*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: firstname.lastname@example.org
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.1Indeed,
increased numbers of neutrophils have been detected in lung lavage
fluid2and tissue3from patients with
pulmonary fibrosis as well as in animal models of the
Although neutrophil elastase has long been thought to be a key player
in the pathogenesis of pulmonary emphysema,5it 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
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.
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-β
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
Supported by a grant from the Medical Research Council (UK).
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