This proposal describes a 5 year mentored training program to provide the candidate with intensive training in the areas of chronic neutrophilic inflammation, matrix destruction and pathogenesis of chronic obstructive pulmonary disease (COPD) which will facilitate his development as an independent investigator. The candidate will be mentored by J. Edwin Blalock PhD and William Bailey, MD who are recognized leaders in immunology and COPD and by a research advisory committee. He will pursue a program of education by completing a Masters of Science degree, attending conferences and seminars and additional professional development activities. The Departments of Medicine and Physiology &Biophysics at UAB provide the ideal environment for training physician-scientists by combining state of the art research facilities, excellent career development resources and a broad clinical base. The candidate will engage in a research project studying a new pathway signaling neutrophil (PMN) influx and damage to the airways that may play a role in COPD. Enzymatic breakdown of collagen releases a tripeptide PGP (Pro-Gly-Pro) that is chemotactic for PMN in vitro and in vivo. PGP is found in the airways of animals exposed to aerosolized IPS and markedly contributes to PMN influx. The enzymatic production of PGP is a stepwise process initially involving matrix metalloproteases with prolyl endopeptidase (PE) catalyzing the final reaction. PGP is present in bronchoalveolar lavage fluids and sputum from virtually all COPD patients but not controls or asthmatics. Sputum from COPD patients but not controls can generate PGP ex vivo from collagen and such PGP production is blocked by the PE inhibitor, ZPP. Collectively, these findings lead us to hypothesize that PGP and PE represent novel biomarkers for COPD that may contribute to disease as well as attractive therapeutic targets in these disorders. In this proposal, we will explore the importance of PE in neutrophilic lung inflammation using a mouse model of acute LPS-induced lung disease. We will identify the pro-inflammatory cytokines and cells responsible for generation of PE in this model. In addition, we will evaluate PGP and PE as novel biomarkers and therapeutic targets for COPD. Lay statement: This research will seek to develop new therapies for COPD, a common and debilitating lung disease caused by smoking for which there are few effective treaments.
Chronic obstructive pulmonary disease (COPD) is caused by cigarette smoking and is a major public health problem in the United States and worldwide. COPD is frequently misdiagnosed or diagnosed at an advanced stage when options for treatment and prevention are limited. In this grant, we are studying fragments of collagen generated by the action of inflammatory cells in the lung which we believe are important in the development of COPD. Detecting and inhibiting these fragments may produce new methods for the early diagnosis and treatment of this devastating disease.
|Wells, J Michael; O'Reilly, Philip J; Szul, Tomasz et al. (2014) An aberrant leukotriene A4 hydrolase-proline-glycine-proline pathway in the pathogenesis of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 190:51-61|
|O'Reilly, Philip J; Jackson, Patricia L; Wells, J Michael et al. (2013) Sputum PGP is reduced by azithromycin treatment in patients with COPD and correlates with exacerbations. BMJ Open 3:e004140|
|O'Reilly, Philip J; Hardison, Matthew T; Jackson, Patricia L et al. (2009) Neutrophils contain prolyl endopeptidase and generate the chemotactic peptide, PGP, from collagen. J Neuroimmunol 217:51-4|
|O'Reilly, Philip J; Gaggar, Amit; Blalock, J Edwin (2008) Interfering with extracellular matrix degradation to blunt inflammation. Curr Opin Pharmacol 8:242-8|