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Serum Ferritin Increases in Hemorrhaged Rats That Develop Acute Lung Injury: Effect of an Iron-Deficient Diet

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Abstract

For unknown reasons, serum ferritin levels increase in patients at risk for and with acute lung injury (ALI). To improve understanding of the relationship between serum ferritin alterations and the development of ALI, we investigated the effect of iron deficiency on the serum ferritin response of rats subjected to hemorrhage. We found that rats fed an iron-deficient diet for 6 weeks had decreased hemoglobin, hematocrit, liver total iron, liver total iron-binding capacity, and liver ferritin concentrations but the same serum ferritin concentrations as rats fed a control diet. Following hemorrhage, serum ferritin concentrations increased rapidly and progressively in rats fed a control diet. Along with increases in serum ferritin concentrations, control diet rats subjected to hemorrhage also had increased lung lavage leukocyte numbers, lung myeloperoxidase activities (lung inflammation), and lung lavage protein concentrations (lung leak) compared to control diet fed rats subjected to sham treatment. By comparison, the serum ferritin concentrations, lung inflammation, and lung leak of hemorrhaged rats fed an iron-deficient diet were decreased compared to hemorrhaged rats fed a control diet. These findings indicate that serum ferritin concentrations increase and acute lung injury develops following hemorrhage in rats fed a control, but not an iron-deficient, diet. A relatively brief exposure to an iron-deficient diet reduces hemorrhage-induced ALI.

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References

  1. Repine, J. E. 1992. Scientific perspectives on adult respiratory distress syndrome. Lancet 339:466–469.

    Google Scholar 

  2. Connelly, K. G. and J. E. Repine. 1997. Markers for predicting the development of acute respiratory distress syndrome. Annu. Rev. Med. 48:429–445.

    Google Scholar 

  3. Pepe, P. E., R. T. Potkin, D. H. Reus, L. D. Hudson, and C. J. Carrico. 1982. Clinical predictors of the adult respiratory distress syndrome. Am. J. Surg. 144:124–130.

    Google Scholar 

  4. Pittet, J. F., R. C. Mackersie, T. R. Martin, and M. A. Matthay. 1997. Biological markers of acute lung injury: Prognostic and pathogenetic significance. Am. J. Resp. Crit. Care. Med. 155:1187–1205.

    Google Scholar 

  5. Connelly, K. G., M. Moss, P. E. Parsons, E. E. Moore, F. A. Moore, P. C. Giclas, P. A. Seligman, and J. E. Repine. 1997. Serum ferritin as a predictor of the acute respiratory distress syndrome. Am. J. Respir. Crit. Care. Med. 155:21–25.

    Google Scholar 

  6. Sharkey, R. A., S. C. Donnelly, K. G. Connelly, C. E. Robertson, C. Haslett, and J. E. Repine. 1999. Initial serum ferritin levels in patients with multiple trauma and the subsequent development of acute respiratory distress syndrome. Am. J. Respir. Crit. Care. Med. 159:1506–1509.

    Google Scholar 

  7. Suleiman, M., E. Wolfovitz, N. Boulman, and Y. Levy. 2002. Adult onset Still's disease as a cause of ARDS and acute respiratory failure. Scand. J. Rheumatol. 31(3):181–183.

    Google Scholar 

  8. Iglesias, J., S. Sathiraju, and P. E. Marik. 1999. Severe systemic inflammatory response syndrome with shock and ARDS resulting from Still's disease: Clinical response with high-dose pulse methylprednisolone therapy. Chest 115(6):1738–1740.

    Google Scholar 

  9. Eisenstein, R. S. and K. P. Blemings. 1998. Iron regulatory proteins, iron responsive elements and iron homeostasis. J. Nutr. 128:2295–2298.

    Google Scholar 

  10. Mateos, F., J. H. Brock, and J. L. Perez-Arellano. 1998. Iron metabolism in the lower respiratory tract. Thorax 53:594–600.

    Google Scholar 

  11. Cavill, I. 1999. Iron status as measured by serum ferritin: The marker and its limitations. Am. J. Kidney Dis. 34(suppl 2):S12-S17.

    Google Scholar 

  12. Cook, J. D., D. A. Lipschitz, L. E. Miles, C. A. Finch. 1974. Serum ferritin as a measure of iron stores of normal subjects. Am. J. Clin. Nutr. 27:681–687.

    Google Scholar 

  13. Jacobs, A. and M. Worwood. 1975. Ferritin in serum. Clinical and biochemical implications. N. Engl. J. Med. 292:951–956.

    Google Scholar 

  14. Kalantar-Zadeh, K., B. R. Don, R. A. Rodriguez, M. H. Humphreys. 2001. Serum ferritin is a marker of morbidity and mortality in hemodialysis patients. Am. J. Kidney Dis. 37:564–572.

    Google Scholar 

  15. Lipschitz, D. A., J. D. Cook, and C. A. Finch. 1974 A clinical evaluation of serum ferritin as an index of iron stores. N. Engl. J. Med. 290:1213–1216.

    Google Scholar 

  16. Sullivan, J. L. 1989. The iron paradigm of ischemic heart disease. Am. Heart J. 117:1177–1188.

    Google Scholar 

  17. Tuomainen, T., K. Punnonen, K. Nyyssonen, J. T. Salonen. 1998. Association between body iron stores and the risk of acute myocar-dial infarction in men. Circulation 97:1461–1466.

    Google Scholar 

  18. Harrison, P. M. and P. Arosio. 1996. The ferritins: Molecular properties, iron storage function and cellular regulation. Biochim. Biophys. Acta. 1275:161–203.

    Google Scholar 

  19. Persijn, J. P., W. Van Der Slik, and A. Riethorst. 1971. Determination of serum iron and latent iron-binding capacity (LIBC). Clin. Chim. Acta. 35:91–98.

    Google Scholar 

  20. Lee, Y. M., B. M. Hybertson, H. G. Cho, L. S. Terada, O. Cho, A. J. Repine, and J. E. Repine. 2000. Platelet-activating factor contributes to acute lung leak in rats given interleukin-1 intratracheally. Am. J. Physiol. 279:L75–80.

    Google Scholar 

  21. Zweifach, B. W. 1974. Mechanisms of blood flow and fluid exchange in microvessels: Hemorrhagic hypotension model. Anesthesiology 41:157–168.

    Google Scholar 

  22. Yang, F., J. J. Coalson, H. H. Bobb, J. D. Carter, J. Banu, and A. J. Ghio. 1974 Resistance of hypotransferrinemic mice to hyperoxia-induced lung injury. Am. J. Physiol. 277:L1214-L1223.

    Google Scholar 

  23. Arosio, P., and S. Levi. 2002. Ferritin, iron homeostasis, and oxidative damage. Free Radic. Biol. Med. 33:457–463. Manuscript submitted for publication. Mepacrine reduces serum ferritin increases and acute lung injury in rats subjected to hemorrhage.

    Google Scholar 

  24. Gutteridge, J. M. C., S. Mumby, G. J. Quinlan, K. F. Chung, and T. W. Evans. 1996. Pro-oxidant iron is present in human pulmonary epithelial lining fluid: Implications for oxidative stress in the lung. Biochem. Biophys. Res. Commun. 220:1024–1027.

    Google Scholar 

  25. Rivera-Chavez, F., L. H. Toledo-Pereyra, D. T. Nora, B. Bachulis, F. Ilgenfritz, and R. E. Dean. 1998. P-selectin blockade is beneficial after uncontrolled hemorrhagic shock. J. Trauma. 45:440–445.

    Google Scholar 

  26. Zhao, G, I. S. Ayene, and A. B. Fisher. 1997. Role of iron in ischemiareperfusion oxidative injury of rat lungs. Am. J. Respir Cell. Mol. Biol. 16:293–299.

    Google Scholar 

  27. Balla, G., H. S. Jacob, J. Balla, M. Rosenberg, K. Nath, F. Apple, J. W. Eaton, and G. M. Vercellotti. 1992. Ferritin: A cytoprotective antioxidant strategem of endothelium. J. Biol. Chem. 267:18148–18153.

    Google Scholar 

  28. Balla, J., K. A. Nath, G. Balla, M. B. Juckett, H. S. Jacob, and G. M. Vercellotti. 1995. Endothelial cell heme oxygenase and ferritin induction in rat lung by hemoglobin in vivo. Am. J. Physiol. 268:L321-L327.

    Google Scholar 

  29. Hybertson, B. M., K. G. Connelly, R. T. Buser, and J. E. Repine. 2002. Ferritin and desferriox amine attenvate xanthine oxidase-dependent leak in isolated perfused rat lungs. Inflammation. 26:153–159.

    Google Scholar 

  30. Anderson, B. O., E. E. Moore, F. A. Moore, J. A. Leff, L. S. Terada, A. H. Harken, and J. E. Repine. 1991. Hypovolemic shock promotes neutrophil sequestration in lungs by a xanthine oxidase-related mechanism. J. Appl. Physiol. 71:1862–1865.

    Google Scholar 

  31. Schwartz, M. D., J. E. Repine, E. Abraham. 1995. Xanthine oxidase-derived oxygen radicals increase lung cytokine expression in mice subjected to hemorrhagic shock. Am. J. Respir. Cell. Mol. Biol. 12:434–440.

    Google Scholar 

  32. Tan, S., Y. Yokoyama, E. Dickens, T. G. Cash, B. A. Freeman, and D. A. Parks. 1993. Xanthine oxidase activity in the circulation of rats following hemorrhagic shock. Free Radic. Biol. Med. 15:407–414.

    Google Scholar 

  33. Cairo, G., L. Tacchini, G. Pogliaghi, E. Anzon, A. Tomasi, and A. Bernelli-Zazzera. 1995. Induction ferritin synthesis by oxidative stress. J. Biol. Chem. 270:700–703.

    Google Scholar 

  34. Ryan, T. P., R. F. Krzesicki, D. P. Blakeman, J. E. Chin, R. L. Griffin, I. M. Richard, S. D. Aust, and T. W. Petry. 1997. Pulmonary ferritin: Differential effects of hyperoxic lung injury in subunit mRNA levels. Free Radic. Biol. Med. 22:901–908.

    Google Scholar 

  35. Saito, M., C. E. Thomas, and S. D. Aust. 1985. Paraquat and ferritin-dependent lipid peroxidation. J. Free Radic Biol. Med. 1:179–185.

    Google Scholar 

  36. Samokyszyn, V. M., C. E. Thomas, D. W. Reif, M. Saito, and S. D. Aust. 1988. Release of iron from ferritin and its role in oxygen radical toxicities. Drug Metab. Rev. 19:283–303.

    Google Scholar 

  37. Marzi, I., C. Bauer, R. Hower, and V. Buhren. 1993. Leukocyteendothelial cell interactions in the liver after hemorrhagic shock in the rat. Circ Shock 40:105–114.

    Google Scholar 

  38. Tran, T. N., S. K. Eubanks, K. J. Schaffer, C. Y. J. Zhou, and M. C. Linder. 1997. Secretion of ferritin by rat hepatoma cell and its regulation by inflammatory cytokine and iron. Blood 90:4979–4986.

    Google Scholar 

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Park, Yy., Hybertson, B.M., Wright, R.M. et al. Serum Ferritin Increases in Hemorrhaged Rats That Develop Acute Lung Injury: Effect of an Iron-Deficient Diet. Inflammation 27, 257–263 (2003). https://doi.org/10.1023/A:1025044732423

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