Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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Effects of Aspirin on the Pathogenesis of Acute Lung Injury in Rats Subjected to Hemorrhage

출혈성 쇼크로 인한 급성 폐손상의 발병기전과 아스피린의 효과

  • Park, Yoon-yub (Department of Physiology, Catholic University of Daegu) ;
  • Lee, Young Man (Department of Physiology, Catholic University of Daegu)
  • 박윤엽 (대구가톨릭대학교 의과대학 생리학교실) ;
  • 이영만 (대구가톨릭대학교 의과대학 생리학교실)
  • Received : 2005.05.26
  • Accepted : 2005.12.26
  • Published : 2006.01.30
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Abstract

Background : For unknown reasons, the serum ferritin concentrations are higher in patients with acute lung injury. A pretreatment with aspirin reduces the acute lung injury in rats subjected severe hemorrhage, and increases the rate of ferritin synthesis in vitro. This study investigated the effect of aspirin on the serum ferritin changes in rats subjected to severe hemorrhage. Methods : Hemorrhagic shock was induced by withdrawing blood (20 ml/kg of B.W.) through the femoral artery for 5 min. The rats were pretreated with aspirin (10 mg/kg, i.v.) 30 min before hemorrhage. Results : The protein content and leukocyte count in the bronchoalveolar lavage fluid, lung tissue myeloperoxidase activities were significantly higher after hemorrhage. The aspirin pretreatment prevented these changes. The serum and lavage fluid ferritin concentrations were elevated higher after hemorrhage. These were also attenuated by the aspirin pretreatment. Conclusion : The changes in the serum and lung lavage ferritin level might be closely related to the severity of hemorrhage-induced acute lung injury. Therefore, the serum and lavage ferritin concentrations can be a useful biomarker for patients with precipitating conditions.

연구배경 : 아스피린이 출혈성 쇼크시 나타나는 급성 폐손상에 미치는 효과와 혈장 및 폐세척액 내 ferritin 농도변화를 알아보고자 본 연구를 시행하였다. 방 법 : 실험동물은 체중 350g 내외의 Sprague-Dawley 종 흰쥐를 사용하였고, 혈압측정 및 출혈을 시키기 위하여 catheter를 양쪽 대퇴동맥에 삽입하였다. 수술 후 polygraph를 이용하여 평균동맥압을 기록하였으며, 출혈은 withdrawal pump를 이용하여 5분간 체중 kg당 20 ml의 혈액을 출혈시켰다. 실험군은 대조군, 출혈군과 아스피린 처치군으로 분류하였다. 대조군은 출혈군과 동일하게 수술하고 출혈은 시키지 않았으며 나머지 과정은 출혈군과 동일하게 처리하였다. 아스피린 처치군은 출혈 30분 전 대퇴정맥으로 아스피린(10mg/kg)을 주입하였고, 출혈군은 체중 당 동일한 양의 생리식염수를 주입하였다. 출혈 2시간 후의 폐손상 정도와 아스피린이 이에 미치는 효과를 알아보기 위하여 폐장내 myeloperoxidase 활성도와 폐세척액 내의 단백함량과 백혈구 수 및 혈장 ferritin 농도와 폐세척액 내 ferritin 농도를 측정하였다. 결 과 : 폐장내 myeloperoxidase 활성도와 폐세척액 내의 단백함량과 백혈구수는 출혈 후 대조군에 비해 유의하게 증가하였다. 이러한 반응은 아스피린 전처치에 의하여 효과적으로 차단되었다. 혈장 및 폐세척액 내 ferritin 농도는 출혈 후 크게 증가하였는데, 아스피린 전처치로 반응이 억제되었다. 결 론 : 심한 출혈 후에 생기는 급성 폐손상은 아스피린 전처치로 효과적으로 예방될 수 있으며, 출혈 후 증가하는 혈장 및 폐세척액 내 ferritin 농도는 급성폐손상이 나타날 수 있는 환자에서 조기진단을 위한 생체지표 로 활용될 수 있다고 생각된다.

Keywords

References

  1. Harrison PM, Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta 1996;1275:161-203 https://doi.org/10.1016/0005-2728(96)00022-9
  2. Torti FM, Torti SV. Regulation of ferritin genes and protein. Blood 2002;99:3505-16 https://doi.org/10.1182/blood.V99.10.3505
  3. Arosio P, Levi S. Ferritin, iron homeostasis, and oxidative damage. Free Radic Biol Med 2002;33:457-63 https://doi.org/10.1016/S0891-5849(02)00842-0
  4. Balla G, Jacob HS, Balla J, Rosenberg M, Nath K, Apple F, et al. Ferritin: a cytoprotective antioxidant strategem of endothelium. J Biol Chem 1992;267: 18148-53
  5. Hybertson BM, Connelly KG, Buser RT, Repine JE. Ferritin and desferrioxamine attenuate xanthine oxidase-dependent leak in isolated perfused rat lungs. Inflammation 2002;26:153-9 https://doi.org/10.1023/A:1016511611435
  6. Park YY, Hybertson BM, Wright RM, Repine JE. Serum ferritin increases in hemorrhaged rats that develop acute lung injury: effect of an iron-deficient diet. Inflammation 2003;27:257-63 https://doi.org/10.1023/A:1025044732423
  7. Park YY, Hybertson BM, Wright RM, Fini MA, Elkins N, Repine JE. Serum ferritin elevation and acute lung injury in rats subjected to hemorrhage: reduction by mepacrine treatment. Exp Lung Res 2004;30:571-84 https://doi.org/10.1080/01902140490489207
  8. Connelly KG, Moss M, Parsons PE, Moore EE, Moore FA, Giclas PC, et al. Serum ferritin as a predictor of the acute respiratory distress syndrome. Am J Respir Crit Care Med 1997;155:21-5 https://doi.org/10.1164/ajrccm.155.1.9001283
  9. Sharkey RA, Donnelly SC, Connelly KG, Robertson CE, Haslett C, Repine JE. Initial serum ferritin levels in patients with multiple trauma and the subsequent development of acute respiratory distress syndrome. Am J Respir Crit Care Med 1999;159:1506-9 https://doi.org/10.1164/ajrccm.159.5.9809027
  10. Pham CG, Bubici C, Zazzeroni F, Papa S, Jones J, Alvarez K, et al. Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species. Cell 2004;119:529-42 https://doi.org/10.1016/j.cell.2004.10.017
  11. Podhaisky HP, Abate A, Polte T, Oberle S, Schroder H. Aspirin protects endothelial cells from oxidative stress: possible synergism with vitamin E. FEBS Lett 1997;417:349-51 https://doi.org/10.1016/S0014-5793(97)01307-0
  12. Wahn H, Hammerschmidt S. Inhibition of PMN- and HOCl-induced vascular injury in isolated rabbit lungs by acetylsalicylic acid: a possible link between neutrophil-derived oxidative stress and eicosanoid metabolism? Biochim Biophys Acta 1998;1408:55-66 https://doi.org/10.1016/S0925-4439(98)00055-6
  13. Carpenter-Deyo L, Roth RA. Cyclooxygenase inhibition in lungs or in neutrophils attenuates neutrophil-dependent edema in rat lungs perfused with phorbol myristate acetate. J Pharmacol Exp Ther 1989;251:983-91
  14. Zanaboni PB, Bradley JD, Baudendistel LJ, Webster RO, Dahms TE. Cyclooxygenase inhibition prevents PMA-induced increases in lung vascular permeability. J Appl Physiol 1990;69:1494-501 https://doi.org/10.1152/jappl.1990.69.4.1494
  15. Shin TR, Lee DU, Park YY. Aspirin reduces acute lung injury in rats subjected to severe hemorrhage. Tuberc Respir Dis 2003;54:522-31 https://doi.org/10.4046/trd.2003.54.5.522
  16. Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 1994;265:956-9 https://doi.org/10.1126/science.8052854
  17. Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 1998;396:77-80 https://doi.org/10.1038/23948
  18. Eisele G, Schwedhelm E, Schieffer B, Tsikas D, Boger RH. Acetylsalicylic acid inhibits monocyte adhesion to endothelial cells by an antioxidative mechanism. J Cardiovasc Pharmacol 2004;43:514-21 https://doi.org/10.1097/00005344-200404000-00006
  19. Brown RE, Jarvis KL, Hyland KJ. Protein measurement using bicinchoninic acid: elimination of interfering substance. Anal Biochem 1989;180:136-9 https://doi.org/10.1016/0003-2697(89)90101-2
  20. Goldblum SE, Wu KM, Jay M. Lung myeloperoxidase as a measure of leukostasis in rabbit. J Appl Physiol 1985;59:1978-85 https://doi.org/10.1152/jappl.1985.59.6.1978
  21. Jang YS, Kim SE, Jheon SH, Shin TR, Lee YM. Phospholipase A2 contributes to hemorrhage-induced acute lung injury through neutrophilic respiratory burst. Tuberc Respir Dis 2001;51:503-16 https://doi.org/10.4046/trd.2001.51.6.503
  22. Repine JE. Scientific perspectives on adult respiratory distress syndrome. Lancet 1992;339:466-9 https://doi.org/10.1016/0140-6736(92)91067-I
  23. Hudson LD, Milberg JA, Anardi D, Maunder RJ. Clinical risks for the development of the acute respiratory distress syndrome. Am J Respir Crit Care Med 1995;151:293-301 https://doi.org/10.1164/ajrccm.151.2.7842182
  24. Hierholzer C, Harbrecht B, Menezes JM, Kane J, MacMicking J, Nathan CF, et al. Essential role of induced nitric oxide in the initiation of the inflammatory response after hemorrhagic shock. J Exp Med 1998;187:917-28 https://doi.org/10.1084/jem.187.6.917
  25. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342:1334-49 https://doi.org/10.1056/NEJM200005043421806
  26. Connelly KG, Repine JE. Markers for predicting the development of acute respiratory distress syndrome. Annu Rev Med 1997;48:429-45
  27. Pepe PE, Potkin RT, Reus DH, Hudson LD, Carrico CJ. Clinical predictors of the adult respiratory distress syndrome. Am J Surg 1982;144:124-30 https://doi.org/10.1016/0002-9610(82)90612-2
  28. Fowler AA, Hamman RF, Good JT, Benson KN, Baird M, Eberle DJ, et al. Adult respiratory distress syndrome: risk with common predispositions. Ann Intern Med 1983;98:593-7 https://doi.org/10.7326/0003-4819-98-5-593
  29. Halliwell B, Gutteridge JM. Oxygen toxicity, oxygen radicals, transition metals and disease. Biochem J 1984;219:1-14 https://doi.org/10.1042/bj2190001
  30. Weiss SJ. Tissue destruction by neutrophils. N Engl J Med 1989;320:365-76 https://doi.org/10.1056/NEJM198902093200606
  31. Gannon DE, Varani J, Phan SH, Ward JH, Kaplan J, Till GO, et al. Source of iron in neutrophil-mediated killing of endothelial cells. Lab Invest 1987;57:37-44
  32. Schraufstatter I, Hyslop PA, Jackson JH, Cochrane CG. Oxidant-induced DNA damage of target cells. J Clin Invest 1988;82:1040-50 https://doi.org/10.1172/JCI113660
  33. Yang F, Coalson JJ, Bobb HH, Carter JD, Banu J, Ghio AJ. Resistance of hypotransferrinemic mice to hyperoxia-induced lung injury. Am J Physiol 1999; 277:L1214-23
  34. Rogers JT, Bridges KR, Durmowicz GP, Glass J, Auron PE, Munro HN. Translational control during the acute phase response: ferritin synthesis in response to interleukin-1. J Biol Chem 1990;265:14572-8
  35. Tran TN, Eubanks SK, Schaffer KJ, Zhou CY, Linder MC. Secretion of ferritin by rat hepatoma cells and its regulation by inflammatory cytokines and iron. Blood 1997;90:4979-86
  36. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999;340:448-54 https://doi.org/10.1056/NEJM199902113400607
  37. Cook JD, Lipschitz DA, Miles LE, Finch CA. Serum ferritin as a measure of iron stores in normal subjects. Am J Clin Nutr 1974;27:681-7 https://doi.org/10.1093/ajcn/27.7.681
  38. Walters GO, Miller FM, Worwood M. Serum ferritin concentration and iron stores in normal subjects. J Clin Pathol 1973;26:770-2 https://doi.org/10.1136/jcp.26.10.770
  39. Zweifach BW. Mechanisms of blood flow and fluid exchange in microvessels: hemorrhagic hypotension model. Anesthesiology 1974;41:157-68 https://doi.org/10.1097/00000542-197408000-00006
  40. Jacobs A, Worwood M. Ferritin in serum: clinical and biochemical implications. N Engl J Med 1975;292:951-6 https://doi.org/10.1056/NEJM197505012921805
  41. McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 1985;312:159-63 https://doi.org/10.1056/NEJM198501173120305
  42. Anderson BO, Moore EE, Moore FA, Leff JA, Terada LS, Harken AH, et al. Hypovolemic shock promotes neutrophil sequestration in lungs by a xanthine oxidase-related mechanism. J Appl Physiol 1991;71:1862-5 https://doi.org/10.1152/jappl.1991.71.5.1862
  43. Tan S, Yokoyama Y, Dickens E, Cash TG, Freeman BA, Parks DA. Xanthine oxidase activity in the circulation of rats following hemorrhagic shock. Free Radic Biol Med 1993;15:407-14 https://doi.org/10.1016/0891-5849(93)90040-2
  44. Schwartz MD, Repine JE, Abraham E. Xanthine oxidase-derived oxygen radicals increase lung cytokine expression in mice subjected to hemorrhagic shock. Am J Respir Cell Mol Biol 1995;12:434-40 https://doi.org/10.1165/ajrcmb.12.4.7695923
  45. Balla J, Nath KA, Balla G, Juckett MB, Jacob HS, Vercellotti GM. Endothelial cell heme oxygenase and ferritin induction in rat lung by hemoglobin in vivo. Am J Physiol 1995;268:L321-7
  46. Kwak EL, Larochelle DA, Beaumont C, Torti SV, Torti FM. Role for NF-kappa B in the regulation of ferritin H by tumor necrosis factor-alpha. J Biol Chem 1995;270:15285-93 https://doi.org/10.1074/jbc.270.25.15285
  47. Holter JF, Weiland JE, Pacht ER, Gadek JE, Davis WB. Protein permeability in the adult respiratory distress syndrome: loss of size selectivity of the alveolar epithelium. J Clin Invest 1986;78:1513-22 https://doi.org/10.1172/JCI112743
  48. Suter PM, Suter S, Girardin E, Roux-Lombard P, Grau GE, Dayer JM. High bronchoalveolar levels of tumor necrosis factor and its inhibitors, interleukin-1, interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis. Am Rev Respir Dis 1992;145:1016-22 https://doi.org/10.1164/ajrccm/145.5.1016
  49. Shenkar R, Abraham E. Mechanisms of lung neutrophil activation after hemorrhage or endotoxemia: roles of reactive oxygen intermediates, NF-kappa B, and cyclic AMP response element binding protein. J Immunol 1999;163:954-62
  50. Abraham E, Carmody A, Shenkar R, Arcaroli J. Neutrophils as early immunologic effectors in hemorrhage-or endotoxemia-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 2000;279:L1137-45 https://doi.org/10.1152/ajplung.2000.279.6.L1137
  51. Tsuji Y, Miller LL, Miller SC, Torti SV, Torti FM. Tumor necrosis factor-alpha and interleukin 1-alpha regulate transferrin receptor in human diploid fibroblasts: relationship to the induction of ferritin heavy chain. J Biol Chem 1991;266:7257-61
  52. Reif DW. Ferritin as a source of iron for oxidative damage. Free Radic Biol Med 1992;12:417-27 https://doi.org/10.1016/0891-5849(92)90091-T
  53. Balla G, Vercellotti GM, Eaton JW, Jacob HS. Iron loading of endothelial cells augments oxidant damage. J Lab Clin Med 1990;116:546-54
  54. Olakanmi O, McGowan SE, Hayek MB, Britigan BE. Iron sequestration by macrophages decreases the potential for extracellular hydroxyl radical formation. J Clin Invest 1993;91:889-99 https://doi.org/10.1172/JCI116310
  55. Orino K, Lehman L, Tsuji Y, Ayaki H, Torti SV, Torti FM. Ferritin and the response to oxidative stress. Biochem J 2001;357:241-7 https://doi.org/10.1042/0264-6021:3570241
  56. Oberle S, Polte T, Abate A, Podhaisky HP, Schroder H. Aspirin increases ferritin synthesis in endothelial cells: a novel antioxidant pathway. Circ Res 1998;82:1016-20 https://doi.org/10.1161/01.RES.82.9.1016