We have described what some have called a paradigm shifting pathway of neutrophilic inflammation which, unlike the "classic" mode associated with IL-8 and other chemokines, can become self propagating in chronic inflammatory diseases such as chronic obstructive pulmonary disease (COPD). Specifically, IL-8 initiates neutrophil (PMN) influx, the PMNs in turn release matrix metallo-proteases (MMPs) and prolyl endopeptidase (PE) which degrade collagen and generate the PMN-specific matrikine, proline-glycine-proline (PGP). PGP then propagates further PMN influx and neutrophilic inflammation after IL-8 has subsided. In more common acute inflammatory circumstances, the PGP pathway is terminated by the aminopeptidase activity of leukotriene A4 hydrolase (LTA4H) which cleaves and inactivates PGP. Cigarette smoking (CS) can cause the PGP pathway to become self propagating and disease provoking by direct and indirect inhibitory effects on LTA4H. CS can chemically modify and inactivate LTA4H's triaminopeptidase (TAP) but not hydrolase activity as well as acetylate PGP which renders it immune to LTA4H degradation and markedly increases the chemotactic activity of the tri-peptide. Once a chronic inflammatory environment is established, elevated acetyl PGP (N--PGP) levels then persist in COPD even after smoking cessation. We believe this persistence is driven by endogenously produced reactive aldehydes, such as acrolein and acetaldehyde, which can acetylate PGP as well as inactivate the aminopeptidase but not hydrolase activity of LTA4H. In a recently completed ancillary study to the COPD Clinical Research Network (CCRN) Macrolide trial, we have observed substantially lower levels of N--PGP in the azithromycin-treated group, which had a lower exacerbation frequency, as compared to placebo-treated individuals. This has led to the main thesis of this project that elevated N--PGP levels may be associated with COPD exacerbations and may define a subpopulation of COPD patients that are frequent exacerbators. The Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort represents an unprecedented opportunity to correlate PGP and LTA4H in sputum, plasma, and urine of COPD patients with numerous disease parameters, in particular exacerbations, degree of emphysema and disease progression. This proposal will also test whether aberrant LTA4H TAP activity continues in COPD even after smoking cessation and whether this defect is associated with PGP levels. Lastly, the study will correlate baseline sputum PGP levels with those of plasma and urine. Plasma and urine will then be used to study PGP levels longitudinally in the SPIROMICS cohort to assess changes with time that may associate with COPD subpopulations and/or with parameters of disease.
We have discovered a means by which smoking and COPD can prevent a natural mechanism that controls lung inflammation by degrading the neutrophil chemokine, PGP. In doing so, chronic PGP-mediated inflammation occurs and contributes to COPD. We are evaluating whether perturbations of this system and increased PGP levels are biomarkers for COPD exacerbations and disease progression.
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