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Pulmonary Arterial Hypertension and Oxidative Stress

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Studies on Respiratory Disorders

Abstract

Pulmonary arterial hypertension (PAH) is a severe disease characterized by pulmonary vascular remodeling, increased pulmonary vascular resistance (PVR), progressive arterial stiffening, and ultimately right ventricular (RV) failure and death. Despite state-of-the-art therapy and recent advances in our understanding of the molecular mechanisms and genetic determinants of disease, morbidity and mortality remain unacceptably high. Vascular remodeling in PAH is characterized by endothelial dysfunction with release of vasoactive mediators, growth factors, and cytokines; smooth muscle cell hyperplasia and hypertrophy with medial wall thickening; and adventitial fibroblast proliferation, extracellular matrix deposition, and myofibroblast differentiation. Growing evidence through animal and human studies suggests that oxidative stress plays a key role in the pathogenesis of PAH. Oxidative stress in PAH is associated with increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), decreased nitric oxide (NO) levels, and mitochondrial dysfunction. Dysregulation of ROS/RNS/NO homeostasis can impair vascular tone and lead to activation of antiapoptotic and pro-proliferative signaling pathways resulting in aberrant vascular remodeling in the lung. Increases in oxidative stress have been demonstrated in animal PH models and PAH patients, and therapies targeting oxidative stress have shown promise in animal models of PH. This chapter will examine the mechanisms of ROS generation in the pulmonary vasculature, review the available animal and human data on the role of oxidative stress in the pathobiology of PAH, and discuss potential therapies targeting oxidative stress for the treatment of patients with PAH.

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    Authors and Affiliations

    1. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA

      Izabela Chrobak Ph.D., Christina Mallarino Haeger M.D. & Laura E. Fredenburgh M.D.

    2. Lovelace Respiratory Research Institute, 2425 Ridgecrest Dr. SE, Albuquerque, NM, 87108, New Mexico

      Izabela Chrobak Ph.D. & Laura E. Fredenburgh M.D.

    3. McGill University, Montreal, QC, Canada

      Marcy E. Maracle

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    1. Izabela Chrobak Ph.D.
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    2. Christina Mallarino Haeger M.D.
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    3. Marcy E. Maracle
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    4. Laura E. Fredenburgh M.D.
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    Correspondence to Laura E. Fredenburgh M.D. .

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    Editors and Affiliations

    1. Department of Biotechnology, National Institute of Immunology, New Delhi, India

      Nirmal K. Ganguly

    2. Department of Pulmonary Medicine, Postgraduate Institute of Medical Educat, Chandigarh, India

      Surinder K. Jindal

    3. Department of Medicine and Oncology, Johns Hopkins College of Medicine, Baltimore, Maryland, USA

      Shyam Biswal

    4. National Heart & Lung Institute, Imperial College London, London, United Kingdom

      Peter J. Barnes

    5. Department of Pediatrics, Nippon Medical School, Tokyo, Japan

      Ruby Pawankar

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    Chrobak, I., Haeger, C.M., Maracle, M.E., Fredenburgh, L.E. (2014). Pulmonary Arterial Hypertension and Oxidative Stress. In: Ganguly, N., Jindal, S., Biswal, S., Barnes, P., Pawankar, R. (eds) Studies on Respiratory Disorders. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0497-6_15

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