Therapeutic neutralization of the matrikine PGP suppresses the development of lung emphysema in cigarette smoke exposed mice

Abstract

COPD is a major cause of mortality worldwide, mainly caused by cigarette smoking and driven by an excessive neutrophilic response. The matrikine ac-pro-gly-pro (acPGP) is derived from collagen and is chemotactic to neutrophils by acting on CXC receptor 2 (CXCR2). The PGP neutralizing peptide L-arg-thr-arg (RTR) was used in a 23 weeks cigarette smoke exposure (CSE) murine model. Mice started the RTR treatment after 10 weeks of CSE and continued the treatment together with the CSE during the last 13 weeks. RTR significantly inhibited neutrophil and macrophage influx into the lungs as seen in the broncho alveolar lavage fluid(Fig 1). Furthermore, mice receiving RTR during the last 13 weeks did not develop an emphysema phenotype and less right ventricular hypertrophy , compared to controls. Finally, in vitro experiments using primary human bronchial epithelial (HBE) cells from healthy individuals or COPD patients were carried out. Pretreatment of the cells with cigarette smoke extract and stimulated with acPGP resulted in a higher CXCR2 protein signal in the COPD cells. Also, acPGP facilitated the release of MMP-9 and interleukine-8 from primary HBE cells, thereby highlighting a new mechanism for acPGP to augment neutrophilic inflammation. Our data strongly underscore an important role for acPGP in the development of the emphysema and epithelial cell dysfunction in COPD.