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A mechanism for matrikine regulation in acute inflammatory lung injury.
Robison, Sarah W; Li, JinDong; Viera, Liliana; Blackburn, Jonathan P; Patel, Rakesh P; Blalock, J Edwin; Gaggar, Amit; Xu, Xin.
  • Robison SW; Department of Medicine, Division of Pulmonology, Allergy and Critical Care Medicine, and.
  • Li J; Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • Viera L; Department of Medicine, Division of Pulmonology, Allergy and Critical Care Medicine, and.
  • Blackburn JP; Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • Patel RP; Birmingham VA Medical Center, Birmingham, Alabama, USA.
  • Blalock JE; Department of Medicine, Division of Pulmonology, Allergy and Critical Care Medicine, and.
  • Gaggar A; Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • Xu X; Department of Medicine, Division of Pulmonology, Allergy and Critical Care Medicine, and.
JCI Insight ; 6(7)2021 04 08.
Article in English | MEDLINE | ID: covidwho-1383578
ABSTRACT
Proline-glycine-proline (PGP) and its acetylated form (Ac-PGP) are neutrophil chemoattractants generated by collagen degradation, and they have been shown to play a role in chronic inflammatory disease. However, the mechanism for matrikine regulation in acute inflammation has not been well established. Here, we show that these peptides are actively transported from the lung by the oligopeptide transporter, PEPT2. Following intratracheal instillation of Ac-PGP in a mouse model, there was a rapid decline in concentration of the labeled peptide in the bronchoalveolar lavage (BAL) over time and redistribution to extrapulmonary sites. In vitro knockdown of the PEPT2 transporter in airway epithelia or use of a competitive inhibitor of PEPT2, cefadroxil, significantly reduced uptake of Ac-PGP. Animals that received intratracheal Ac-PGP plus cefadroxil had higher levels of Ac-PGP in BAL and lung tissue. Utilizing an acute LPS-induced lung injury model, we demonstrate that PEPT2 blockade enhanced pulmonary Ac-PGP levels and lung inflammation. We further validated this effect using clinical samples from patients with acute lung injury in coculture with airway epithelia. This is the first study to our knowledge to determine the in vitro and in vivo significance of active matrikine transport as a mechanism of modulating acute inflammation and to demonstrate that it may serve as a potential therapeutic target.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Oligopeptides / Proline / Cefadroxil / Symporters / Acute Lung Injury / COVID-19 / Inflammation Type of study: Prognostic study Limits: Animals / Humans Language: English Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Oligopeptides / Proline / Cefadroxil / Symporters / Acute Lung Injury / COVID-19 / Inflammation Type of study: Prognostic study Limits: Animals / Humans Language: English Year: 2021 Document Type: Article