Therapeutics for Chronic Lung Diseases: Antagonists of PGP, Chemokines and CXCR

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In this proposal, we describe a new pathway signaling PMN influx and damage to the airways that may play a role as an initiator or cofactor for chronic obstructive pulmonary disease (COPD). Specifically, chemical or enzymatic breakdown of collagen releases a tripeptide, PGP, and/or a related PGP-containing sequence that is chemotactic for PMN in vitro. We demonstrate that introduction of PGP into the airways causes a robust influx of PMN, but not monocytes. Remarkably, the PMN chemotactic activity of PGP may be due to a marked structural relatedness to a receptor binding domain of CXC chemokines such as IL-8 which contain this collagen sequence or a close analog. Prolonged airway exposure to this peptide causes alveolar enlargement and right ventricular hypertrophy and thus recapitulates aspects of COPD. Furthermore, using electrospray ionization-liquid chromatography-mass spectrometry (ESI-LC-MS/MS), PGP is found in the airways of animals exposed to aerosolized LPS and markedly contributes to PMN influx. We have converted PGP from a CXC receptor (R) agonist to a partial agonist and finally an antagonist by systematically exchanging L with D isomers of P on the N and/or C termini. (D-P)G(D-P) antagonizes PGP as well as IL-8 chemotactic activity in vitro. We have found that PGP is present in bronchoalveolar lavage fluids (BALF) and/or sputum from virtually all COPD patients but not controls or asthmatics. Furthermore, sputum from COPD patients but not control individuals contains all the enzymatic machinery necessary for the ex vivo generation of PGP from purified collagen. Collectively, these findings lead us to hypothesize that PGP represents a novel biomarker for COPD that may contribute to disease. As a corollary, we theorize that PGP represents an attractive therapeutic target in COPD. These hypotheses will be tested via a multidisciplinary, multifaceted approach to develop (D-P)G(D-P) as a new therapeutic that will simultaneously inhibit both the IL- 8 and PGP pathways of neutrophilic inflammation and, consequently, may be useful in the management of COPD. In addition, we will evaluate PGP as a novel biomarker for COPD as well as a prognosticator of potential utility of (D-P)G(D-P) as a therapeutic agent.