Pulmonary hypertension (PH) is a disorder characterized by abnormally elevated pulmonary artery (PA) pressures. PH associated with chronic obstructive pulmonary disease (COPD) affects a significant number of patients and is associated with worsened lung function decline, increased frequency of exacerbations, and increased mortality. There are currently no therapies available for treatment of COPD-associated PH and thus new pathways and therapeutic targets are needed to address this critical need. Recent work in our laboratory has identified acetyl-proline-glycine-proline (AcPGP), the end result of cigarette- smoke induced collagen destruction, as a key marker for COPD pathogenesis. PGP acts on inflammatory cells through CXC receptors (CXCR1/2). Signaling through this CXCR2 receptor has been implicated in the development of PH. As an extension, the hypothesis that AcPGP mediates pulmonary vascular endothelial cell dysfunction and serves as a risk factor for the development of PH in COPD will be tested through the following independent but inter-related aims: 1. Study the phenotype and mechanism of COPD-associated PH in murine models of exogenous AcPGP administration 2. Determine the role of the neutrophil and CXCR1/2 in AcPGP mediated pulmonary vascular remodeling 3. Investigate the predictive value of AcPGP levels in the development of pulmonary vascular disease detected by CT in a cohort of COPD patients This project explores new concepts in the pathobiology of COPD-associated PH through PA endothelial cells, a novel animal model of disease, and translates these findings into human disease. This career development plan and the research aims as outlined above are of equal importance. Combined with a strong mentoring committee, additional training in immunology, metabolism, cardiopulmonary physiology, study design, methodology, and statistical analysis will meet Dr. Wells'specific educational needs as a budding academician. The opportunities created by this career development award will result in the creation of a physician-scientist with the skills necessary to accurately and ethically answer important scientific questions related to COPD-associated PH, successfully obtain future independent funding, and make important differences in the lives of patients affected with these devastating illnesses.

Public Health Relevance

Pulmonary hypertension occurs in many patients affected by chronic obstructive pulmonary disease (COPD). These two illnesses coexist through complex interactions between many different pathologic processes and there are no therapies that alter the natural history of these combined diseases. Exploring new pathways involved in the remodeling process may lead to novel therapies for COPD-associated pulmonary hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1)
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Colombini-Hatch, Sandra
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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Wells, J Michael; Morrison, Joshua B; Bhatt, Surya P et al. (2016) Pulmonary Artery Enlargement Is Associated With Cardiac Injury During Severe Exacerbations of COPD. Chest 149:1197-204
Rahaghi, Farbod N; Wells, J Michael; Come, Carolyn E et al. (2016) Arterial and Venous Pulmonary Vascular Morphology and Their Relationship to Findings in Cardiac Magnetic Resonance Imaging in Smokers. J Comput Assist Tomogr 40:948-952
Bhatt, Surya P; Soler, Xavier; Wang, Xin et al. (2016) Association between Functional Small Airway Disease and FEV1 Decline in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 194:178-84
Lee, Jin Hwa; Cho, Michael H; Hersh, Craig P et al. (2015) IREB2 and GALC are associated with pulmonary artery enlargement in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 52:365-76
Wells, J Michael; Gaggar, Amit; Blalock, J Edwin (2015) MMP generated matrikines. Matrix Biol 44-46:122-9
Wells, J Michael; Jackson, Patricia L; Viera, Liliana et al. (2015) A Randomized, Placebo-controlled Trial of Roflumilast. Effect on Proline-Glycine-Proline and Neutrophilic Inflammation in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 192:934-42
Hahn, Cornelia S; Scott, David W; Xu, Xin et al. (2015) The matrikine N-α-PGP couples extracellular matrix fragmentation to endothelial permeability. Sci Adv 1:
Wells, J Michael; Gaggar, Amit; Nicod, Laurent P (2015) A Fragment in Time. Elastin Peptides and Progression of Emphysema. Am J Respir Crit Care Med 192:1141-3
Wells, J Michael; Iyer, Anand S; Rahaghi, Farbod N et al. (2015) Pulmonary artery enlargement is associated with right ventricular dysfunction and loss of blood volume in small pulmonary vessels in chronic obstructive pulmonary disease. Circ Cardiovasc Imaging 8: