H Mitsuhashi, S Asano, T Nonaka, I Hamamura, K Masuda and M Kiyoki
Teijin Institute for Bio-Medical Research, Hino, Tokyo, Japan.

The purposes of this study were to investigate the effect of our recently developed truncated secretory leukoprotease inhibitor (SLPI) on bleomycin (BLM)-induced lung injury and fibrosis in hamsters, which is widely used as a model of interstitial pulmonary fibrosis, and to assess the possible involvement of neutrophil elastase in the pathogenesis of pulmonary fibrosis. The fibrosis model was prepared by administration of BLM (10 mg/kg) intratracheally to hamsters. The truncated SLPI was administered at a dose 5 or 15 mg/kg intraperitoneally twice a day only for 10 d starting from the time of BLM administration. BLM administration resulted in decreases in body weight and survival rate. Elastase activity in the supernatant of bronchoalveolar lavage (BAL) fluids was increased at 3 and 7 d after BLM administration in parallel with the increase in the number of neutrophils in the fluids. Histopathologically, at 14 and 28 d after BLM administration, diffuse thickening and fibrosis of alveolar walls with marked cell infiltration and severe distortion of alveolar structure, including honeycomb lung, were observed to have occurred. In this model, the decreases in body weight and survival rate and the increase in elastase activity were inhibited by the truncated SLPI dose- dependently, and pulmonary fibrosis was significantly ameliorated by the administration of this shortened form of SLPI. These results suggest that neutrophil elastase may be implicated in the pathogenesis of BLM-induced pulmonary fibrosis and that the truncated SLPI might be a promising therapeutic in the treatment of interstitial pulmonary fibrosis.

This article has been cited by other articles:

				D.M. Dalgetty, J.M. Sallenave, H.O.D. Critchley, A.R. Williams, W.Y. Tham, A.E. King, and A.W. Horne Altered secretory leukocyte protease inhibitor expression in the uterine decidua of tubal compared with intrauterine pregnancy Hum. Reprod., July 1, 2008; 23(7): 1485 - 1490. [Abstract] [Full Text] [PDF]

				A. W Horne, S. J Stock, and A. E King Innate immunity and disorders of the female reproductive tract Reproduction, June 1, 2008; 135(6): 739 - 749. [Abstract] [Full Text] [PDF]

				G. J. Laurent, R. J. McAnulty, M. Hill, and R. Chambers Escape from the Matrix: Multiple Mechanisms for Fibroblast Activation in Pulmonary Fibrosis Proceedings of the ATS, April 15, 2008; 5(3): 311 - 315. [Abstract] [Full Text] [PDF]

				N. Pottier, C. Chupin, V. Defamie, B. Cardinaud, R. Sutherland, G. Rios, F. Gauthier, P. J. Wolters, Y. Berthiaume, P. Barbry, et al. Relationships between Early Inflammatory Response to Bleomycin and Sensitivity to Lung Fibrosis: A Role for Dipeptidyl-Peptidase I and Tissue Inhibitor of Metalloproteinase-3? Am. J. Respir. Crit. Care Med., December 1, 2007; 176(11): 1098 - 1107. [Abstract] [Full Text] [PDF]

				F. Chua and G. J. Laurent Neutrophil elastase: mediator of extracellular matrix destruction and accumulation. Proceedings of the ATS, July 1, 2006; 3(5): 424 - 427. [Abstract] [Full Text] [PDF]

				V. L. Kinnula, C. L. Fattman, R. J. Tan, and T. D. Oury Oxidative Stress in Pulmonary Fibrosis: A Possible Role for Redox Modulatory Therapy Am. J. Respir. Crit. Care Med., August 15, 2005; 172(4): 417 - 422. [Abstract] [Full Text] [PDF]

				A. Pardo, V. Ruiz, J. L. Arreola, R. Ramirez, J. Cisneros-Lira, M. Gaxiola, R. Barrios, S. V. Kala, M. W. Lieberman, and M. Selman Bleomycin-induced Pulmonary Fibrosis Is Attenuated in {gamma}-Glutamyl Transpeptidase-Deficient Mice Am. J. Respir. Crit. Care Med., March 15, 2003; 167(6): 925 - 932. [Abstract] [Full Text] [PDF]

				Y. Li, A. Azuma, S. Takahashi, J. Usuki, K. Matsuda, A. Aoyama, and S. Kudoh Fourteen-Membered Ring Macrolides Inhibit Vascular Cell Adhesion Molecule 1 Messenger RNA Induction and Leukocyte Migration: Role in Preventing Lung Injury and Fibrosis in Bleomycin-Challenged Mice Chest, December 1, 2002; 122(6): 2137 - 2145. [Abstract] [Full Text] [PDF]

				A Serrano-Mollar, D Closa, J Cortijo, E J Morcillo, N Prats, M Gironella, J Panes, J Rosello-Catafau, and O Bulbena P-selectin upregulation in bleomycin induced lung injury in rats: effect of N-acetyl-L-cysteine Thorax, July 1, 2002; 57(7): 629 - 634. [Abstract] [Full Text] [PDF]

				C. Delacourt, S. Herigault, C. Delclaux, A. Poncin, M. Levame, A. Harf, F. Saudubray, and C. Lafuma Protection Against Acute Lung Injury by Intravenous or Intratracheal Pretreatment with EPI-HNE-4, a New Potent Neutrophil Elastase Inhibitor Am. J. Respir. Cell Mol. Biol., March 1, 2002; 26(3): 290 - 297. [Abstract] [Full Text] [PDF]

				S. E. Dunsmore, J. Roes, F. J. Chua, A. W. Segal, S. E. Mutsaers, and G. J. Laurent Evidence That Neutrophil Elastase-Deficient Mice Are Resistant to Bleomycin-Induced Fibrosis Chest, July 1, 2001; 120(2007): 35S - 36S. [Full Text] [PDF]

				A. Azuma, Y. Li, J. Usuki, A. Aoyama, T. Enomoto, and S. Kudoh Fourteen-Membered Ring Macrolides Inhibit Vascular Cell Adhesion Molecule-1 Messenger RNA Induction Preventing Neutrophil-Induced Lung Injury and Fibrosis in Bleomycin-Challenged Mice Chest, July 1, 2001; 120(2007): 20S - 22S. [Full Text] [PDF]

				E. Cavarra, P.A. Martorana, B. Bartalesi, S. Fineschi, F. Gambelli, M. Lucattelli, L. Ortiz, and G. Lungarella Genetic deficiency of {alpha}1-PI in mice influences lung responses to bleomycin Eur. Respir. J., March 1, 2001; 17(3): 474 - 480. [Abstract] [Full Text] [PDF]

				T. Kikuchi, T. Abe, M. Yaekashiwa, Y. Tominaga, H. Mitsuhashi, K. Satoh, T. Nakamura, and T. Nukiwa Secretory Leukoprotease Inhibitor Augments Hepatocyte Growth Factor Production in Human Lung Fibroblasts Am. J. Respir. Cell Mol. Biol., September 1, 2000; 23(3): 364 - 370. [Abstract] [Full Text]

				N. SATO, Y. SUZUKI, K. NISHIO, K. SUZUKI, K. NAOKI, K. TAKESHITA, H. KUDO, N. MIYAO, H. TSUMURA, H. SERIZAWA, et al. Roles of ICAM-1 for Abnormal Leukocyte Recruitment in the Microcirculation of Bleomycin-induced Fibrotic Lung Injury Am. J. Respir. Crit. Care Med., May 1, 2000; 161(5): 1681 - 1688. [Abstract] [Full Text]

				A. Azuma, S. Takahashi, M. Nose, K. Araki, M. Araki, T. Takahashi, M. Hirose, H. Kawashima, M. Miyasaka, and S. Kudoh Role of E-selectin in bleomycin induced lung fibrosis in mice Thorax, February 1, 2000; 55(2): 147 - 152. [Abstract] [Full Text]

				T. S. Gipson, N. M. Bless, T. P. Shanley, L. D. Crouch, M. R. Bleavins, E. M. Younkin, V. Sarma, D. F. Gibbs, W. Tefera, P. C. McConnell, et al. Regulatory Effects of Endogenous Protease Inhibitors in Acute Lung Inflammatory Injury J. Immunol., March 15, 1999; 162(6): 3653 - 3662. [Abstract] [Full Text] [PDF]

				C. Sano, T. Shimizu, K. Sato, H. Kawauchi, S. Kawahara, and H. Tomioka Therapeutic Effects of Benzoxazinorifamycin KRM-1648 Administered Alone or in Combination with a Half-Sized Secretory Leukocyte Protease Inhibitor or the Nonsteroidal Anti-Inflammatory Drug Diclofenac Sodium against Mycobacterium avium Complex Infection in Mice Antimicrob. Agents Chemother., February 1, 1999; 43(2): 360 - 364. [Abstract] [Full Text]

				H. A. JONES, J. B. SCHOFIELD, T. KRAUSZ, A. R. BOOBIS, and C. HASLETT Pulmonary Fibrosis Correlates with Duration of Tissue Neutrophil Activation Am. J. Respir. Crit. Care Med., August 1, 1998; 158(2): 620 - 628. [Abstract] [Full Text] [PDF]

				A. Azuma, T. Furuta, T. Enomoto, Y. Hashimoto, K. Uematsu, N. Nukariya, A. Murata, and S. Kudoh Preventive effect of erythromycin on experimental bleomycin-induced acute lung injury in rats Thorax, March 1, 1998; 53(3): 186 - 189. [Abstract] [Full Text]

				Y. TAOOKA, A. MAEDA, K. HIYAMA, S. ISHIOKA, and M. YAMAKIDO Effects of Neutrophil Elastase Inhibitor on Bleomycin-Induced Pulmonary Fibrosis in Mice Am. J. Respir. Crit. Care Med., July 1, 1997; 156(1): 260 - 265. [Abstract] [Full Text]