Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Angiotensin-converting enzyme defines matrikine-regulated inflammation and fibrosis
Philip J. O’Reilly, … , Robert J. Snelgrove, J. Edwin Blalock
Philip J. O’Reilly, … , Robert J. Snelgrove, J. Edwin Blalock
Published November 16, 2017
Citation Information: JCI Insight. 2017;2(22):e91923. https://doi.org/10.1172/jci.insight.91923.
View: Text | PDF
Research Article Pulmonology

Angiotensin-converting enzyme defines matrikine-regulated inflammation and fibrosis

  • Text
  • PDF
Abstract

The neutrophil chemoattractant proline-glycine-proline (PGP) is generated from collagen by matrix metalloproteinase-8/9 (MMP-8/9) and prolyl endopeptidase (PE), and it is concomitantly degraded by extracellular leukotriene A4 hydrolase (LTA4H) to limit neutrophilia. Components of cigarette smoke can acetylate PGP, yielding a species (AcPGP) that is resistant to LTA4H-mediated degradation and can, thus, support a sustained neutrophilia. In this study, we sought to elucidate if an antiinflammatory system existed to degrade AcPGP that is analogous to the PGP-LTA4H axis. We demonstrate that AcPGP is degraded through a previously unidentified action of the enzyme angiotensin-converting enzyme (ACE). Pulmonary ACE is elevated during episodes of acute inflammation, as a consequence of enhanced vascular permeability, to ensure the efficient degradation of AcPGP. Conversely, we suggest that this pathway is aberrant in chronic obstructive pulmonary disease (COPD) enabling the accumulation of AcPGP. Consequently, we identify a potentially novel protective role for AcPGP in limiting pulmonary fibrosis and suggest the pathogenic function attributed to ACE in idiopathic pulmonary fibrosis (IPF) to be a consequence of overzealous AcPGP degradation. Thus, AcPGP seemingly has very divergent roles: it is pathogenic in its capacity to drive neutrophilic inflammation and matrix degradation in the context of COPD, but it is protective in its capacity to limit fibrosis in IPF.

Authors

Philip J. O’Reilly, Qiang Ding, Samia Akthar, Guoqiang Cai, Kristopher R. Genschmer, Dhiren F. Patel, Patricia L. Jackson, Liliana Viera, Mojtaba Roda, Morgan L. Locy, Ellen A. Bernstein, Clare M. Lloyd, Kenneth E. Bernstein, Robert J. Snelgrove, J. Edwin Blalock

×

Figure 1

An extracellular enzymatic activity that degrades AcPGP.

Options: View larger image (or click on image) Download as PowerPoint
An extracellular enzymatic activity that degrades AcPGP.
Tissue homogena...
Tissue homogenates (A) or BALF and serum (B) from naive Balb/c mice were incubated with AcPGP, and degradation was assessed after 24 hours by mass spectrometry. (C and D) Serum from naive lta4h–/– mice and littermate controls was incubated with AcPGP and degradation assessed at multiple time points by mass spectrometry (C) or release of free proline (D). Serum from naive Balb/c mice was heat inactivated (HI) for 10 min at 100°C (E) or preincubated with selective inhibitors (all at 1 μM) for 30 min at 37°C (F) prior to incubation with AcPGP. Degradation of AcPGP was subsequently assessed by mass spectrometry (E and F). A and B are from 4 mice/group and representative of 3 experiments. C–F are triplicates and representative of 2 independent studies. Results depicted as mean ± SEM. *P < 0.05 or **P < 0.01 using Mann–Whitney statistical test (A, B, and E) or Kruskal-Wallis with Dunn’s post test (F).

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts