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.
Highlights
Acute lung injury (ALI) is a clinical syndrome, with acute respiratory distress syndrome (ARDS) at the severe end of the disease spectrum, defined by bilateral noncardiogenic pulmonary infiltrates with hypoxemic respiratory failure [1]
Labeled Ac-PGP peptide was intratracheally administered to mice, and bronchoalveolar lavage (BAL) was collected at various time points after treatment
The BAL fluid was further analyzed for evidence of neutrophilic inflammation
Summary
Acute lung injury (ALI) is a clinical syndrome, with acute respiratory distress syndrome (ARDS) at the severe end of the disease spectrum, defined by bilateral noncardiogenic pulmonary infiltrates with hypoxemic respiratory failure [1]. This critical illness remains a major cause of morbidity and mortality in the ICU [2, 3]. A key feature of ARDS is proteolytic degradation of the extracellular matrix that leads to organ remodeling and defects in lung ventilation/perfusion [7,8,9]. Matrix-derived bioactive peptides are increasingly appreciated as critical mediators of inflammatory tissue injury in chronic lung disease [12]
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