Timothy R. Nurkiewicz, Ph.D.
Associate Professor, Department of Physiology and Pharmacology
Graduate Training: West Virginia University
Fellowship: Texas A&M University
PO Box 9105
Morgantown, WV 26506
Figure 1: Fluorescent images after dihydroethidine exposure indicating oxidative stress in the arteriolar wall. Pictures are from the rat spinotrapezius muscle. Left picture, normal arcade bridge arteriole. Right picture, arcade bridge arteriole in a rat 24 hours post PM exposure (2 mg).
Figure 2: Transillumination of the spinotrapezius muscle displaying leukocyte adhesion. Top, normal venule. Bottom, venule in rat treated with PM. Rolling and adhering leukocytes are the white “spots” in the venular lumen.
Figure 3: Myeloperoxidase staining (green) lateral to the endothelium in a post capillary venule after particle exposure. The endothelium is labeled red (vWF), erythrocytes display yellow autofluorescence and the nuclei of neutrophils are blue.
Ambient air pollution is a nationwide problem, particularly in states such as West Virginia where industry, population and general growth are rapidly rising. Particulate matter (PM) is one of the six principle air pollutants nationally tracked by the U.S. Environmental Protection Agency. Acute exposure to PM increases morbidity and mortality, as evidenced by the increased occurrence of cardiovascular dysfunction on high pollution days. Populations such as the young, elderly and ill are at greater risk when exposed to PM. While the association between untoward health effects and PM exposure is now known, the fundamental mechanisms by which PM elicits cardiovascular dysfunction remain largely unknown. Only recently have scientists begun to explore the possibility that the systemic effects of PM may be more important than those traditionally investigated in the lung.
A second and equally important problem that is under active investigation is nanoparticle toxicity. Nanotechnology has firmly integrated itself into virtually every aspect of our daily lives. However, the short- and long-term health effects of nanoparticle exposure are also poorly understood. Through a variety of techniques (inhalation exposure, intravital microscopy, isolated-cannulated microvessels, biosensing, histology), and collaborative efforts with the National Institute for Occupational Safety and Health and the U.S. Environmental Protection Agency; the cardiovascular toxicity of a variety of nanoparticles are evaluated in our laboratory. As with PM, this toxicity most notably manifests itself at the microvascular level, and lays the foundation for widespread cardiovascular dysfunction.
The ability of the microcirculation to maintain blood flow in any tissue is dependent on many factors including: 1) endothelial interaction with smooth muscle, and 2) chemical communication between arterioles and venules. My laboratory has recently discovered that endothelium-dependent arteriolar dilation is profoundly impaired after PM exposure. This dysfunction is associated with endothelium-derived nitric oxide, as well as other endothelial factors that influence arteriolar smooth muscle tone.
To better understand why arteriolar dilation is impaired after PM or nanoparticle exposure, we use fluorescent markers to characterize microvascular oxidative stress. Oxidative stress in the microcirculation is capable of disrupting endothelial-smooth muscle cell interactions. Figure 1 indicates that oxidative stress is prominent in the arteriolar wall after PM exposure (similar results are produced after nanoparticle exposure).
We have also explored the potential source of oxidative stress after particle exposure. Exposure to toxic stimuli initiates a complex systemic inflammatory response. One characteristic of an inflammatory response is increased leukocyte adhesion and rolling in the microcirculation. Leukocytes generate oxidative stress liberally as part of a normal immune response. Figure 2 shows that microvascular leukocyte adhesion and rolling is significantly increased after particle exposure. Once leukocytes have slowed and are interacting with the venular endothelium, hemoproteins such as myeloperoxidase can be deposited in the vascular wall. Figure 3 displays myeloperoxidase deposition in the microvascular wall after particle exposure.
The primary goal of our research is to identify the adverse effects of particle exposure on microvascular function, and determine the mechanisms that cause these potentially lethal effects. A second goal is to characterize why large “at risk” populations are more prone to be victims of PM exposure. Additional images and video from our studies can be found in the Media Library.
Cardiovascular Toxicology Speciality Section:
The Cardiovascular Toxicology Specialty Section (CVT SS) of the Society of Toxicology (SOT) is being established to lead the response to these challenges in our immediate and not so distant futures. The CVT SS is committed to excellence in all aspects of research and will serve to unite cardiovascular toxicologists from academia, government, industry and the private sector. This unification will serve to merge conventional techniques and methods in an interdisciplinary fashion that will fortify the education of our students and fellows that will become the next generation of cardiovascular toxicologists.
Click on the image to visit the CVT SS Web Site.