Neutrophil elastase promotes myofibroblast differentiation in lung fibrosis.
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.
Departments of *Medicine and Pathology, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; and Division of Pulmonary and Critical Care, University of Washington, Seattle, Washington, USA.
Alyssa D
AD
Gregory
Departments of *Medicine and Pathology, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; and Division of Pulmonary and Critical Care, University of Washington, Seattle, Washington, USA.
Corrine R
CR
Kliment
Departments of *Medicine and Pathology, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; and Division of Pulmonary and Critical Care, University of Washington, Seattle, Washington, USA.
Heather E
HE
Metz
Departments of *Medicine and Pathology, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; and Division of Pulmonary and Critical Care, University of Washington, Seattle, Washington, USA.
Kyoung-Hee
KH
Kim
Departments of *Medicine and Pathology, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; and Division of Pulmonary and Critical Care, University of Washington, Seattle, Washington, USA.
Julia
J
Kargl
Departments of *Medicine and Pathology, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; and Division of Pulmonary and Critical Care, University of Washington, Seattle, Washington, USA.
Brittani A
BA
Agostini
Departments of *Medicine and Pathology, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; and Division of Pulmonary and Critical Care, University of Washington, Seattle, Washington, USA.
Lauren T
LT
Crum
Departments of *Medicine and Pathology, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; and Division of Pulmonary and Critical Care, University of Washington, Seattle, Washington, USA.
Elizabeth A
EA
Oczypok
Departments of *Medicine and Pathology, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; and Division of Pulmonary and Critical Care, University of Washington, Seattle, Washington, USA.
Tim A
TA
Oury
Departments of *Medicine and Pathology, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; and Division of Pulmonary and Critical Care, University of Washington, Seattle, Washington, USA houghton@fhcrc.org.
A McGarry
AM
Houghton
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000276:immunology; D019272:Leukocyte Elastase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D051379:Mice; D058628:Myofibroblasts / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D009504:Neutrophils / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D011656:Pulmonary Emphysema / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019272:Leukocyte Elastase
IRS-1; asbestos; fibroblasts