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Current Research Projects

Alison Elder, PhD.

Hazard Assessment and Risk Estimation of Inhaled Nanomaterials Exposure

The use of engineered nanomaterials (ENM) in consumer products has raised concerns about risks to human health following release into workplaces or the environment and some recent studies have described adverse outcomes following in vitro and in vivo exposures. We will conduct comprehensive studies – including workplace exposure characterizations, acellular ENM functional characterizations, in vitro tests of effects in cultured target cells, and in vivo effects and material distribution studies in rodents – to assess dose-related effects in the lung, pleura, and central nervous system following realistic inhalation exposures to ENM that are delivered in their native state without additional surface modifications. These results will be used to develop and validate short-term tests that can be used for estimating potential human risk following ENM exposure.

Rat alveolar macrophages that took up multi-walled carbon nanotubes following respiratory tract exposure were not able to completely engulf the rigid fibers

 

Mark W. Frampton, M.D.

Cardiovascular Effects of Ultrafine Particles in Genetically Susceptible Subjects

Increases in particulate air pollution are associated with increases in deaths from cardiovascular disease, but we know relatively little about how this happens, and who is most susceptible. Our proposed studies will determine the effects of very small (ultrafine) outdoor air pollution particles on blood vessel and heart function in people who may have increased susceptibility based on their genetic makeup. Healthy volunteers with and without specific gene mutations will inhale concentrated outdoor ultrafine particles on one occasion, and clean air on another occasion. Detailed measurements of lung, blood vessel, and heart function, and markers of effects in the blood, will be made before and at intervals up to 48 hours after the 2-hour exposure. We expect to see the strongest effects in the subjects with gene mutations that increase susceptibility. These studies will help determine how exposure to air pollution particles contributes to heart and vascular disease, determine whether genetic makeup affects susceptibility, and help to develop strategies to protect the most susceptible people.

 

B. Paige Lawrence, PhD.

Developmental toxicity of Bisphenol A and Immune-mediated diseases.

The objective of our project is to provide the most detailed analysis to-date of the impact of bisphenol A (BPA) on immune system development and function. We are specifically testing the hypothesis that maternal BPA exposure enhances susceptibility of her offspring to three common diseases later in life. The three disease models we will examine are influenza A virus infection, asthma, and inflammatory bowel disease.

 

IFN g staining is intracellular and Gr1+IFN g + cells are not CD8+

 

Frances Lund, PhD.

Mechanism(s) that control inflammation in response to infectious, allergic and autoimmune diseases.

We are examining the role that extracellular nucleotides play in regulating inflammatory processes. Our primary focus has been on CD38; an ectoenzyme that catabolizes extracellular NAD into three products that are each involved in calcium signaling. We previously showed that CD38, through the production of these calcium-mobilizing metabolites, regulates innate and adaptive immune responses by modulating signaling through chemokine receptors and controlling the trafficking of neutrophils, monocytes and dendritic cells to sites of inflammation and infection. Based on these data, we hypothesize that extracellular NAD, like other extracellular nucleotides such as ATP, plays a critical role in regulating the immune system and inflammatory responses. Our current experiments address whether we can modulate cell trafficking and pulmonary inflammation by manipulating extracellular NAD levels in models of pathogen, allergen and particulate exposure. We are also addressing whether experimentally decreasing the concentration of extracellular NAD is sufficient to impact NAD homeostasis, thereby affecting oxidative stress responses during exposure to particulates and allergens.

 

Allergen-induced pulmonary inflammation is attenuated in mice that are deficient in the NAD-metabolizing ecto-enzyme CD38. CD38 deficient mice and wild-type controls (C57BL/6J) were first sensitized with the allergen ovalbumin adsorbed to alum and later challenged with ovalbumin delivered to the lungs. Tissue sections from the lungs of the ovalbumin challenged mice were prepared and stained with hematoxylin and eosin to visualize the pulmonary inflammatory cell infiltrate. Significantly less pulmonary inflammation was induced in the CD38 deficient mice.

 

Richard Phipps , PhD.

Human Disease and Cigarette Smoke

Age-related Macular Degeneration (AMD) is the leading cause of blindness among the elderly in industrialized nations. Cigarette smoking is the single most important environmental risk factor for developing AMD. Current smokers are estimated to have a 45% greater probability of developing early AMD and exhibit worse AMD disease progression, compared with nonsmokers. Smoking intensity also increases the risk of developing AMD, likely through oxidative injury. Cigarette smoke yields an estimated 10 17 oxidant molecules per puff that can damage retinal pigment epithelial (RPE) cells. In addition to evidence of oxidative damage in AMD patients, oxidative stress can alter RPE cells and increase the expression of growth factors conducive to vascular endothelial cell growth. Subsequent loss of RPE cells due to oxidative stress caused by cigarette smoke exposure may underlie AMD pathogenesis and/or contribute to disease progression.

 

Human retinal pigment epithelial cells damaged by cigarette smoke extract

 

Gloria Pryhuber, M.D.

Our laboratory has been interested in inflammatory lung injury, both acute and chronic, especially as related to host defense against pathogens and environmental particles. Our long-standing project studies lung injury as mediated by the cytokine tumor necrosis factor alpha (TNF- a ) and its effects on alveolar epithelial cell function and survival. In these studies, we have demonstrated, in bone marrow transplant models of injury induced by hyperoxia, by crystalline silica or by the pathogen Pneumocystis carinii , the importance of parenchymal cell TNF receptor function, especially in the development of chronic disease and fibrosis. Utilizing in vitro epithelial cell cultures and transgenic mice, we are also investigating the role of TNF receptor associated factors (TRAF 1 and 2) in lung and liver cell responses to TNF, directly and indirectly.

More recent studies address pulmonary issues of premature birth. One series of projects is based on observations made in neonatal lung samples that represent prematurity, developmental abnormalities and the chronic lung disease of prematurity, bronchopulmonary dysplasia (BPD). Infants born prematurely are at increased risk for respiratory insufficiency while in the intensive care unit, although the majority do well and are discharged to home from the hospital. Unfortunately, many remain at risk for recurrent, wheezy, asthma-like events and are especially susceptible to viral infections in their first years of life. Some of these children, especially those with BPD, have evidence of chronic obstructive pulmonary disease (COPD) as adults. In BPD, lung development is arrested and in more severe cases, the disease is complicated by edema, fibrosis, inflammatory cell infiltration, capillary bed dysplasia and alveolar epithelial cell hyperplasia. Done in collaboration with Dr. Tom Mariani at the University of Rochester and with support of the UR CTSI, our genome-wide, expression analysis and validation studies on human lung suggest novel genes and gene networks of interest as potential biomarkers of disease as well as in understanding mechanisms involved in BPD.

A third set of studies, integrated into the NHLBI multi-center Prematurity and Respiratory Outcomes Program (PROP), are undertaking lymphocyte immuno-phenotyping and transcriptomic approaches to study relationships between innate and adaptive immune maturation and clinical respiratory outcomes of premature infants. These studies will identify alterations in maturation and subsequent function of lymphocytes occurring in premature infants at birth, NICU discharge and at one year follow-up, in comparison to infants born full-term, as a function of measures of oxidative stress and environmental exposures.

Troy Randall, PhD.

Pulmonary immunity to viruses, tumors and allergens

One of the major projects in my lab is to determine how local lymphoid tissues develop and function in the respiratory tract in response to respiratory viruses, lung tumors and allergens. We find that, although naïve mice lack detectable lymphoid areas in their lungs, organized lymphoid tissues can be formed in response to either infection or inflammmation. These tissues have separated B and T cell areas, germinal centers, high endothelial venules and specialized dendritic cells. These tissues appear similar to conventional secondary lymphoid tissues, therefore, we have termed these sites "inducible Bronchus Associated Lymphoid Tissue" (iBALT). We have also found that immune responses to influenza can be generated at sites of iBALT in mice that completely lack lymph nodes, Peyer's patches and spleen. In fact, mice lacking conventional lymphoid organs are more resistant to influenza than normal mice. Thus, iBALT is not simply an area of inflammation, but is a site that can actively participate in the immune response and appears to regulate respiratory immune responses in a way that leads to less morbidity and mortality. We have also shown that long-lived immune memory (both B and T cell dependent) to influenza is intact in mice that lack peripheral lymphoid organs. These data demonstrate that local, inducible lymphoid tissues are an important component of protective immune responses in the respiratory tract. However, we also find that iBALT is generated in the lungs of humans with a wide variety of pulmonary diseases. In particular, humans with lung disease associated with rheumatoid arthritis are very prone to developing extensive areas of iBALT. We suspect that these local lymphoid tissues are responding to autoantigens and exacerbating pulmonary disease. Interestingly, we have also found that there is a developmental window in neonatal mice during which iBALT is most easily formed. This window corresponds to a time when children are at risk of developing asthma in response to respiratory viruses, such as RSV. Thus, I BALT is probably involved in both helpful and harmful immune responses in the lung. Since the development of iBALT (and Nasal Associated Lymphoid Tissue -NALT) appears to be controlled by unique mechanisms and does not follow the program of lymphoid organ development that is proposed for lymph nodes and Peyer's patches, it is probable that we will identify ways to trigger or prevent iBALT development without disrupting the development or function of other lymphoid organs.

 

David Topham, PhD.

The Pivotal Role of VLA-1 in T cell Immunity to Influenza

Optimal T cell mediated immunity to virus infection of peripheral tissues depends on the ability of the T cells to home to, function, and be retained in these sites. Because of the diversity in the structure and function of peripheral organs, a mechanism to regulate T cells in different organs must involve components shared by many tissues. A feature common to many tissues is the presence of extracellular matrix. Collagen IV is uniquely found in the basement membranes that form the foundation for all epithelial and endothelial surfaces. The receptor for collagen IV is the alpha-1 beta-1 integrin heterodimer, Very Late Antigen-1 (VLA-1). VLA-1 is expressed by subsets of activated and memory T cells of both the CD4 and CD8 lineages. It is important for the maintenance of memory T cells in peripheral non-lymphoid tissues, especially the lung and other mucosal sites. More recently, VLA-1 expression was associated with localization of T cells in proximity to epithelial surfaces and in promoting their survival during the acute phase of infections. Thus not only can it function to maintain memory T cells, it also is important for protection of effector T cells during the acute response. We study the function of VLA-1 in T cell memory and migration of the T cells along the respiratory epithelium.

 

 

Copyright 2010 University of Rochester Medical Center, Dept of Environmental Medicine.