Browsing by Subject "emphysema"

Now showing 1 - 5 of 5
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    DNA Repair as an Emerging Target for COPD-Lung Cancer Overlap
    (Elsevier, 2019-03) Sears, Catherine R.; Medicine, School of Medicine
    Cigarette smoking is the leading cause of lung cancer and chronic obstructive pulmonary disease (COPD). Many of the detrimental effects of cigarette smoke have been attributed to the development of DNA damage, either directly from chemicals contained in cigarette smoke or as a product of cigarette smoke-induced inflammation and oxidative stress. In this review, we discuss the environmental, epidemiological, and physiological links between COPD and lung cancer and the likely role of DNA damage and repair in COPD and lung cancer development. We explore alterations in DNA damage repair by DNA repair proteins and pathways. We discuss emerging data supporting a key role for the DNA repair protein, xeroderma pigmentosum group C (XPC), in cigarette smoke-induced COPD and early lung cancer development. Understanding the interplay between cigarette smoke, DNA damage repair, COPD, and lung cancer may lead to prognostic tools and new, potentially targetable, pathways for lung cancer prevention and treatment.
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    EMPHYMAB BIOTECH, MEDICAL THERAPIES FOR EMPHYSEMA
    (Office of the Vice Chancellor for Research, 2013-04-05) Johnstone, Brian; Claus, Matthias; Petrache, Irina
    Emphymab™ Biotech was formed to develop and commercialize medical therapies that address serious lung diseases. The founders are scientists and clinicians at Indiana University School of Medicine. Emphymab’s lead technology is based on a novel monoclonal antibody that inactivates a newly discovered pathway involved in lung diseases and, thereby, halts progressive loss of lung function associated with emphysema. This technology has the potential to address the huge unmet medical need of patients suffering from chronic obstructive pulmonary disease (COPD) with emphysema, which is the 3rd leading cause of death worldwide.
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    HIV envelope protein gp120-induced apoptosis in lung microvascular endothelial cells by concerted upregulation of EMAP II and its receptor, CXCR3
    (American Physiological Society (APS), 2014-02-15) Green, Linden A.; Yi, Ru; Petrusca, Daniela; Wang, Ting; Elghouche, Alhasan; Gupta, Samir K.; Petrache, Irina; Clauss, Matthias; Department of Cellular & Integrative Physiology, IU School of Medicine
    Chronic lung diseases, such as pulmonary emphysema, are increasingly recognized complications of infection with the human immunodeficiency virus (HIV). Emphysema in HIV may occur independent of cigarette smoking, via mechanisms that are poorly understood but may involve lung endothelial cell apoptosis induced by the HIV envelope protein gp120. Recently, we have demonstrated that lung endothelial apoptosis is an important contributor to the development of experimental emphysema, via upregulation of the proinflammatory cytokine endothelial monocyte-activating polypeptide II (EMAP II) in the lung. Here we investigated the role of EMAP II and its receptor, CXCR3, in gp120-induced lung endothelial cell apoptosis. We could demonstrate that gp120 induces a rapid and robust increase in cell surface expression of EMAP II and its receptor CXCR3. This surface expression occurred via a mechanism involving gp120 signaling through its CXCR4 receptor and p38 MAPK activation. Both EMAP II and CXCR3 were essentially required for gp120-induced apoptosis and exposures to low gp120 concentrations enhanced the susceptibility of endothelial cells to undergo apoptosis when exposed to soluble cigarette smoke extract. These data indicate a novel mechanism by which HIV infection causes endothelial cell loss involved in lung emphysema formation, independent but potentially synergistic with smoking, and suggest therapeutic targets for emphysema prevention and/or treatment.
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    HIV-Nef Protein Persists in the Lungs of Aviremic Patients with HIV and Induces Endothelial Cell Death
    (ATS, 2019-03) Chelvanambi, Sarvesh; Bogatcheva, Natalia V.; Bednorz, Mariola; Agarwal, Stuti; Maier, Bernhard; Alves, Nathan J.; Li, Wei; Syed, Farooq; Saber, Manal M.; Dahl, Noelle; Lu, Hongyan; Day, Richard B.; Smith, Patricia; Jolicoeur, Paul; Yu, Qigui; Dhillon, Navneet K.; Weissmann, Norbert; Twigg, Homer L., III; Clauss, Matthias; Medicine, School of Medicine
    It remains a mystery why HIV-associated end-organ pathologies persist in the era of combined antiretroviral therapy (ART). One possible mechanism is the continued production of HIV-encoded proteins in latently HIV-infected T cells and macrophages. The proapoptotic protein HIV-Nef persists in the blood of ART-treated patients within extracellular vesicles (EVs) and peripheral blood mononuclear cells. Here we demonstrate that HIV-Nef is present in cells and EVs isolated from BAL of patients on ART. We hypothesize that HIV-Nef persistence in the lung induces endothelial apoptosis leading to endothelial dysfunction and further pulmonary vascular pathologies. The presence of HIV-Nef in patients with HIV correlates with the surface expression of the proapoptotic endothelial-monocyte–activating polypeptide II (EMAPII), which was implicated in progression of pulmonary emphysema via mechanisms involving endothelial cell death. HIV-Nef protein induces EMAPII surface expression in human embryonic kidney 293T cells, T cells, and human and mouse lung endothelial cells. HIV-Nef packages itself into EVs and increases the amount of EVs secreted from Nef-expressing T cells and Nef-transfected human embryonic kidney 293T cells. EVs from BAL of HIV+ patients and Nef-transfected cells induce apoptosis in lung microvascular endothelial cells by upregulating EMAPII surface expression in a PAK2-dependent fashion. Transgenic expression of HIV-Nef in vascular endothelial–cadherin+ endothelial cells leads to lung rarefaction, characterized by reduced alveoli and overall increase in lung inspiratory capacity. These changes occur concomitantly with lung endothelial cell apoptosis. Together, these data suggest that HIV-Nef induces endothelial cell apoptosis via an EMAPII-dependent mechanism that is sufficient to cause pulmonary vascular pathologies even in the absence of inflammation.
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    Structural Changes of Alpha 1-Antitrypsin under Osmotic Pressure and in the Presence of Lipid Membranes
    (Poster session presented at IUPUI Research Day 2013, Indianapolis, Indiana., 2013-04-05) Palacio, Luis A.; Stanley, Christopher B.; Fraser, Andrew K.; Johnson, Merrell A.; Petrache, Horia I.
    Alpha 1-Antitrypsin (A1AT) is a glycoprotein that has been shown to have protective roles of lung cells against emphysema, a disease characterized by lung tissue destruction. Most known glycoproteins have been shown to play a role in cellular interactions but the exact role of the glycan chains is still under investigation. Previous electrophysiological measurements show that A1AT has a strong affinity to lipid bilayers perturbing the function of ion channels present in the membrane. We have performed contrastmatching small-angle neutron scattering (SANS) experiments to study the conformational changes of the glycosylated form of A1AT for different concentrations of the osmolyte poly(ethelene glycol) (PEG) and in the presence of two different lipid membranes: POPC and POPS. We also monitor the structural changes of the lipid vesicles in the presence of A1AT by SANS. Guinier fits were used as a first approximation to obtain the radius of gyration (Rg) of A1AT. Bragg peaks were used to study structural changes of lipid vesicles. We observed that the Rg of A1AT changes as a function of PEG concentration in solution and when in the presence of lipid vesicles. The deformations monitored through changes in A1AT’s Rg in the presence of lipid vesicles are compared to the deformations of the glycoprotein observed under osmotic pressure and to the structural changes observed in the lipid vesicles.