Differential responses to targeting matrix metalloproteinase 9 in idiopathic pulmonary fibrosis

Milena S. Espindola, David M. Habiel, Ana Lucia Coelho, Barry Stripp, William C. Parks, Justin Oldham, Fernando J. Martinez, Imre Noth, David Lopez, Amanda Mikels-Vigdal, Victoria Smith, Cory M. Hogaboam

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Rationale: Aberrant lung remodeling in idiopathic pulmonary fibrosis (IPF) is characterized by elevated MMP9 (matrix metalloproteinase 9) expression, but the precise role of this matrix metalloproteinase in this disease has yet to be fully elucidated. Objectives: To evaluate antifibrotic effects of MMP9 inhibition on IPF. Methods: Quantitative genomic, proteomic, and functional analyses both in vitro and in vivo were used to determine MMP9 expression in IPF cells and the effects of MMP9 inhibition on profibrotic mechanisms. Measurements and Main Results: In the present study, we demonstrate that MMP9 expression was increased in airway basal cell (ABC)-like cells from IPF lungs compared with ABC cells from normal lungs. The inhibition of MMP9 activity with an anti-MMP9 antibody, andecaliximab, blocked TGF-b1 (transforming growth factor b1)-induced Smad2 phosphorylation. However, in a subset of cells from patients with IPF, TGF-b1 activation in their ABC-like cells was unaffected or enhanced by MMP9 blockade (i.e., nonresponders). Further analysis of nonresponder ABC-like cells treated with andecaliximab revealed an association with type 1 IFN expression, and the addition of IFNa to these cells modulated both MMP9 expression and TGF-b1 activation. Finally, the inhibition of MMP9 ameliorated pulmonary fibrosis induced by responder lung cells but not a nonresponder in a humanized immunodeficient mouse model of IPF. Conclusions: Together, these data demonstrate that MMP9 regulates the activation of ABC-like cells in IPF and that targeting this MMP might be beneficial to a subset of patients with IPF who show sufficient expression of type 1 IFNs.

Original languageEnglish (US)
Pages (from-to)458-470
Number of pages13
JournalAmerican journal of respiratory and critical care medicine
Volume203
Issue number4
DOIs
StatePublished - Feb 15 2021

Keywords

  • Airway basal cells
  • Andecaliximab
  • Idiopathic pulmonary fibrosis
  • Metalloproteinase 9
  • Type I IFNs

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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