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Am J Respir Cell Mol Biol. 2019 Apr 8. doi: 10.1165/rcmb.2018-0216OC. [Epub ahead of print]

Proline-Glycine-Proline Peptides Are Critical in the Development of Smoke-Induced Emphysema.

Author information

1
Universiteit Utrecht Departement Farmaceutische Wetenschappen, 84898, Utrecht, Netherlands.
2
University of Alabama at Birmingham, 9968, Birmingham, Alabama, United States.
3
UAB, Medicine, Birmingham, Alabama, United States.
4
University of Alabama at Birmingham, 9968, Medicine, Gregory Fleming James Cystic Fibrosis Research Center, Birmingham, Alabama, United States.
5
National Jewish Health, 2930, Denver, Colorado, United States.
6
University of Alabama at Birmingham Department of Medicine, 164494, Birmingham, Alabama, United States.
7
University of Alabama at Birmingham, Pulmonary, Allergy and Critical Care Medicine, Birmingham, Alabama, United States.
8
University of Alabama at Birmingham, 9968, Cell Developmental and Integrative Biology, Cystic Fibrosis Research Center, Birmingham, Alabama, United States.
9
Utrecht University, Pharmaceutical Sciences, Div. Pharmacology, Utrecht, Netherlands.
10
University of Utrecht, Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, Netherlands.
11
University of Alabama at Birmingham, 9968, Birmingham, Alabama, United States ; agaggar@uabmc.edu.

Abstract

Chronic obstructive pulmonary disease (COPD) is a major cause of worldwide mortality and is characterized by an excessive airway neutrophilic response. The neutrophil chemoattractant proline-glycine-proline (PGP) and its more potent acetylated form (acPGP) have been found to be elevated in COPD patients and act via CXCR2. Here, we investigate the impact of neutralizing PGP peptides in a murine model for emphysema. The PGP neutralizing peptide L-arginine-threonine-arginine (RTR) was used first in a 6-week model of cigarette smoke exposure, where it attenuated lung inflammation. Further a chronic cigarette smoke exposure was conducted with mice starting RTR treatment after 10 weeks of smoke exposure and then continuing the treatment together with the smoke exposure during the last 13 weeks, totaling 23 weeks of smoke exposure. RTR significantly inhibited neutrophil and macrophage influx into the lungs in the 6-week model of exposure. RTR also attenuated the development of emphysema, normalized lung volumes, and reduced right ventricular hypertrophy (RVH) in the chronic exposure model. Murine epithelia expressed CXCR2 and this expression was increased after smoke exposure. In vitro, human bronchial epithelial (HBE) cells also demonstrated robust expression for CXCR2 and stimulation of primary HBE cells with acPGP led to increased release of MMP-9 and IL-8. Overall, these results provide evidence for a critical role of acPGP during emphysema development in cigarette smoke-induced injury and highlight a new epithelial mechanism by which acPGP augments neutrophilic inflammation.

KEYWORDS:

ECM fragmentation; copd; emphysema; neutrophils

PMID:
30958968
DOI:
10.1165/rcmb.2018-0216OC

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