Am. J. Respir. Crit. Care Med., Volume 162, Number 4, October 2000, 1561-1568

Antisense Oligonucleotides to NF-B Improve Survival in Bleomycin-induced Pneumopathy of the Mouse

XIAO YE ZHANG, SANAE SHIMURA, TOHRU MASUDA, HIROKI SAITOH, and KUNIO SHIRATO

First Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan

We examined the effect of antisense oligonucleotides to the p65 subunit of NF-B on the survival of bleomycin (BLM)-induced pneumonitis in C57BL/6 mice (female, 8 wk of age, 17 to 20 g body weight). Fifty-three percent and all control mice died within 6 to 9 d after intravenous administration of 150 and 300 mg/kg BLM alone, respectively. The intravenous administration of the antisense oligonucleotides (900 µg/animal dissolved in 200 µl saline, 6 h before and 5 d after BLM administration) significantly improved the survival rate to 100 and 40% in 150- and 300-mg/kg-treated animals, respectively. The antisense oligonucleotides also significantly improved the loss of body weight, the increase in lung hydroxyproline, and histologic changes by BLM, whereas the antisense oligonucleotides themselves did not produce any significant changes in the behavior or lung histology. Both peripheral blood monocytes and alveolar macrophages were confirmed to contain large amounts of intracellular antisense oligonucleotides after BLM injection by FITC-labeled fluorescent microscopy. Further, Western blotting confirmed the inhibition of NF-B in macrophages by the antisense oligonucleotides. These findings suggest that the antisense oligonucleotides are incorporated into activated alveolar macrophages and ameleriorate the lung injury and pneumonitis/fibrosis, thereby improving the survival of BLM-induced pneumopathy in mice.

This article has been cited by other articles:

				S. Fineschi, M. Bongiovanni, Y. Donati, S. Djaafar, F. Naso, L. Goffin, C. Barazzone Argiroffo, J.-C. Pache, J.-M. Dayer, S. Ferrari-Lacraz, et al. In Vivo Investigations on Anti-Fibrotic Potential of Proteasome Inhibition in Lung and Skin Fibrosis Am. J. Respir. Cell Mol. Biol., October 1, 2008; 39(4): 458 - 465. [Abstract] [Full Text] [PDF]

				M. Inayama, Y. Nishioka, M. Azuma, S. Muto, Y. Aono, H. Makino, K. Tani, H. Uehara, K. Izumi, A. Itai, et al. A Novel I{kappa}B Kinase-beta Inhibitor Ameliorates Bleomycin-induced Pulmonary Fibrosis in Mice Am. J. Respir. Crit. Care Med., May 1, 2006; 173(9): 1016 - 1022. [Abstract] [Full Text] [PDF]

				S. F. Liu and A. B. Malik NF-{kappa}B activation as a pathological mechanism of septic shock and inflammation Am J Physiol Lung Cell Mol Physiol, April 1, 2006; 290(4): L622 - L645. [Abstract] [Full Text] [PDF]

				W. Matsuyama, M. Watanabe, Y. Shirahama, H. Mitsuyama, I. Higashimoto, M. Osame, and K. Arimura Discoidin Domain Receptor 1 Contributes to the Survival of Lung Fibroblast in Idiopathic Pulmonary Fibrosis Am. J. Pathol., March 1, 2006; 168(3): 866 - 877. [Abstract] [Full Text] [PDF]

				H. Ishii, H. Mukae, T. Kakugawa, T. Iwashita, H. Kaida, T. Fujii, T. Hayashi, J.-i. Kadota, and S. Kohno Increased expression of collagen-binding heat shock protein 47 in murine bleomycin-induced pneumopathy Am J Physiol Lung Cell Mol Physiol, October 1, 2003; 285(4): L957 - L963. [Abstract] [Full Text] [PDF]

				W. Huang, G. Wang, D. S. Phelps, H. Al-Mondhiry, and J. Floros Combined SP-A-bleomycin effect on cytokines by THP-1 cells: impact of surfactant lipids on this effect Am J Physiol Lung Cell Mol Physiol, July 1, 2002; 283(1): L94 - L102. [Abstract] [Full Text] [PDF]

				M. J. TOBIN Tuberculosis, Lung Infections, and Interstitial Lung Disease in AJRCCM 2000 Am. J. Respir. Crit. Care Med., November 15, 2001; 164(10): 1774 - 1788. [Full Text] [PDF]