Am. J. Respir. Crit. Care Med., Volume 165, Number 3, February 2002, 406-411

Bilirubin Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Rats

HOU-DONG WANG, MUTSUO YAMAYA, SHOJI OKINAGA, YU-XIA JIA, MASAHITO KAMANAKA, HIDENORI TAKAHASHI, LI-YA GUO, TAKASHI OHRUI, and HIDETADA SASAKI

Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Sendai, Japan

Many possible treatments for pulmonary fibrosis have been investigated, but except for some current clinical trials, none have succeeded in clinical trials. On the basis of the antioxidant action of bilirubin (BIL), we examined the effects of hyperbilirubinemia on the development of bleomycin (BLM)-induced pulmonary fibrosis in rats. The animals' plasma BIL level was kept within 3 and 10 mg/dl by repeated intravenous infusion of a high dose of BIL. We studied the inhibitory effects of hyperbilirubinemia on BLM-induced pulmonary fibrosis through histopathologic and biochemical analyses. Mortality of rats with BLM-induced pulmonary fibrosis was significantly lower in the three groups with hyperbilirubinemia. The ameliorating effect of hyperbilirubinemia on pulmonary fibrosis was shown by lung histology, as well as by a decreased lung content of hydroxyproline and reduced bronchoalveolar lavage fluid (BALF) concentration of transforming growth factor (TGF)-₁. The number of polymorphonuclear leukocytes and lymphocytes in BALF was also decreased in the groups with hyperbilirubinemia. Furthermore, oxidative metabolites of BIL in urine were present at significantly higher levels in BLM-treated rats with hyperbilirubinemia than in those without hyperbilirubinemia. These data suggest that the antioxidative action of BIL can attenuate BLM-induced pulmonary fibrosis, partly by inhibiting lung inflammation and production of TGF-1.

This article has been cited by other articles:

				Q. Ye, Y. Dalavanga, N. Poulakis, S. U. Sixt, J. Guzman, and U. Costabel Decreased expression of haem oxygenase-1 by alveolar macrophages in idiopathic pulmonary fibrosis Eur. Respir. J., May 1, 2008; 31(5): 1030 - 1036. [Abstract] [Full Text] [PDF]

				A. Traylor, T. Hock, and N. Hill-Kapturczak Specificity protein 1 and Smad-dependent regulation of human heme oxygenase-1 gene by transforming growth factor-beta1 in renal epithelial cells Am J Physiol Renal Physiol, September 1, 2007; 293(3): F885 - F894. [Abstract] [Full Text] [PDF]

				L. E. Fredenburgh, M. A. Perrella, and S. A. Mitsialis The Role of Heme Oxygenase-1 in Pulmonary Disease Am. J. Respir. Cell Mol. Biol., February 1, 2007; 36(2): 158 - 165. [Abstract] [Full Text] [PDF]

				S. W. Ryter, D. Morse, and A. M. K. Choi Carbon Monoxide and Bilirubin: Potential Therapies for Pulmonary/Vascular Injury and Disease Am. J. Respir. Cell Mol. Biol., February 1, 2007; 36(2): 175 - 182. [Abstract] [Full Text] [PDF]

				S. W. Ryter, J. Alam, and A. M. K. Choi Heme Oxygenase-1/Carbon Monoxide: From Basic Science to Therapeutic Applications Physiol Rev, April 1, 2006; 86(2): 583 - 650. [Abstract] [Full Text] [PDF]

				T. W. Sedlak and S. H. Snyder Messenger Molecules and Cell Death: Therapeutic Implications JAMA, January 4, 2006; 295(1): 81 - 89. [Abstract] [Full Text] [PDF]

				J. K. Sarady-Andrews, F. Liu, D. Gallo, A. Nakao, M. Overhaus, R. Ollinger, A. M. Choi, and L. E. Otterbein Biliverdin administration protects against endotoxin-induced acute lung injury in rats Am J Physiol Lung Cell Mol Physiol, December 1, 2005; 289(6): L1131 - L1137. [Abstract] [Full Text] [PDF]

				D. Morse and A. M. K. Choi Heme Oxygenase-1: From Bench to Bedside Am. J. Respir. Crit. Care Med., September 15, 2005; 172(6): 660 - 670. [Abstract] [Full Text] [PDF]

				W. E. Lawson, V. V. Polosukhin, O. Zoia, G. T. Stathopoulos, W. Han, D. Plieth, J. E. Loyd, E. G. Neilson, and T. S. Blackwell Characterization of Fibroblast-specific Protein 1 in Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., April 15, 2005; 171(8): 899 - 907. [Abstract] [Full Text] [PDF]

				A. Almolki, C. Taille, G. F. Martin, P. J. Jose, C. Zedda, M. Conti, J. Megret, D. Henin, M. Aubier, and J. Boczkowski Heme oxygenase attenuates allergen-induced airway inflammation and hyperreactivity in guinea pigs Am J Physiol Lung Cell Mol Physiol, July 1, 2004; 287(1): L26 - L34. [Abstract] [Full Text] [PDF]

				T. W. Sedlak and S. H. Snyder Bilirubin Benefits: Cellular Protection by a Biliverdin Reductase Antioxidant Cycle Pediatrics, June 1, 2004; 113(6): 1776 - 1782. [Full Text] [PDF]

				N. Kaminski, J. A. Belperio, P. B. Bitterman, L. Chen, S. W. Chensue, A. M.K. Choi, S. Dacic, J. H. Dauber, R. M. du Bois, J. J. Enghild, et al. Idiopathic Pulmonary Fibrosis Am. J. Respir. Cell Mol. Biol., September 1, 2003; 29(3): S1 - 105. [Full Text] [PDF]

				J. A. Araujo, L. Meng, A. D. Tward, W. W. Hancock, Y. Zhai, A. Lee, K. Ishikawa, S. Iyer, R. Buelow, R. W. Busuttil, et al. Systemic Rather Than Local Heme Oxygenase-1 Overexpression Improves Cardiac Allograft Outcomes in a New Transgenic Mouse J. Immunol., August 1, 2003; 171(3): 1572 - 1580. [Abstract] [Full Text] [PDF]

				M. J. Tobin Tuberculosis, Lung Infections, Interstitial Lung Disease, and Journalology in AJRCCM 2002 Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 345 - 355. [Full Text] [PDF]

				D. A. Greenberg The jaundice of the cell PNAS, December 10, 2002; 99(25): 15837 - 15839. [Full Text] [PDF]