title: The matrikine N-α-PGP couples extracellular matrix fragmentation to endothelial permeability.
abstract: The compartmentalization and transport of proteins and solutes across the endothelium is a critical biologic function altered during inflammation and disease, leading to pathology in multiple disorders. The impact of tissue damage and subsequent extracellular matrix (ECM) fragmentation in regulating this process is unknown. We demonstrate that the collagen-derived matrikine acetylated proline-glycine-proline (N-α-PGP) serves as a critical regulator of endothelial permeability. N-α-PGP activates human endothelial cells via CXC-chemokine receptor 2 (CXCR2), triggering monolayer permeability through a discrete intracellular signaling pathway. In vivo, N-α-PGP induces local vascular leak after subcutaneous administration and pulmonary vascular permeability after systemic administration. Furthermore, neutralization of N-α-PGP attenuates lipopolysaccharide-induced lung leak. Finally, we demonstrate that plasma from patients with acute respiratory distress syndrome (ARDS) induces VE-cadherin phosphorylation in human endothelial cells, and this activation is attenuated by N-α-PGP blockade with a concomitant improvement in endothelial monolayer impedance. These results identify N-α-PGP as a novel ECM-derived matrikine regulating paracellular permeability during inflammatory disease and demonstrate the potential to target this ligand in various disorders characterized by excessive matrix turnover and vascular leak such as ARDS.
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA ; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Cornelia S
authors.initials: CS
authors.lastname: Hahn
authors.affiliation: Department of Cell Biology and Physiology, and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA ; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA ; Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA ; Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3508 TB Utrecht, Netherlands.
authors.forename: Mojtaba Abdul
authors.initials: MA
authors.lastname: Roda
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Payne
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA ; Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA ; Lung Health Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA ; Medical Service at Birmingham VA Medical Center, Birmingham, AL 35233, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Wells
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA ; Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Liliana
authors.initials: L
authors.lastname: Viera
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Colleen J
authors.initials: CJ
authors.lastname: Winstead
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA ; Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Preston
authors.initials: P
authors.lastname: Bratcher
authors.affiliation: Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3508 TB Utrecht, Netherlands.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Sparidans
authors.affiliation: Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3508 TB Utrecht, Netherlands.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Redegeld
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA ; Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA ; Lung Health Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Jackson
authors.affiliation: Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3508 TB Utrecht, Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Folkerts
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA ; Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA ; Lung Health Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA ; Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: J Edwin
authors.initials: JE
authors.lastname: Blalock
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA ; Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Rakesh P
authors.initials: RP
authors.lastname: Patel
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA ; Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA ; Lung Health Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA ; Medical Service at Birmingham VA Medical Center, Birmingham, AL 35233, USA ; Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Gaggar