Fibrotic Lung Disease Alters Neutrophil Trafficking and Promotes Neutrophil Elastase and Extracellular Trap Release.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible disease characterized by collagen deposition within the interstitium of the lung. This impairs gas exchange and results in eventual respiratory failure. Clinical studies show a correlation between elevated neutrophil numbers and IPF disease progression; however, the mechanistic roles neutrophils play in this disease are not well described. In the present study, we describe alterations to the trafficking and function of neutrophils after the development of fibrosis. We observed increased numbers of total and aged neutrophils in peripheral tissues of fibrotic mice. This appeared to be driven by an upregulation of neutrophil chemokine Cxcl2 by lung cells. In addition, neutrophil recruitment back to the bone marrow for clearance appeared to be impaired, because we saw decreased aged neutrophils in the bone marrow of fibrotic mice. Neutrophils in fibrosis were activated, because ex vivo assays showed increased elastase and extracellular trap release by neutrophils from fibrotic mice. This likely mediated disease exacerbation, because mice exhibiting a progressive disease phenotype with greater weight loss and mortality had more activated neutrophils and increased levels of extracellular DNA present in their lungs than did mice with a nonprogressive disease phenotype. These findings further our understanding of the dynamics of neutrophil populations and their trafficking in progressive fibrotic lung disease and may help inform treatments targeting neutrophil function for patients with IPF experiencing disease exacerbation in the future.

• Authors: Helen I Warheit-Niemi, Gabrielle P Huizinga, Summer J Edwards, Yizhou Wang, Susan K Murray, David N O'Dwyer, Bethany B Moore
• Journal: ImmunoHorizons (Immunohorizons) Vol. 6 Issue 12 Pg. 817-834 (12 01 2022) ISSN: 2573-7732 [Electronic] United States
• PMID: 36534439 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2022 The Authors.

Chemical References

• Leukocyte Elastase

Topics

• Animals
• Mice
• Neutrophils
• Leukocyte Elastase
• Extracellular Traps
• Fibrosis
• Idiopathic Pulmonary Fibrosis
• Disease Progression