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(Chest. 2001;120:S35-S36.)
© 2001 American College of Chest Physicians

Evidence That Neutrophil Elastase-Deficient Mice Are Resistant to Bleomycin-Induced Fibrosis*

Sarah E. Dunsmore, PhD; Jurgen Roes, PhD; Felix J. Chua, MD; Anthony W. Segal, PhD; Steven E. Mutsaers, PhD and Geoffrey J. Laurent, PhD

* From the Centres for Molecular Medicine (Drs. Roes and Segal) and Respiratory Research (Drs. Dunsmore, Chua, Mutsaers, and Laurent), University College London, London, UK.

Correspondence to: Sarah E. Dunsmore, PhD, Centre for Respiratory Research, The Rayne Institute, University College London Medical School, 5 University St, London WC1E 6JJ, UK; e-mail: s.dunsmore{at}ucl.ac.uk

Pulmonary fibrosis, a disease characterized by excess collagen deposition, may result from a variety of insults to the lung. Despite much progress in understanding the mechanisms of collagen synthesis and deposition in the lung, therapeutic agents for this disease are limited, and prognosis for patients with pulmonary fibrosis remains poor. Theories on the development of pulmonary fibrosis largely center on the hypothesis that in response to injury, inflammatory and immune cells, such as neutrophils, enter the lung and together with activated resident cells, release mediators that induce fibroblasts to proliferate and/or produce excess collagen.1 Indeed, increased numbers of neutrophils have been detected in lung lavage fluid2 and tissue3 from patients with pulmonary fibrosis as well as in animal models of the disease.4

Although neutrophil elastase has long been thought to be a key player in the pathogenesis of pulmonary emphysema,5 it is not commonly thought of as an important molecule in the pathogenesis of pulmonary fibrosis. Neutrophil elastase is present in patients with pulmonary fibrosis,6 7 however, and some evidence does suggest that inhibition of its activity may attenuate development of the disease.8 9 10

We have studied the pathogenesis of pulmonary fibrosis in mice with targeted deletions of the neutrophil elastase gene.11 The intratracheal instillation of bleomycin in mice leads to pulmonary fibrosis with marked increases in total lung collagen. We have used this model to examine collagen deposition by both biochemical and histologic methods. Total lung collagen was measured by high-pressure liquid chromatography analysis of hydroxyproline 30 days after administration of bleomycin (0.05 U/mouse or 0.1 U/mouse) or saline solution (Fig 1 ). In Sv129 wild-type mice, total lung collagen in bleomycin-treated animals was twofold greater than that of saline solution-treated control animals. Total lung collagen in bleomycin-treated neutrophil elastase-deficient mice was not significantly different from that in saline solution-treated animals.



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  		Figure 1. Total lung collagen is not increased in neutrophil elastase-deficient mice. Neutrophil elastase-deficient (NE -/-) or wild-type (WT) mice were intratracheally injected with saline solution, 0.05 U of bleomycin (bleo), or 0.1 U of bleomycin. Total lung collagen was measured by reverse-phase high-pressure liquid chromatography 30 days following bleomycin injection; n = 6 for each treatment group.

 
Histologic analyses included staining with hematoxylin-eosin or Massons trichrome as well as immunohistochemistry with antibodies specific for type I and type IV collagen. Lungs of wild-type animals treated with bleomycin showed many characteristics of interstitial fibrosis with large areas of the distal lung staining positively for collagen. In contrast, lungs of bleomycin-treated neutrophil elastase-deficient mice were characterized by the presence of inflammatory cells and areas of alveolar collapse. Basement membranes, however, appeared intact, and there was little evidence of increased collagen deposition.

We have begun to examine the mechanisms by which neutrophil elastase might participate in the processes leading to activation of matrix-producing cells. Current work focuses on three areas: neutrophil emigration, epithelial damage, and transforming growth factor-ß activation. We anticipate that these studies may aid in the identification of new targets for therapeutic intervention and, in the long term, will lead to more effective treatment of interstitial lung diseases.

Footnotes

Supported by a grant from the Medical Research Council (UK).

References

  1. Coker, RK, Laurent, GJ, Shahzeidi, S, et al (1997) Transforming growth factors-ß1, -ß2, and -ß3 stimulate fibroblast procollagen production in vitro but are differentially expressed during bleomycin-induced lung fibrosis. Am J Pathol 150,981-991[Abstract]
  2. Harrison, NK, McAnulty, RJ, Haslam, PL, et al (1990) Evidence for protein oedema, neutrophil influx, and enhanced collagen production in lungs of patients with systemic sclerosis. Thorax 45,606-610[Abstract]
  3. Obayashi, Y, Yamadori, I, Fujita, J, et al (1997) The role of neutrophils in the pathogenesis of idiopathic pulmonary fibrosis. Chest 112,1338-1343[Abstract/Free Full Text]
  4. Giri, SN, Hyde, DM, Nakashima, JM (1986) Analysis of bronchoalveolar lavage fluid from bleomycin-induced pulmonary fibrosis in hamsters. Toxicol Pathol 14,149-157[Medline]
  5. Snider, GL, Ciccolella, DE, Morris, SM, et al (1991) Putative role of neutrophil elastase in the pathogenesis of emphysema. Ann N Y Acad Sci 624,45-59[Abstract]
  6. Yamonouchi, H, Fujita, J, Hojo, S, et al (1998) Neutrophil elastase: {alpha}1-proteinase inhibitor complex in serum and bronchoalveolar lavage fluid in patients with pulmonary fibrosis. Eur Respir J 11,120-125[Abstract/Free Full Text]
  7. Hojo, S, Fujita, J, Yoshinouchi, T, et al (1997) Hepatocyte growth factor and neutrophil elastase in idiopathic pulmonary fibrosis. Respir Med 91,511-516[CrossRef][ISI][Medline]
  8. Taooka, Y, Maeda, A, Hiyama, K, et al (1997) Effects of neutrophil elastase inhibitor on bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med 156,260-265[Abstract/Free Full Text]
  9. Mitsuhashi, H, Asano, S, Nonake, T, et al (1996) Administration of truncated secretory leukoprotease inhibitor ameliorates bleomycin-induced pulmonary fibrosis in hamsters. Am J Respir Crit Care Med 153,369-374[Abstract]
  10. Nagai, A, Aoshiba, K, Ishihara, Y, et al (1992) Administration of {alpha}1-proteinase inhibitor ameliorates bleomycin-induced pulmonary fibrosis in hamsters. Am Rev Respir Dis 145,651-656[ISI][Medline]
  11. Tkalcevic, J, Novelli, M, Phylactides, M, et al (2000) Impaired immunity and enhanced resistance to endotoxin in the absence of neutrophil elastase and cathepsin G. Immunity 12,210-210



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