Joining the UA faculty in 2015, Dr. Steve Black is a professor of medicine and physiology and director of the UA Lung Vascular Pathobiology Program. He earned a bachelor’s degree in molecular biology and a doctorate in molecular pharmacology from the University of Edinburgh in Scotland. Afterward, he did a postdoctoral research internship in molecular endocrinology at the University of California San Francisco, where he was also an assistant professor. From 1999 to 2006, he was an associate professor at Northwestern University, the University of Montana and the University of Washington. Before coming to Tucson, he was a Regents’ Professor at the Medical College of Georgia, now part of Augusta University. Continuously funded by the NIH for two decades, he also is the winner of the National Institutes of Health James A. Shannon Director’s Award (1998) and a March of Dimes Basic Research Award (2000). Over the years, he has been a member or chair of several study groups within the American Heart Association.
Pulmonary hypertension (PH) is a progressive disease characterized by an increase in pulmonary vascular resistance (PVR). PH constitutes a heterogeneous group of clinical entities sharing similar pathologies that are categorized as pulmonary arterial hypertension, pulmonary venous hypertension, PH associated with hypoxia, and PH associated with chronic thrombotic disease. Histologically, PH is characterized by muscularization of peripheral arteries, medial hypertrophy of muscular arteries, loss of small pre-capillary arteries, and neointima formation. In the later stages of the disease, endothelial cell proliferation leads to the development of plexiform lesions, which are aberrant channels in the obliterated vessel lumen and in the adventitia. The vascular changes in PH are collectively referred to as pulmonary vascular remodeling. Research in the division is focused on elucidating the mechanisms underlying the development of PH and on developing new therapies for this devastating disease. Work in Dr. Stephen Black’s laboratory is focused on understanding the mechanisms underlying the development of the endothelial dysfunction that precedes the development of PH, the role of reactive oxygen species in this process, and understanding how decreased NO signaling leads to the pulmonary vascular remodeling that is associated with more advanced disease. Endothelial cell dysfunctionThe endothelium provides a semi-permeable barrier between the vascular and extravascular fluid compartments and is intimately involved in the regulation of vascular tone, growth, and differentiation. Prior to the development of PH there is endothelial injury that can be associated with a number of insults including hypoxia, increased flow (shear stress), drugs (dexfenfluramine), or toxins (adulterated rapeseed oil). The result is a decrease in the ability of the endothelium to generate nitric oxide (NO). NO, synthesized largely by endothelial nitric oxide synthase (eNOS) in endothelial cells in the pulmonary vessels, is a vasodilator and suppressor of SMC proliferation. Work in Dr. Black’s lab is investigating the link between decreased mitochondrial function and loss of NO signaling. Pulmonary vascular remodeling in pulmonary hypertensionVascular remodeling is a multi-factorial, multi-cellular process that involves a change in maximal lumen diameter (inward/outward) and alterations in cellular processes such as: cell growth, death, migration, and production and redistribution of extracellular matrix. These lasting alterations in vessel structure contribute to increases in pulmonary vascular resistance and pulmonary arterial pressure. Vascular remodeling is dependent on dynamic interactions between locally generated growth factors, vasoactive substances, and hemodynamic forces. The stimuli responsible for remodeling involve changes in transmural pressure, stretch, shear stress, hypoxia, various mediators (angiotensin II, endothelin (ET)-1, 5-hydroxytryptamine (5-HT), growth factors, and inflammatory cytokines), increased serine elastase activity, and increased production of reactive oxygen species. Work in Dr. Black’s lab is elucidating the mechanisms by which changes in biomechanical forces leads to increased cellular proliferation and the role played by growth factors and increased generation of reactive oxygen species. Reactive Oxygen Species (ROS)ROS include free radicals that are naturally formed as byproducts of oxygen metabolism, such as hydroxyl (OH•), superoxide (O2-), peroxyl (RO2•), lipid peroxyl (LOO•), and non radical species, such as hydrogen peroxide (H2O2), hypochloric acid (HOCl), ozone (O3), and lipid peroxide (LOOH). ROS can act as intermediates in signaling pathways in much the same manner as classical second messengers. The main ROS involved in cell signaling pathways are O2- and H2O2. In the lung, endothelial cells, neutrophils, eosinophils, alveolar macrophages, and alveolar epithelial cells are all major sites of ROS generation. ROS in the pulmonary vasculature can be produced from complexes in the cell membrane, cellular organelles such as, peroxisomes and mitochondria and in the cytoplasm. In addition eNOS can become “uncoupled”, producing a shift from NO generation to ROS production. Thus, the aberrant generation of ROS during the development of PH is complex and involves several systems. These include NADPH oxidase, uncoupled NOS, dysfunctional mitochondria, and xanthine oxidase. Work in Dr. Black’s laboratory is trying to determine the mechanisms by which these systems become dysregulated and to identify the proteins that, through oxidative modification, lead to the development of PH.