Fig. 1.

Illustration of the Pro-Gly-Pro (PGP) pathology in neutrophilic inflammation. 1: Cigarette smoke inhalation causes tissue resident cells such as macrophages and epithelial cells to release several mediators, including prolyl endopeptidase (PE), IL-8, leukotriene A₄ hydrolase (LTA₄H), and matrix metalloproteinase (MMP)8/9. 2 and 3: The neutrophilic chemokine IL-8 attracts neutrophils from the capillary via binding with CXCR1/2. 4 and 5: Neutrophils subsequently release MMPs and PE, which cleave collagen from the extracellular matrix to release the tripeptide and neutrophil chemoattractant PGP. LTA₄H can cleave and inactivate PGP. However, components of cigarette smoke, such as acrolein, inhibit LTA₄H and can acetylate the PGP to form the more potent acetylated form of PGP (N-α-PGP). Moreover, N-α-PGP cannot be cleaved by LTA₄H. PGP-generating enzymes can now be released by neutrophils after recruitment and activation by PGP: a self-sustaining neutrophilic inflammation. ROS, reactive oxygen species; P+GP, proline + glycine-proline.