Neutrophil elastase promotes myofibroblast differentiation in lung fibrosis

J Leukoc Biol. 2015 Aug;98(2):143-52. doi: 10.1189/jlb.3HI1014-493R. Epub 2015 Mar 5.


IPF is a progressive lung disorder characterized by fibroblast proliferation and myofibroblast differentiation. Although neutrophil accumulation within IPF lungs has been negatively correlated with outcomes, the role played by neutrophils in lung fibrosis remains poorly understood. We have demonstrated previously that NE promotes lung cancer cell proliferation and hypothesized that it may have a similar effect on fibroblasts. In the current study, we show that NE(-/-) mice are protected from asbestos-induced lung fibrosis. NE(-/-) mice displayed reduced fibroblast and myofibroblast content when compared with controls. NE directly both lung fibroblast proliferation and myofibroblast differentiation in vitro, as evidenced by proliferation assays, collagen gel contractility assays, and αSMA induction. Furthermore, αSMA induction occurs in a TGF-β-independent fashion. Treatment of asbestos-recipient mice with ONO-5046, a synthetic NE antagonist, reduced hydroxyproline content. Thus, the current study points to a key role for neutrophils and NE in the progression of lung fibrosis. Lastly, the study lends rationale to use of NE-inhibitory approaches as a novel therapeutic strategy for patients with lung fibrosis.

Keywords: IRS-1; asbestos; fibroblasts.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Disease Models, Animal
  • Gene Expression Regulation
  • Humans
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / immunology
  • Leukocyte Elastase / genetics
  • Leukocyte Elastase / immunology
  • Leukocyte Elastase / metabolism*
  • Lung / enzymology*
  • Lung / immunology
  • Lung / pathology
  • Mice
  • Myofibroblasts / enzymology*
  • Myofibroblasts / immunology
  • Myofibroblasts / pathology
  • Neutrophils / enzymology*
  • Neutrophils / immunology
  • Neutrophils / pathology
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / immunology
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / immunology
  • Pulmonary Emphysema / enzymology*
  • Pulmonary Emphysema / genetics
  • Pulmonary Emphysema / immunology
  • Pulmonary Emphysema / pathology
  • Pulmonary Fibrosis / enzymology*
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / immunology
  • Pulmonary Fibrosis / pathology
  • Signal Transduction


  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Leukocyte Elastase