호흡곤란증후군과 기관지폐이형성증 예측 인자로서의 미숙아 제대혈 IL-10, IL-12

Cord blood IL-10, IL-12 in preterm newborns as predictors of respiratory distress syndrome and bronchopulmonary dysplasia

  • 박지윤 (이화여자대학교 의과대학 소아과학교실) ;
  • 김지영 (이화여자대학교 의과대학 소아과학교실) ;
  • 조수진 (이화여자대학교 의과대학 소아과학교실) ;
  • 김영주 (이화여자대학교 의과대학 산부인과학교실) ;
  • 박혜숙 (이화여자대학교 의과대학 예방의학과학교실) ;
  • 하은희 (이화여자대학교 의과대학 예방의학과학교실) ;
  • 박은애 (이화여자대학교 의과대학 소아과학교실)
  • Park, Jee Yoon (Department of Pediatrics, Ewha Womans University, College of Medicine) ;
  • Kim, Ji Young (Department of Pediatrics, Ewha Womans University, College of Medicine) ;
  • Cho, Soo Jin (Department of Pediatrics, Ewha Womans University, College of Medicine) ;
  • Kim, Young Ju (Department of Obstetrics and Gynecology, Ewha Womans University, College of Medicine) ;
  • Park, Hye Sook (Department of Preventive Medicine, Ewha Womans University, College of Medicine) ;
  • Ha, Eun Hee (Department of Preventive Medicine, Ewha Womans University, College of Medicine) ;
  • Park, Eun Ae (Department of Pediatrics, Ewha Womans University, College of Medicine)
  • 투고 : 2006.11.22
  • 심사 : 2007.02.13
  • 발행 : 2007.03.15

초록

목 적 : 최근 RDS나 BPD이 폐의 미성숙함 뿐만 아니라 손상과 재생, 염증 반응 기전이 관여할 것이라는 주장과 연구들이 대두되고 있다. 이에 본 연구에서는 미숙아의 제대혈에서 IL-10, IL-12를 측정하여 RDS, BPD 발생의 관련성을 살펴보고자 하였다. 방 법 : 2003년 1월부터 2005년 6월까지 임신 중기부터 이대 목동 병원에서 산전 관리를 받고 보호자 동의하에 제대혈 검사가 가능하였던 재태 기간 34주 미만의 미숙아 40명을 대상으로 하였다. 출생 당시 제대혈을 채취하여 혈청 분리 후 영하 $70^{\circ}C$에 보관하였다가 ELISA법을 이용하여 IL-10, IL-12를 측정하였고, 각 주수 기간에 따라 RDS가 있는 군(RDS군)과 RDS가 없는 군(non-RDS군)으로, 그리고 RDS군내에서 BPD가 있는 군(BPD군)과 BPD가 없는 군(non-BPD군)으로 나누어 IL-10, IL-12 및 임상자료들을 비교하고 분석하였다. 이들의 임상적인 자료는 의무기록을 통하여 후향적인 방법으로 얻었다. 결 과 : IL-10은 재태 연령(r=-0.391, P=0.005)이나 출생체중(r=-0.442, P=0.001)과 역의 상관관계가 있었고, IL-12는 재태 연령이나 출생체중과는 상관관계가 없었다. 30-34주 사이의 미숙아를 대상으로 보았을 때 RDS군에서 non-RDS군에 비해 의미 있게 높은 IL-10수치를 나타냈다(1.0 vs 0.1 pg/mL; P=0.001). 하지만 IL-12는 두 군 간의 유의한 차이가 없었다. BPD군과 non-BPD군을 비교하면 IL-10, IL-12 모두 통계적으로 유의한 차이가 없었다. 결 론 : 제대혈 IL-10 농도는 태아의 성숙도를 예측하는 지표로 사용될 수 있을 것으로 생각되고, 높은 IL-10의 수치로 RDS로의 이환을 예측하는 지표로 사용할 수 있을 것으로 생각된다. 그러나 제대혈 IL-10이 BPD로의 이환을 예측하기는 어려울 것으로 보이며, 이에 대한 연구가 더 필요할 것으로 보인다.

Purpose : Inflammation plays a major role in the pathogenesis of RDS and BPD in the immature lung. We investigated the possible role of IL-10 and IL-12 in the cord blood of preterm newborns with RDS or BPD. Methods : Forty preterm newborns whose mothers received antenatal care at Ewha Womans University Mokdong Hospital between January 2003 to June 2005, and agreed to testing their cord blood samples were enrolled. The gestational ages were below 34 weeks. Cord blood level of IL-10 and IL-12 were determined by ELISA. We separated the patients into 2 groups (RDS group and non-RDS group, BPD group and non-BPD group) and compared the cytokine levels and clinical records of the groups. Results : Cord blood IL-10 level showed a significant inverse correlation with gestational age and birth weight (P=0.001, P=0.005). Preterm infants with RDS showed higher IL-10 level (1.0 vs 0.1 pg/mL; P=0.001) in the cord blood than those without RDS. The differences remained statistically significant after correction for the effect of gestational age between both preterm groups. Despite similar cord blood IL-10 levels, preterm infants with BPD showed no significant difference with those without BPD. Conclusion : Cord blood IL-10 levels are increased in preterm infants which may be due to the immuno-suppression occurring during pregnancy and to fetal immaturity because these levels are inversely correlated with the gestational age. So, Cord blood IL-10 level can be used as the predictor of RDS.

키워드

과제정보

연구 과제 주관 기관 : 서울시정 개발연구원

참고문헌

  1. Frank L. Antioxidants, nutrition, and bronchopulmonary dysplasia. Clin Perinatol 1992;19:541-62 https://doi.org/10.1016/S0095-5108(18)30445-7
  2. Ollikainen J, Heiskanen-Kosma T, Korppi M, Katila ML, Heinonen K. Clinical relevance of Ureaplasma urealyticum colonization in preterm infants. Acta Paediatr 1998;87:1075-8 https://doi.org/10.1080/080352598750031419
  3. Abele-Horn M, Peters J, Genzel-Boroviczeny O, Wolff C, Zimmermann A, Gottschling W. Vaginal Ureaplasma urealyticum colonization: Influence on pregnancy outcome and neonatal morbidity. Infection 1997;25:286-91 https://doi.org/10.1007/BF01720398
  4. Pacifico L, Panero A, Roggini M, Rossi N, Bucci G, Chiesa C. Ureaplasma urealyticum and pulmonary outcome in a neonatal intensive care population. Pediatr Infect Dis J 1997; 16:579-86 https://doi.org/10.1097/00006454-199706000-00008
  5. Ogden BE, Murphy S, Saunders GC, Johnson JD. Lung lavage of newborns with respiratory distress syndrome: prolonged neutrophil influx is associated with bronchopulmonary dysplasia. Chest 1983;83:31-3
  6. Edwards DK, Colby TV, Northway WH. Radiographic-pathologic correlation in bronchopulmonary dysplasia. J Pediatr Radiol 1979;95:834-6 https://doi.org/10.1016/S0022-3476(79)80445-X
  7. Rozycki HJ. Bronchoalveolar lavage interleukin-1$\beta$ in infants on day 1 of life. South Med J 1994;87:991-6 https://doi.org/10.1097/00007611-199410000-00005
  8. Groneck P, Gotae-Speer B, Oppermann M, Eiffert H, Speer CP. Association of pulmonary inflammation and increased microvascular permeability during the development of bronchopulmonary dysplasia: A sequential analysis of inflammatory mediators in respiratory fluids of high risk preterm neonates. Pediatrics 1994;93:712-8
  9. Bagchi A, Viscardi RM, Taciak V, Ensor JE, McCrea KA, Hasday JD. Increased activity of interleukin-6 but not tumor necrosis factor-$\alpha$ in lung lavage of premature infants is associated with the development of bronchopulmonary dysplasia. Pediatr Res 1994;36:244-52 https://doi.org/10.1203/00006450-199408000-00017
  10. Groneck P, Speer CP. Inflammatory mediators and bronchopulmonary dysplasia. Arch Dis Child Fetal Neonatal Ed 1995;73:1-3 https://doi.org/10.1136/fn.73.1.F1
  11. Kotecha S. Cytokines in chronic lung disease of prematurity. Eur J Pediatr 1996;155(2 suppl):14S-17S https://doi.org/10.1007/BF01958074
  12. Jones CA, Cayabyab RG, Kwong KY, Stotts C, Wong B, Hamdan H, et al. Undetectable interluekin(IL)-10 and persistent IL-8 expression early in Hyaline membrane disease: a possible developmental basis for the predisposition to chronic lung inflammation in preterm newborns. Pediatr Res 1996;39:966-75 https://doi.org/10.1203/00006450-199606000-00007
  13. Kwong KY, Jones CA, Cayabyab RG, Lecart C, Stotts CL, Randhawa I, et al. Differential regulation of IL-8 by IL-1$\beta$ and TNF$\alpha$ in hyaline membrane disease. J Clin Immunol 1998;18:71-80 https://doi.org/10.1023/A:1023244005765
  14. Tullus K, Noack GW, Burman LG, Nilsson R, Wretlind B, Brauner A. Elevated cytokine levels in tracheobronchial aspirate fluids from ventilator treated neonates with bronchopulmonary dysplasia. Eur J Pediatr 1996;155:112-6 https://doi.org/10.1007/BF02075762
  15. Robertson B. The evolution of neonatal respiratory distress syndrome into chronic lung disease. Eur Respir J 1989;3 (Suppl 1):33-7
  16. Northway WH Jr. Bronchopulmonary dysplasia: Then and now. Arch Dis Child 1990;65:1076-81 https://doi.org/10.1136/adc.65.10_Spec_No.1076
  17. Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O'Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol 1991;147:3815-22
  18. de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: An autoregulatory role of IL-10 produced by monocytes. J Exp Med 1991;174:1209-20 https://doi.org/10.1084/jem.174.5.1209
  19. Niiro H, Otsuka T, Kuga S, Nemoto Y, Abe M, Hara N, et al. IL-10 inhibits prostaglandin E2 production by lipopolysaccharide-stimulated monocytes. Int Immunol 1994;6:661-4 https://doi.org/10.1093/intimm/6.4.661
  20. Fujimura T, Yamanashi R, Masuzawa M, Nomoto K. Convertsion of the CD4(+) T cell profile from Th2 dominant type to Th1 dominant type after varicella-zoster virus infection in atopic dermatitis. J Allerg Clin Immunol 1997;100: 274-82 https://doi.org/10.1016/S0091-6749(97)70236-7
  21. Krug N, Frew AJ. The Th2 cell in asthma: initial expectations yet to be realised. Clin Exp Allergy 1997;27:142-50 https://doi.org/10.1111/j.1365-2222.1997.tb00685.x
  22. Bengtsson A, Holm L, Back O, Fransson J, Scheynius A. Elevated serum levels of soluble CD30 in patients with atopic dermatitis(AD). Clin Exp Immunol 1997;109:533-7 https://doi.org/10.1046/j.1365-2249.1997.4731373.x
  23. Raghupathy R. Th1-type immunity is incompatible with successful pregnancy. Immunol Today 1997;18:478-82 https://doi.org/10.1016/S0167-5699(97)01127-4
  24. Naseer T, Minshall EW, Martin R, Laberge S, Ernst P, Martin RJ, et al. Expression of IL-12 and IL-13 mRNA in asthma and their modulation in response to steroid therapy. Am J Resp Crit Care Med 1997;155:845-51 https://doi.org/10.1164/ajrccm.155.3.9117015
  25. Kim TS, DeKruyff RH, Rupper R, Maecker HT, Levy S, Umetsu DT. An ovalbumin-IL-12 fusion protein is more effective than ovalbumin plus free recombinant IL-12 in inducing a T-helper cell type 1-dominated immune response and inhibiting antigen-specific IgE production. J Immunol 1997;158:4137-44
  26. Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a Th2 phenomenon? Immunol Today 1993;14:353-6 https://doi.org/10.1016/0167-5699(93)90235-D
  27. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-9 https://doi.org/10.1164/ajrccm.163.7.2011060
  28. Confraveux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T. The Pregnancy Multiple Sclerosis Group. Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med 1998;339:285-91 https://doi.org/10.1056/NEJM199807303390501
  29. Moore KW, O'Garra A, de Waal Malefyt R, Vieira P, Mosmann TR. Interleukin-10. Annu Rev Immunol 1993;11:165-90 https://doi.org/10.1146/annurev.iy.11.040193.001121
  30. Raghupathy R. Pregnancy: success and failure within the Th1/Th2/Th3 paradigm. Seminar Immunol 2001;13:219-27
  31. Chace JH, Hooker NA, Mildenstein KL, Krieg AM, Cowdery JS. Bacterial DNA-induced NK cell IFN$\gamma$ production is dependent on macrophage secretion of IL-12. Clin Immunol Immunopathol 1997;84:185-93 https://doi.org/10.1006/clin.1997.4380
  32. Smart JM, Kemp AS. Ontogeny of T-helper 1 and T-helper 2 cytokine production in childhood. Pediatr Allergy Immunol 2001;12:181-7 https://doi.org/10.1034/j.1399-3038.2001.012004181.x
  33. Dudley DJ, Hunter C, Mitchell MD, Varner MW, Gately M. Elevations of serum interleukin-12 concentrations in women with severe pre-eclampsia and HELLP syndrome. J Reprod Immunol 1996;31:97-107 https://doi.org/10.1016/0165-0378(96)00976-X
  34. Wilson R, McInnes I, Leung B, McKillop JH, Walker JJ. Altered interleukin 12 and nitric oxide levels in recurrent miscarriage. Eur J Obstet Gynecol Reprod Biol 1997;75: 211-4 https://doi.org/10.1016/S0301-2115(97)00124-3
  35. Blanco-Quiros A, Arranz E, Solis G, Villar A, Ramos A, Coto D. Cord blood interleukin-10 levels are increased in preterm newborns. Eur J Pediatr 2000;159:420-3 https://doi.org/10.1007/s004310051299
  36. Blanco-Quiros A, Arranz E, Solis G, Garrote JA, Mayo A. High cord blood IL-10 levels in preterm newborns with repiratory distress syndrome. Allergol Immunopathol 2004; 32:189-96 https://doi.org/10.1157/13064922
  37. Bancalari E. Corticosteroids and neonatal chronic lung disease. Eur J Pediatr 1998;157:31-7 https://doi.org/10.1007/PL00014290
  38. Jonsson B, Tullus K, Brauner A, Lu Y, Noack G. Early increase of TNFa and IL-6 in tracheobronchial aspirate fluid indicator of subsequent chronic lung disease in preterm infants. Arch Dis Child Fetal Neonatal Ed 1997;77:198-201 https://doi.org/10.1136/fn.77.3.F198
  39. McColm JR, Stenson BJ, Biermasz N, Mclntosh N. Measurement of interleukin 10 in bronchoalveolar lavage from preterm ventilated infants. Arch Dis Child 2000;82:156-9 https://doi.org/10.1136/fn.82.2.F156