랏트의 기관내 Fe 노출후 Fe 이동에 대한 연구

The Mechanism of Iron Transport after Intratracheal Instillation of Iron in Rats

  • 권민 (중앙대학교 의과대학 예방의학교실) ;
  • 최병선 (중앙대학교 의과대학 예방의학교실) ;
  • 박언섭 (중앙대학교 의과대학 병리학교실) ;
  • 정남현 (고려대학교 생명환경과학대학) ;
  • 박성조 ;
  • 임영 (가톨릭대학교 성모병원 산업의학과) ;
  • 박정덕 (중앙대학교 의과대학 예방의학교실)
  • Kwon, Min (Department of Preventive Medicine, College of Medicine, Chung-Ang University) ;
  • Choi, Byung-Sun (Department of Preventive Medicine, College of Medicine, Chung-Ang University) ;
  • Park, Eon-Sub (Department of Pathology, College of Medicine, Chung-Ang University) ;
  • Chung, Nam-Hyun (College of Life and Environmental Sciences, Korea University) ;
  • Park, Sung-Jo (Department of Biochemistry and Molecular Biology, Mayo Clinic and Foundation) ;
  • Lim, Young (Department of Occupational and Environmental Medicine, St. Mary s Hospital, The Catholic University of Korea) ;
  • Park, Jung-Duck (Department of Preventive Medicine, College of Medicine, Chung-Ang University)
  • 발행 : 2004.12.01

초록

Objectives : Iron (Fe) is an essential element in biological processes; however excessive Fe is harmful to human health. Some air pollutants contain a high level of Fe, and the human lung could therefore be over-exposed to Fe through inhaled air pollutants. This study was performed to investigate the role of metal transporters (divalent metal transporter 1, DMT1, and metal transporter protein 1, MTP1) in the lung under the environments of Fe deficiency in the body and Fe over-exposure in the lung. Methods : Rats were fed Fe deficient (FeD, 2-6 mg Fe/kg) or Fe supplemented (FeS, 120 mg Fe/kg) diet for 4 weeks, followed by a single intratracheal instillation of ferrous sulfate at low (10 mg/kg) or high (20 mg/kg) dose. Fe concentration was analyzed in the serum, lung and liver, and histopathological findings were observed in the lung at 24 hours after Fe administration. The level of DMT1 and MTP1 expression in the lung was analyzed by RT-PCR. Also, the effect of Fe deficiency in the body was evaluated on the level of Fe concentration and metal transporters compared to FeS-diet fed rats at the end of 4-week FeD or FeS diet. Results : The 4-week FeD diet in rats induced an Fe deficiency anemia with decreased serum total Fe, increased unsaturated Fe binding capacity and hypochromic microcytic red blood cells. The concentration of Fe in the lung and liver was lower in the FeD-diet fed rats than in the FeS-diet fed rats. The level of metal transporters mRNA expression was higher in the FeD-diet fed rats than in the FeS-diet. The concentration of Fe in the lung was increased in a dose-dependent pattern after intratracheal instillation of Fe into the rats, while the level of Fe in the serum and liver was not increased in the low-dose Fe administered rats. Therefore, DMT1 and MTP1 mRNA was highly expressed in both FeD-diet and FeS-diet fed rats, after intratracheal instillation of Fe. Conclusions : DMT1 and MTP1 mRNA were more highly expressed in FeD-diet fed rats than in FeS-diet fed rats. The over-exposure of Fe intratracheally induced high expression of metal transporters and increased Fe deposition in the lung in both FeD-diet and FeS-diet fed rats, but did not increase the Fe level of the serum and liver in low-dose Fe administered rats. These results suggest that the role of metal transporters in the lung might be different in a part from the duodenum under the environment of over-exposure to Fe.

키워드

참고문헌

  1. Reid D, Snell G,Ward C, Krishnaswamy R, Ward R, Zheng L, Williams T, Walters, Iron overload and nitric oxide-derived oxidative stress following lung transplantation. J Heart Lung Transplant 2001; 20:840-849
  2. Quinlan GJ, Evans TW, Gutteridge JM, Iron and the redox status of the lungs. Free Radic Biol Med 2002; 33:1306-1313
  3. Sung J, Cho SH, Kang D, Yoo. KY. Lung cancer, chronic obstructive. pulmonary disease and air pollution. Korean J Prev Med 1997; 30(3): 585-598 (Korean)
  4. Ghio AJ, Richards JH, Carter JD, Madden MC. Accumulation of iron in the rat lung after tracheal instillation of diesel particles. Toxicol Palhol 2000; 28: 619-627 https://doi.org/10.1177/019262330002800416
  5. Umbreit JN, Conrad ME, Moore EG, Desai MP, Turrens J. Paraferritin: a protein complex with ferrireductase activity is associated with iron absorption in rats. Biochemistry 1996; 35: 6460-6469 https://doi.org/10.1021/bi951927s
  6. Richardson DR, Ponka P. The molecular mechanisms of the metabolisrn and transport of iron in normal and neoplastic cell. Biochim Biophys Acta 1997; 14: 1-40 https://doi.org/10.1016/0006-3002(54)90123-7
  7. Gunshin H, MackenzieB, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA, Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 1997; 388: 482-488
  8. Fleming MD, Trenor CC, 3rd, Su MA, Foernzler D, Beier DR, Dietrich WF, Andrews NC. Microcytic anaemia mice have a nutation in Nramp2, a candidate iron transporter gene, Nat Genet 1997; 16: 383-386
  9. Abboud S, Haile DJ. A novel mammalian iron regulated protein involved in intracellular iron metabolism. J Biol Chem 2000; 275: 19906-19912 https://doi.org/10.1074/jbc.M000713200
  10. Georgieff MK, Wobken JK, Welle J, Burdo JR, Connor JR, Identification and lccalization of divalent metal transporter-1 (DMT-1) in term hrrran placenta, Placenta 2000; 21: 799-804
  11. Oates PS, Trinder D, Morgan EH. Gastrointestinal function, divalent metal transporter-I expression and intestinal iron absorption. Pflugers Arch 2000; 440: 496-502 https://doi.org/10.1007/s004240000319
  12. Yeh KY, Yeh M, Watkins JA, Rodriguez-Paris J, Glass J. Dietary iron induces rapid changes in rat intestinal divalent metal transporter expression. Am J Physiol Gastrointest Liver Physiol 2000; 279: 1070-1079 https://doi.org/10.1152/ajpgi.2000.279.5.G1070
  13. Burdo JR, Menzies SL, Simpson IA, Garrick LM, Garrick MD, Dolan KG, Haile DJ, Beard JL, Connor JR. Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat. J Neurosci Res 2001;66: 1198-1207 https://doi.org/10.1002/jnr.1256
  14. Zoller H, Koch RO, Theurl I, Obrist P, Pietrangelo A, Montosi G, Haile DJ, Vogel W, Weiss G. Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload. Gastroenterology 2001; 120: 1412-1419 https://doi.org/10.1053/gast.2001.24033
  15. Garrbling L, Danzeisen R, Gair S, Lea RG, Charania Z, Solanky N, Joory KD, Srai SK, McArdle HJ. Effect of iron deficiency on placental transfer of iron and expression of iron transport proteins in vivo and in vitro, Biochem J 2001; 15: 883-889
  16. Frazer DM, Wilkins SJ, Becker EM, Vulpe CD, McKie AT, Trinder D, Anderson GJ Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats, Gastroenterology 2002; 123: 835-844
  17. Chen H, Su T, Attieh ZK, Fox TC, McKie AT, Anderson GJ, Vulpe CD, Systemic regulation of Hephaestin and Ireg1 revealed in studies of genetic and nutritional iron deficiency. Blood 2003; 102: 1893-1899
  18. Muckenthaler M, Roy CN, Custodio AO, Minana B, deGraaf J, Montross LK, Andrews NC, Hentze MW. Regulatory defects in liver and intestine irrplicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis, Nat Genet 2003; 34: 102-107 https://doi.org/10.1038/ng1152
  19. Stuart KA, Anderson GJ, Frazer DM, Powell LW, McCullen M, Fletcher LM, Crawford DH. Duodenal expression of iron transport molecules in untreated haemochromatosis subjects, Gut 2003; 52: 953-959 https://doi.org/10.1136/gut.52.7.953
  20. Fleming RE, Migas MC, Zhou X, Jiang J, Britton RS, Brunt EM, Tomatsu S, Waheed A, Bacon BR, Sly WS, Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: increased duodenal expression of the iron transporter DMT1. Proc Natl Acad Sci USA 1999; 96: 3143-3148 https://doi.org/10.1073/pnas.96.6.3143
  21. Picad V, Govoni G, Jabado N, GrosP, Nramp 2 (DCT1/DMT1) expressed at the plasma membrane transports iron and other divalent cations into a calcein-accessible cytoplasmic pool. J Bioi Chern 2000; 275: 35738-35745
  22. Srai SK, Bomford A, McArdle HJ. Iron transport across cell membranes: molecular understanding of duodenal and placental iron uptake, Best Pract Res Clin Haematol 2002; 15: 243-259
  23. Yamamoto K, Yoshida K, Miyagoe Y, Ishikawa A, Hanaoka K, Nomoto S, Kaneko K, Ikeda S, Takeda S, Quantitative evaluation of expression of iron-metabolism genes in ceruloplasmin-deficient mice. Biochim Biophys Acta 2002; 1588: 195-202
  24. Yang F, Liu XB, Quinones M, Melby PC, Ghio A, Haile DJ. Regulation of reticuloen-dothelial iron transporter MTP1 (S1c11a3) by inflammation, J Bioi Chem 2002a; 277: 39786-39791
  25. Yang F, Wang X, Haile DJ, Piantadosi CA, Ghio AJ. Iron increases expression of iron-export protein MTP1 in lung cells. Am J Physiol Lung CelI MoI physioI 2002b; 283: 932-939 https://doi.org/10.1152/ajplung.00114.2002
  26. Wang X, Ghio AJ, Yang F, Dolan KG, Garrick MD, Piantadcsi CA. Iron uptake and Nramp2/DMT1/DCT1 in human bronchial epithelial cells. Am J Physiol Lung Cell Mol PhysioI 2002; 282: 987-995 https://doi.org/10.1152/ajplung.00253.2001