CXC chemokines and antagonists in chronic airway inflammation

Chronic inflammation can be caused by a sustained influx of macrophages and neutrophils, which leads to tissue remodeling and collagen breakdown. Recently, we have identified a collagen breakdown product (Proline-Glycine-Proline, PGP) that can activate and attract inflammatory cells via the CXC 1 & 2 receptor. By using a technique called “inverted hydropathy”, a small peptide was synthesized that interact specifically with PGP to inactivate it. We hypothesize that both CXCL8 and PGP might be involved in the continuous recruitment and activation of neutrophils during chronic inflammatory processes, which will lead to an excessive release of proteases and an ongoing PGP formation. PGP generation is a multistep process involving MMP-9,and the serine protease family, prolyl endopeptidase (PE). Proteases, such as MMP-9, proteolytically cleave collagen to smaller fragments and create an optimal substrate for PE. These collagen fragments are then further cleaved to PGP by PE. Data will be presented that the different components involved in this proteolytic cascade generating the chemoattractant PGP are indeed present in the lungs of mice during chronic inflammatory reactions. The peptide that inactivated PGP inhibited neutrophil influx, heart hypertrophy and lung emphysema in animal models and are likely to be useful in other diseases that are characterized by a chronic inflammation such as rheumatoid arthritis and inflammatory bowel diseases where neutrophils are potential target cells. Moreover, inhibitors of PE, like valproic acid, might be a new direction to arrest chronic inflammatory reactions.