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Biochem Biophys Res Commun. 2019 Oct 1;517(4):691-696. doi: 10.1016/j.bbrc.2019.07.111. Epub 2019 Aug 7.

Benzyloxycarbonyl-proline-prolinal (ZPP): Dual complementary roles for neutrophil inhibition.

Author information

1
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Lung Health Center, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA. Electronic address: dwrussell@uabmc.edu.
2
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Lung Health Center, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
3
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Gregory Fleming James Cystic Fibrosis Research Center, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
4
Department of Pediatrics, National Jewish Health, Denver, CO, 80206, USA.
5
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Gregory Fleming James Cystic Fibrosis Research Center, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Division of Pharmacology, Utrecht Institute for Pharmaceutical Science, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
6
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Gregory Fleming James Cystic Fibrosis Research Center, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
7
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Lung Health Center, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Gregory Fleming James Cystic Fibrosis Research Center, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
8
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Lung Health Center, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Program in Protease and Matrix Biology, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Gregory Fleming James Cystic Fibrosis Research Center, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
9
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Lung Health Center, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Program in Protease and Matrix Biology, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Gregory Fleming James Cystic Fibrosis Research Center, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Medical Service, Birmingham VA Medical Center Birmingham, AL, 35294, USA.
10
University of Montevallo, Montevallo, AL, 35115, USA.

Abstract

Neutrophil influx and activation contributes to organ damage in several major lung diseases. This inflammatory influx is initiated and propagated by both classical chemokines such as interleukin-8 and by downstream mediators such as the collagen fragment cum neutrophil chemokine Pro-Gly-Pro (PGP), which share use of the ELR + CXC receptor family. Benzyloxycarbonyl-proline-prolinal (ZPP) is known to suppress the PGP pathway via inhibition of prolyl endopeptidase (PE), the terminal enzyme in the generation of PGP from collagen. However, the structural homology of ZPP and PGP suggests that ZPP might also directly affect classical glutamate-leucine-arginine positive (ELR+) CXC chemokine signaling. In this investigation, we confirm that ZPP inhibits PE in vitro, demonstrate that ZPP inhibits both ELR + CXC and PGP-mediated chemotaxis in human and murine neutrophils, abrogates neutrophil influx induced by murine intratracheal challenge with LPS, and attenuates human neutrophil chemotaxis to sputum samples of human subjects with cystic fibrosis. Cumulatively, these data demonstrate that ZPP has dual, complementary inhibitory effects upon neutrophil chemokine/matrikine signaling which make it an attractive compound for clinical study of neutrophil inhibition in conditions (such as cystic fibrosis and chronic obstructive pulmonary disease) which evidence concurrent harmful increases of both chemokine and matrikine signaling.

KEYWORDS:

Benzyloxycarbonyl-proline-prolinal; COPD; CXCR; PGP; Prolyl-endopeptidase; ZPP

PMID:
31400851
DOI:
10.1016/j.bbrc.2019.07.111
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