wheezers exact test를이용하였다. 상관관계분석에는 Pearson 또는 Spearman correlation coefficient를이용하였다. P < 0.05를통계학적으로유의한것으로보았다. 결과 상의동반이관찰되었으나비인두분비물의바이러스검사에서는 28명 (73%) 에서원인바이러스가검출되었고 10명에서는확인이되지않았다. 검출된바이러스들은 respiratory syncytial virus (15 명 ), rhinovirus (3명 ), bocavirus (3 명 ), adenovirus (1 명 ), influenza A virus (1 명 ), 중복감염 (5명) 등이었다. 1. 대상군의임상적특징두환자군, 아토피소아천식군과반복적천명군들과각연령별대조군들간에연령및성별의차이는없었다 (Table 1). 2세이하의반복적천명군 (n= 38) 을아토피군 (n=19) 과비아토피군 (n=19) 으로구분하여비교해보았을때연령, 성별및입원중증상의심한정도, 일반적인검사실소견에는차이가없었고, 혈청총 IgE 치는아토피군에서유의하게높았다 (P<0.0001) (Table 2). 퇴원이후 1년간의경과를추적하여천명의재발이있었던군 (n= 28) 과없었던군 (n=10) 으로구분하였을때도두군간임상양상과검사실소견에는차이가없었다 (Table 3). 반복적천명군에속한모든소아들에서입원전상기도감염증 2. 소아천식군및반복적천명군과각연령별대조군간의사이토카인반응입원당시분리한혈청에서측정한 sst2의측정치는아토피천식군과반복적천명군에서모두연령별대조군과비교하여증가해있는양상을보였다 (P = 0.02, P = 0.01, respectively). IL-5의측정치도아토피천식군과반복적천명군에서모두연령별대조군과비교하여증가해있는양상을보였다 (P = 0.004, P = 0.001, respectively). IL-33은아토피천식군에서대조군과비교하여유의한차이를보이지않았으며반복적천명군에서도대조군과비교하여유의한차이를보이지않았다 (P = 0.6, P = 0.2, respectively). 또한 IFN-γ는아토피천식군에서대조군과비교하여유의한차이를보이지않았 Table 1. Demographic findings and serum cytokine levels in patient groups and age-matched controls Variable Young children group Older children group P-value Recurrent wheezer (n= 38) Control (n= 15) Atopic asthmatic (n= 21) Control (n= 15) Age, mean (range) 10.8 (8 24)* 12.3 (11 24)* (6 14) 8.6 (8 12) Male sex, n (%) 24 (63) 7 (46) (76) 8 (53) Blood eosinophils (/ml) 215± ± ± ± IL-33 (pg/ml) 38.5.± ± ± ± sst2 (pg/ml) 786.4± ± ± ± IL-5 (pg/ml) 2.2± ± ± ± IFN-γ (pg/ml) 17.4± ± ± ± Values are presented as mean± standard deviation unless otherwise indicated. *Months. Years. Table 2. Demographic findings and cytokine levels in atopic and nonatopic wheezers Variable Atopic wheezer (n= 19) Nonatopic wheezer (n= 19) P-value Age (mo), mean (range) 10.4 (8 24) 11.8 (9 24) Male sex, n (%) 13 (68) 11 (58) Parental allergic disease, n (%) 11 (58) 2 (10) Severity score, median (range) 2 (0 4) 2 (0 4) Wheezing relapse, n (%) 12 (63) 16 (84) Total serum IgE (ku/ml) 286.6± ± Blood eosinophils (/ml) 248± ± IL-33 (pg/ml) 37.3± ± sst2 (pg/ml) 697.5± ± IL-5 (pg/ml) 2.5± ± IFN-γ (pg/ml) 16.5± ± Values are presented as mean± standard deviation unless otherwise indicated. P-value 316

4 추미애외 소아천식군과영유아천명군에서 sst2 상승의의의 Table 3. Demographic findings and serum cytokine levels in patients with vs. without wheezing relapse after discharge Patients with relapse (n= 28) Patients without relapse (n= 10) P-value Age (mo), mean (range) 10.2 (8 24) 10.6 (8 24) 0.8 Male sex, n (%) 16 (57) 5 (50) 0.7 Severity score, median (range) 2 (0 4) 2 (0 4) 0.2 Atopic patients, n (%) 12 (43) 7 (70) 0.3 Blood eosinophils (/ml) 222± ± Total serum IgE (ku/l) 139.8± ± IL-33 (pg/ml) 62.3± ± sst2 (pg/ml) 821.9± ± IL-5 (pg/ml) 2.5± ± IFN-γ (pg/ml) 19.6± ± Values are presented as mean± standard deviation unless otherwise indicated. Table 4. Correlation between severity score and each cytokine level in two patient groups 으며반복적천명군에서도대조군과비교하여유의한차이를보이 지않았다 (P = 0.6, P = 0.7, respectively) (Table 1). 3. 반복적천명군에서아토피유무및천명재발에따른 사이토카인반응 sst2 와 IL-33 측정치들은아토피군과비아토피군에서의측정 치간에유의한차이를보이지않았다 (P = 0.6, P = 0.9, respectively). IL-5 측정치는아토피군에서비아토피군에비해유의하게높은 측정치를나타내었으나 (P = 0.04), IFN-γ 측정치는두군간에유의 한차이를보이지않았다 (P = 0.9) (Table 2). 퇴원후 1 년간의추적관찰에서천명의재발이관찰되었던군과 그렇지않았던군간에각각의사이토카인측정치를비교한결과 에서, sst2, IL-33, IL-5 및 IFN-γ 들은모두두군간유의한차이를 보이지않았다 (Table 3). Recurrent wheezer (n= 38) Atopic asthmatic (n= 21) 4. 소아천식군및반복적천명군에서입원중증상점수와 사이토카인측정치간의관련성 r P-value r P-value IL sst IL IFN-γ 아토피천식군에서 sst2 측정치는입원중증상점수와유의한양 의상관관계를나타내었다 (r = 0.63, P = 0.004). 또한 IFN-γ 측정치 는증상점수와유의한관련성을보였으나 (r = 0.46, P = 0.03), IL-33 과 IL-5 측정치는입원중증상점수와관련성을보이지않았다. 반복적천명군에서는 IFN-γ 측정치만입원중증상점수와약한관련성을보였고 (r = 0.35, P = 0.03), IL-33, sst2 및 IL-5 측정치들은관련성을보이지않았다 (Table 4). 5. 혈청 sst2 측정치와혈청총 IgE 및호산구수와의관련성아토피소아천식군에서혈청 sst2 측정치는혈청총 IgE와는의미있는관련성을보이지않았으나 (data not shown) 말초혈액의호산구수와는유의한음의상관관계를나타내었다 (r = 0.45, P = 0.04) (Fig. 1A). 반복적천명군전체에서조사한결과에서보면혈청 sst2 측정치는혈청총 IgE 및말초혈액호산구수와의미있는관련성을보이지않았으나 (r = 0.27, P = 0.1) (Fig. 1B), 그중아토피군에서는말초혈액호산구수와유의한음의상관관계가관찰되었다 (r = 0.54, P = 0.02) (Fig. 1C). sst2 이외의다른사이토카인들의측정치들은혈청총 IgE 또는말초혈액의호산구수와어떠한관련성도나타내지않았다 (data not shown). 고찰본연구의결과에서급성천식악화상태에있는아토피소아천식환자들의혈청에서 IL-33의가용성수용체인 sst2와 Th2 사이토카인인 IL-5 측정치가의미있게증가해있었으며, 급성천명의재발을보인 2세이하연령의반복적천명군에서도동일한양상이관찰되었다. ST2의 3가지 isoform 중 Th2 세포의세포막에존재하는 ST2L은 IL-4를분비하는 Th2 세포의선택적표지자로서 Th1 세포와 Th2 세포를구분하는기준이될수있고동시에 Th2 세포의생성과기능에도중요한영향을미치는것으로알려져있다. 1-4) 그러나혈청내에존재하는 sst2는여러가지질환들의급성기에 tumor necro

5 Chu MA, et al. Increased sst2 in recurrent early wheezers sst2 (pg/ml) sst2 (pg/ml) sst2 (pg/ml) 1,500 1,250 1, , ,200 1, r= 0.45, P= ,000 1,500 2,000 2,500 Eosinophil count (/ml) r= 0.27, P= Eosinophil count (/ml) r= 0.54, P= Eosinophil count (/ml) Fig. 1. Correlation between serum soluble ST2 levels and peripheral blood eosinophil counts in asthmatic children (A), recurrent early wheezers (B), and atopic wheezers (C). sis factor (TNF)-α, IL-1 등의염증유발사이토카인들에의해생성 이유도되며염증반응에의한손상으로부터조직을보호하는역 할을하는것으로알려졌고 10-12) 호산구성알레르기염증질환인천 식에서도급성천식의악화가있을때혈청내 sst2가상승하는양상이보고되었다. 7,8) 최근의한연구는 sst2가 IL-33-ST2L의결합에경쟁적으로작용하여 Th2 사이토카인의생성유도를억제하는기전을보고하였다. 13) 실제로천식동물에게 sst2를투여하였을때기도의알레르기성염증반응이억제되었고기관지폐포세척액내의호산구수와 IL-4와 IL-5 등이감소하는현상이관찰된바있다. 6) 본연구에서급성천식악화로인해입원하였던아토피소아천식군에서혈청 sst2와 IL-5들은대조군에비해유의하게증가되어있음이관찰되었으며같은양상이이전의다른연구에서도관찰된바있다. 8) 그러나본연구에서는천명증상의재발로인해입원하였던 2세이하반복적천명군에서도 sst2와 IL-5가소아천식에서와동일하게증가되어있는양상을관찰하였으며특히 IL-5는아토피군에서비아토피군에비해유의하게높은양상을보였다. 본연구에서 sst2 측정치는아토피소아천식군에서입원중증상의심한정도, 즉증상점수와유의한관련성을보였으며말초혈액의호산구수와유의한역상관관계를나타내었다. 이러한결과는급성천식상태에서호산구염증반응에의한심한천식증상을조절하는데 sst2가중요한역할을담당한다는것을시사하는것으로생각된다. 이전의연구결과들을보면동물실험에서혈청내 sst2의증가로인해기관지폐포세척액내의호산구수감소와기도의알레르기염증반응의완화가유도된다고하였고, 6) 실제로소아천식환자들에서혈청 sst2와말초혈액의호산구수간에유의한역상관관계가관찰되었다는보고가있었다. 7) 반면성인천식환자들에서는혈청 sst2가심한천식을가진경우에더높았으나말초혈액의호산구수와는관련성이없었다고하는등 8) 성인과소아에서서로다른결과들이보고된바있어앞으로더연구가필요할것으로생각된다. 본연구의반복적천명군에서 sst2 측정치는입원중증상점수와유의한관련성을보이지않았으나아토피천명군에서는소아천식군에서와같이 sst2 측정치와말초혈액호산구수간에유의한역상관관계가관찰되었다. 이전의연구에의하면혈청 sst2는반드시 Th2 면역반응에의해서만생성이유도되는것은아니고바이러스감염에의해생성이증가하는 TNF-α 또는 IL-1 등의사이토카인들에의해서도유도될수있다고하였다. 14) 본연구에포함된반복적천명군의소아들에서천명증상의악화와관련된상기도감염이선행하였으므로, 앞서제시한이전연구결과는본연구에서반복적천명군의 sst2가증가하며아토피군과비아토피군간에차이를보이지않았던반면호산구수와관련된역상관관계는아토피군에서만관찰되었던양상을설명해줄수있을것으로생각된다. IL-33은 IL-1 계열에속하며그면역학적인특성이비교적최근에규명되었고 IL-4, IL-5, IL-13 등의생성을유도하여 Th2 면역반응을유도하는것으로알려졌다 ) 동물실험에서 IL-33의투여에의한폐조직의손상은호산구성염증반응의특징을나타내었고 18) 318

6 추미애외 소아천식군과영유아천명군에서 sst2 상승의의의 심한성인천식환자들의기도조직소견에서 IL-33 의표현이증가 되어있음이관찰되었다. 19,20) 최근의한연구에서는천식을가진소 아들에서안정기에측정한혈청과유도객담의 sst2 와 IL-33 이함 께증가해있는양상이보고된바있다. 21) 본연구에서는급성천식 상태또는천명의재발로인해입원하였던아토피소아천식군과 반복적천명군에서 IL-33 이대조군과비교하여유의한차이를보 이지않았다. 측정당시대상군들의상태가이전의연구와차이가 있으므로앞으로더연구가필요할것으로생각된다. 급성천식상태에서 Th1 사이토카인인 IFN-γ 의생성증가는 Th2 면역반응을억제하여급성천식의악화를조절하는데필요한 생리적방어작용으로볼수있다. 22,23) 실제로천식환자들에서급성 천식악화시기에혈청 IFN-γ 가현저히증가하였다가치료에의해 증상이호전된후감소하는양상은과거연구에서관찰되었고 24) 비 교적최근에말초혈액의 CD161+T 세포가천식악화상태에서이러 한 IFN-γ 의생성을주로담당하는것으로보고된바있다. 25) 본연 구의아토피천식소아군과반복적천명군에서대조군에비해 IFN-γ 가유의하게증가하지는않았으나두환자군모두에서증상 의심한정도, 즉증상점수와는유의한관련성을가지는것을관찰 할수있었다. 본연구에서는급성천식악화상태로입원한아토피소아천식 군과비교하여천명증상의재발로인해입원하였던 2 세이하반복 적천명군에서관찰되는 Th1 또는 Th2 면역반응이어떤공통점, 또 는차이점이있는지알아보고자하였으나제한점들이존재한다. 영유아기의천명은매우다양한표현형을나타내며그런표현형은 천명유발의원인이되는바이러스감염, 아토피소아들의원인알 레르겐, 가족력, 기도과민성등에의해결정되므로면역반응과관 련된연구에서는그러한요소들과의관련성이함께반영되어야하 나 26) 본연구에서는그렇게하지못하였고또한아토피를가지지않 은소아천식군은연구에충분한대상군을확보하지못하여함께 조사하지못하였다. 결론적으로, 본연구의결과는 sst2 가급성천식또는천명의악 화상태에서호산구성알레르기염증을억제하여심한증상을조 절하는역할을할가능성을제시하고있으며반복적인천명양상 을보이는영유아들의치료와경과관찰에있어고려해야할부분 으로생각된다. REFERENCES 1. Tago K, Noda T, Hayakawa M, Iwahana H, Yanagisawa K, Yashiro T, et al. Tissue distribution and subcellular localization of a variant form of the human ST2 gene product, ST2V. Biochem Biophys Res Commun 2001; 285: Iwahana H, Hayakawa M, Kuroiwa K, Tago K, Yanagisawa K, Noji S, et al. Molecular cloning of the chicken ST2 gene and a novel variant form of the ST2 gene product, ST2LV. Biochim Biophys Acta 2004;1681: Oboki K, Ohno T, Kajiwara N, Saito H, Nakae S. IL-33 and IL-33 receptors in host defense and diseases. Allergol Int 2010;59: Trajkovic V, Sweet MJ, Xu D. T1/ST2--an IL-1 receptor-like modulator of immune responses. Cytokine Growth Factor Rev 2004;15: Hayakawa H, Hayakawa M, Kume A, Tominaga S. Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. J Biol Chem 2007;282: Oshikawa K, Yanagisawa K, Tominaga S, Sugiyama Y. Expression and function of the ST2 gene in a murine model of allergic airway inflammation. Clin Exp Allergy 2002;32: Ali M, Zhang G, Thomas WR, McLean CJ, Bizzintino JA, Laing IA, et al. Investigations into the role of ST2 in acute asthma in children. Tissue Antigens 2009;73: Oshikawa K, Kuroiwa K, Tago K, Iwahana H, Yanagisawa K, Ohno S, et al. Elevated soluble ST2 protein levels in sera of patients with asthma with an acute exacerbation. Am J Respir Crit Care Med 2001;164: Smith PH, Ownby DR. Clinical significance of immunoglobulin E. In: Adkinson NF, Busse WW, Bochner BS, Holgate ST, Simons FE, Lemanske RF, editors. Allergy: principles and practice. 7th ed. St Louis: Mosby; 2008: Sweet MJ, Leung BP, Kang D, Sogaard M, Schulz K, Trajkovic V, et al. A novel pathway regulating lipopolysaccharide-induced shock by ST2/T1 via inhibition of Toll-like receptor 4 expression. J Immunol 2001;166: Brunner M, Krenn C, Roth G, Moser B, Dworschak M, Jensen-Jarolim E, et al. Increased levels of soluble ST2 protein and IgG1 production in patients with sepsis and trauma. Intensive Care Med 2004;30: Shimpo M, Morrow DA, Weinberg EO, Sabatine MS, Murphy SA, Antman EM, et al. Serum levels of the interleukin-1 receptor family member ST2 predict mortality and clinical outcome in acute myocardial infarction. Circulation 2004;109: Yin H, Li XY, Liu T, Yuan BH, Zhang BB, Hu SL, et al. Adenovirus-mediated delivery of soluble ST2 attenuates ovalbumin-induced allergic asthma in mice. Clin Exp Immunol 2012;170: Morrison PT, Thomas LH, Sharland M, Friedland JS. RSV-infected airway epithelial cells cause biphasic up-regulation of CCR1 expression on human monocytes. J Leukoc Biol 2007;81: Chow JY, Wong CK, Cheung PF, Lam CW. Intracellular signaling mechanisms regulating the activation of human eosinophils by the novel Th2 cytokine IL-33: implications for allergic inflammation. Cell Mol Immunol 2010;7: Pecaric-Petkovic T, Didichenko SA, Kaempfer S, Spiegl N, Dahinden CA. Human basophils and eosinophils are the direct target leukocytes of the novel IL-1 family member IL-33. Blood 2009;113: Oboki K, Nakae S, Matsumoto K, Saito H. IL-33 and Airway Inflammation. Allergy Asthma Immunol Res 2011;3: Kondo Y, Yoshimoto T, Yasuda K, Futatsugi-Yumikura S, Morimoto M, Hayashi N, et al. Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. Int Immunol 2008;20: Préfontaine D, Nadigel J, Chouiali F, Audusseau S, Semlali A, Chakir J, et al. Increased IL-33 expression by epithelial cells in bronchial asthma. J Allergy Clin Immunol 2010;125: Prefontaine D, Lajoie-Kadoch S, Foley S, Audusseau S, Olivenstein R, Halayko AJ, et al. Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells. J Immunol 2009; 183: Hamzaoui A, Berraies A, Kaabachi W, Haifa M, Ammar J, Kamel H. Induced sputum levels of IL-33 and soluble ST2 in young asthmatic chil

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ÀÇÇÐ°�ÁÂc00Ì»óÀÏ˘ Common Allergic Diseases in Children Sang - Il Lee, M.D. Department of pediatrics Sungkyunkwan University School of Medicine, Samsung Medical Center E - mail : silee@smc.samsung.co.kr Abstract Allergy