This project will facilitate the development of the principal investigator into an independent translational researcher investigating systemic vascular injury in Chronic obstructive pulmonary disease (COPD). This will be accomplished in the rich academic environment at the University of Pittsburgh, under the guidance of a highly accomplished team of mentors, and in the conduct of multidisciplinary research project that will develop autoimmunity as a novel mechanism for atherosclerosis in COPD. The increased risk of atherosclerosis in COPD is not explained by smoking, age, hypertension, and other established vascular disease risk factors. Chronic inflammation has recently been implicated as an atherogenic mechanism in COPD. We and others have reported that chronic inflammation in COPD may be propagated by humoral autoimmunity. Specifically, smokers with COPD have greatly increased levels of circulating autoantibodies that demonstrate in vitro pathogenic effects. Our subsequent studies also show that these autoantibodies target at least 50 different autoantigens and consistently target glucose regulated protein 78 (GRP78), particularly in patients with parenchymal lung destruction, i.e. emphysema. GRP78 is present in the endoplasmic reticulum, where it regulates the unfolded protein response, and is also a multifunction cell surface receptor. Studies in cancer patients suggest that ligation of the N-terminus of cell surface GRP78 by anti-GRP78 IgG transduces pro-inflammatory and pro-proliferative signals by activation of the AKT pathway, followed by NF?B activation. Additional in vivo studies have identified anti-GRP78 IgG with affinity for the C-terminus of cell surface GRP78 that produce counteracting anti-inflammatory effects by suppressing AKT activation. Our preliminary work shows that circulating anti-GRP78 IgG in COPD patients binds to macrophages and leads to increased NF?B activation and production of atherogenic inflammatory mediators by them. The macrophage is critical in the development of both atherosclerosis and COPD. Also, cross-sectional studies in our cohort find that levels of circulating anti-GRP78 IgG are strongly associated with carotid atherosclerosis in patients with emphysema, independent of established vascular risk factors. Therefore, we hypothesize that autoimmune responses against GRP78 are a mechanism for atherosclerosis in COPD. During this award, we will: (1) Test the hypothesis that elevated levels of circulating anti-GRP78 IgG predict progression of carotid atherosclerosis in patients with emphysema independent of established risk factors over 4 year follow up; (2) Test the hypothesis that anti-GRP78 IgG binds to the N-terminus of cell surface GRP78 and activates the AKT pathway followed by NF?B activation and production of inflammatory mediators using a variety of cell function assays, and provide proof of concept for two potential therapeutic strategies; (3) Test the hypothesis that there are other antigen-specific immune responses associated with atherosclerosis in COPD by using machine learning to analyze high-throughput data on a large number of circulating autoantibody levels.

Public Health Relevance

Chronic obstructive pulmonary disease (COPD) is a lung disease caused by smoking that kills more and more Americans each year, and is now the third leading cause of death in the US. Although it is largely viewed as a disease of the lungs, the most common cause of death in patients with COPD are blockages in blood vessels. This research project will investigate why patients with COPD are so prone to develop these blood vessel blockages.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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NHLBI Mentored Patient-Oriented Research Review Committee (MPOR)
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Tigno, Xenia
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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Ajala, Oluremi; Zhang, Yingze; Gupta, Aman et al. (2018) Decreased serum TRAIL is associated with increased mortality in smokers with comorbid emphysema and coronary artery disease. Respir Med 145:21-27
Chandra, Divay; Palevsky, Paul; Sciurba, Frank C (2017) EnRAGEed Kidneys in Chronic Obstructive Pulmonary Disease? Am J Respir Crit Care Med 195:1411-1413
Chandra, Divay; Gupta, Aman; Leader, Joseph K et al. (2017) Assessment of coronary artery calcium by chest CT compared with EKG-gated cardiac CT in the multicenter AIDS cohort study. PLoS One 12:e0176557