Pharmacology, Toxicology and Environmental Health Commons^™

Particulate Hexavalent Chromium Inhibits Homologous Recombination Repair By Targeting Rad51 Paralogs In Human Lung Fibroblasts., Aggie R. Williams

Electronic Theses and Dissertations

Hexavalent Chromium [Cr(VI)] is a known human lung carcinogen and general health hazard. The mechanism of carcinogenesis remains poorly understood, but chromosome instability (CIN) is the major theory in its carcinogenic mechanism. Homologous recombination (HR) repair is a DNA repair pathway that prevents CIN by repairing DNA double-strand breaks. RAD51, a key mediator protein of HR repair, along with the RAD51 paralogs (RAD51B, C, D, XRCC2, and 3) are required for HR repair. During HR, RAD51 loads and forms a helical nucleoprotein filament structure to promote DNA strand exchange and stimulate pairing activity of DNA. Cr(VI) exposures have been shown …

Cannabinoids And Retinal Fibrotic Disorders., Lucy June Sloan

Electronic Theses and Dissertations

Retinal fibrosis is detrimental to vision. Retinal pigment epithelial (RPE) cells contribute to several retinal fibrotic diseases. Upon exposure to TGF-β, a key fibrotic cytokine, RPE cells trans-differentiate to myofibroblasts marked by the integration of α-SMA fibers into F-actin stress fibers, which confer strong contractility. Myofibroblasts produce and contract the collagen-rich fibrotic scar and disrupt retinal architecture. In this study, we investigated the in vitro effects of the putative endocannabinoid compound N-oleoyl dopamine (OLDA) on TGF-β2 induced porcine RPE cell contraction and α-SMA expression. Using an in vitro collagen matrix contraction assay, we found that OLDA inhibited TGF-β2 induced contraction …

Implementation Of A Drive-Through Covid-19 Mass Vaccination Site: Experiences From Louvax–Broadbent In Louisville, Kentucky, Ruth Carrico, Sarah Beth Hartlage, Valenchia Brown Msn, Aprn, Fnp-C, Sarah M. Bishop, Luanne Didelot, William Hayden, Beverly Williams Coleman, Sarah Tan, Delanor Manson, Kellie Kane, Dawn Balcom, Paul Kern

The University of Louisville Journal of Respiratory Infections

Background: Response to the COVID-19 pandemic has required innovative approaches to vaccination, including methods to rapidly and safely immunize communities. A major challenge to such a response involved access to untapped healthcare worker resources. The Louisville, Kentucky, response involved the use of a large volunteer workforce to supplement local public health employees in planning and implementing a large-scale drive-through vaccination event. The objective of this manuscript was to outline processes involved in training a mass immunization workforce and implementating a large-scale COVID-19 community vaccination.

Approach: Competency-based and standardized training was provided for every volunteer before working their shift. Volunteers worked …

Surveillance Of Rnase P, Pmmov, And Crassphage In Wastewater As Indicators Of Human Fecal Concentration Across Urban Sewer Neighborhoods, Louisville, Kentucky., R. H. Holm, M. Nagarkar, R. A. Yeager, D. Talley, A. C. Chaney, J. P. Rai, A. Mukherjee, S. N. Rai, A. Bhatnagar, T. Smith

Faculty and Staff Scholarship

Wastewater surveillance has been widely used as a supplemental method to track the community infection levels of severe acute respiratory syndrome coronavirus 2. A gap exists in standardized reporting for fecal indicator concentrations, which can be used to calibrate the primary outcome concentrations from wastewater monitoring for use in epidemiological models. To address this, measurements of fecal indicator concentration among wastewater samples collected from sewers and treatment centers in four counties of Kentucky (N = 650) were examined. Results from the untransformed wastewater data over 4 months of sampling indicated that the fecal indicator concentration of human ribonuclease P (RNase …

Combining Community Wastewater Genomic Surveillance With State Clinical Surveillance: A Framework For Sars-Cov-2 Public Health Practice., Ted Smith, Rochelle H. Holm, Ray Yeager, Joseph B. Moore Iv, Eric C. Rouchka, Kevin J. Sokoloski, Daymond Talley, Vaneet Arora, Sarah Moyer, Aruni Bhatnagar

Faculty and Staff Scholarship

Study objective: To garner a framework for combining community wastewater surveillance with state clinical surveillance that influence confirmation of SARS-CoV-2 variants within the community, and recommend how the flow of such research evidence could be expanded and employed for public health response. Design, setting, and participants: This work involved analyzing wastewater samples collected weekly from 17 geographically resolved locations in Louisville/Jefferson County, Kentucky from February 10 to November 29, 2021. Genomic surveillance and RT-qPCR platforms were used as screening to identify SARS-CoV-2 in wastewater, and state clinical surveillance was used for confirmation. Main results: The results demonstrate increased epidemiological value …

Translating Particulate Hexavalent Chomium-Induced Chromosome Instability, Loss Of Homologous Recombination Repair And Targeting Of Rad51 From Human Lung Fibroblasts To Human Bronchial Epithelial Cells., Idoia Meaza Isusi

Electronic Theses and Dissertations

Particulate hexavalent chromium [Cr(VI)] is a well-established human lung carcinogen. RAD51, a key protein in homologous recombination repair pathway, is inhibited after prolonged exposure to Cr(VI), leading to an increase in chromosome instability after prolonged exposures in human lung fibroblasts. chromosome instability is the proposed driver of Cr(VI) carcinogenesis. Since tumors from chromate workers develop from epithelial cells, we sought to translate these findings from human bronchial fibroblasts to human bronchial epithelial cells. We hypothesized Cr(VI) inhibits RAD51 after prolonged exposure leading to an increase in chromosome instability in human bronchial epithelial cells (BEP2D). We characterized the cytotoxicity and measured …

Characterizing The Role Of Macrophages In Cisplatin-Induced Kidney Injury And Progression To Chronic Kidney Disease., Sophia M. Sears

Electronic Theses and Dissertations

Cisplatin is a commonly used chemotherapeutic for treatment of many solid-organ cancers. Unfortunately, 30% of patients treated with cisplatin develop acute kidney injury (AKI), and even patients who do not develop AKI are at risk for long term declines in kidney function and development of chronic kidney disease (CKD). While traditional rodent toxicity studies have utilized a single, lethal dose of cisplatin, new models of cisplatin-induced kidney injury have revealed that repeated, low doses of cisplatin lead to development of kidney fibrosis. This model can be used to examine AKI-to-CKD transition processes. C57BL/6 mice are one of the most used …

The Role Of Sphingolipids In Aki And The Progression To Ckd: Potential Therapuetic Targets., Nicholas A. Hoffman

Electronic Theses and Dissertations

Acute Kidney Injury (AKI) is most simply defined as a rapid decline in kidney function over a period of hours to days. There is currently a lack of effective treatment options for patients with AKI, highlighting the need to identify new therapeutic targets. Sphingolipids play a number of roles in different models of AKI, suggesting they could be promising future targets for treating kidney injury. Specifically, sphingosine-1-phosphate (S1P) and its receptors (S1PRs) have been implicated in numerous inflammatory disorders and models of AKI. The purpose of this review is to better characterize the role of S1P receptors in models of …

Public Awareness And Support For Use Of Wastewater For Sars-Cov-2 Monitoring: A Community Survey In Louisville, Kentucky., Rochelle H. Holm, J. Michael Brick, Alok R. Amraotkar, Joy L. Hart, Anish Mukherjee, Jacob Zeigler, Adrienne M. Bushau-Sprinkle, Lauren B. Anderson, Kandi L. Walker, Daymond Talley, Rachel J. Keith, Shesh N. Rai, Kenneth E. Palmer, Aruni Bhatnagar, Ted Smith

Faculty and Staff Scholarship

The majority of sewer systems in the United States and other countries, are operated by public utilities. In the absence of any regulation, public perception of monitoring wastewater for population health biomarkers is an important consideration for a public utility commission when allocating resources for this purpose. In August 2021, we conducted a survey as part of an ongoing COVID-19 community prevalence study in Louisville/Jefferson County, KY. The survey comprised of seven questions about awareness of and privacy concerns and was sent to 32,000 households randomly distributed within the county. A total of 1,220 sampled adults participated in the probability …

High-Throughput Sequencing Of Sars-Cov-2 In Wastewater Provides Insights Into Circulating Variants., Rafaela S. Fontenele, Simona Kraberger, James Hadfield, Erin M. Driver, Devin Bowes, La Rinda A. Holland, Temitope O.C. Faleye, Sangeet Adhikari, Rahul Kumar, Rosa Inchausti, Wydale K. Holmes, Stephanie Deitrick, Philip Brown, Darrell Duty, Ted Smith, Aruni Bhatnagar, Ray A. Yeager, Rochelle H. Holm, Natalia Hoogesteijn Von Reitzenstein, Elliott Wheeler, Kevin Dixon, Tim Constantine, Melissa A. Wilson, Efrem S. Lim, Xiaofang Jiang, Rolf U. Halden, Matthew Scotch, Arvind Varsani

Faculty and Staff Scholarship

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) likely emerged from a zoonotic spill-over event and has led to a global pandemic. The public health response has been predominantly informed by surveillance of symptomatic individuals and contact tracing, with quarantine, and other preventive measures have then been applied to mitigate further spread. Non-traditional methods of surveillance such as genomic epidemiology and wastewater-based epidemiology (WBE) have also been leveraged during this pandemic. Genomic epidemiology uses high-throughput sequencing of SARS-CoV-2 genomes to inform local and international transmission events, as well as the diversity of circulating variants. WBE uses wastewater to analyse community spread, …

The Rapid Assessment Of Aggregated Wastewater Samples For Genomic Surveillance Of Sars-Cov-2 On A City-Wide Scale., Eric C. Rouchka, Julia H. Chariker, Kumar Saurabh, Sabine Waigel, Wolfgang Zacharias, Mei Zhang, Daymond Talley, Ian Santisteban, Madeline Puccio, Sarah Moyer, Rochelle H. Holm, Ray A. Yeager, Kevin J. Sokoloski, Joshua Fuqua, Aruni Bhatnagar, Ted Smith

Faculty and Staff Scholarship

Throughout the course of the ongoing SARS-CoV-2 pandemic there has been a need for approaches that enable rapid monitoring of public health using an unbiased and minimally invasive means. A major way this has been accomplished is through the regular assessment of wastewater samples by qRT-PCR to detect the prevalence of viral nucleic acid with respect to time and location. Further expansion of SARS-CoV-2 wastewater monitoring efforts to include the detection of variants of interest/concern through next-generation sequencing has enhanced the understanding of the SARS-CoV-2 outbreak. In this report, we detail the results of a collaborative effort between public health …

Novel Pilot Development Of A Closed-Loop Sustainable System Between Biogas Renewable Energy, Distilling, And Aquaculture By Vermiculture Of Stillage Wastes, Samuel C. Kessler

The Cardinal Edge

This study provides a mixed-methods approach in analyzing a potential closed-loop system between renewable biogas production from anaerobic digestion, vermiculture production, aquaculture production, and organic wastes with a particular focus on stillage wastes. Such system may hold significant promise for significantly reducing organic carbon and methane emissions from its components, and should be assessed for such. The 2021 IPCC report essentially identified methane reduction as the single fastest way to slow global warming (IPCC, 2021), making the study and implementation of methane-reducing systems and supportive policy for them critical. Knowledge gaps to implementing this system were qualitatively identified as disconnect …

Standardizing Data Reporting In The Research Community To Enhance The Utility Of Open Data For Sars-Cov-2 Wastewater Surveillance., Jill S. Mcclary-Gutierrez, Zachary T. Aanderud, Mitham Al-Faliti, Claire Duvallet, Raul Gonzalez, Joe Guzman, Rochelle H. Holm, Michael A. Jahne, Rose S. Kantor, Panagis Katsivelis, Katrin Gaardbo Kuhn, Laura M. Langan, Cresten Mansfeldt, Sandra L. Mclellan, Lorelay M. Mendoza Grijalva, Kevin S. Murnane, Colleen C. Naughton, Aaron I. Packman, Sotirios Paraskevopoulos, Tyler S. Radniecki, Fernando A. Roman, Abhilasha Shrestha, Lauren B. Stadler, Joshua A. Steele, Brian M. Swalla, Peter Vikesland, Brian Wartell, Carol J. Wilusz, Judith Chui Ching Wong, Alexandria B. Boehm, Rolf U. Halden, Kyle Bibby, Jeseth Delgado Vela

Faculty and Staff Scholarship

SARS-CoV-2 RNA detection in wastewater is being rapidly developed and adopted as a public health monitoring tool worldwide. With wastewater surveillance programs being implemented across many different scales and by many different stakeholders, it is critical that data collected and shared are accompanied by an appropriate minimal amount of meta-information to enable meaningful interpretation and use of this new information source and intercomparison across datasets. While some databases are being developed for specific surveillance programs locally, regionally, nationally, and internationally, common globally-adopted data standards have not yet been established within the research community. Establishing such standards will require national and …

Rsv-Induced Guillain–Barré Syndrome, Priyanga Jayakumar, Christe Shen, Dylan Goldsmith, Steven Lippmann

The University of Louisville Journal of Respiratory Infections

A patient with respiratory syncytial virus-induced Guillain–Barré Syndrome and acute disseminated encephalomyelitis is presented. This virus is the most common cause of upper respiratory infections, and it can become an etiology for extra-pulmonary pathology with serious complications. Such a case is rare, but the possibility of adverse comorbidities makes early diagnosis and treatment important.

Investigating The Effects Of Perfluorooctanoic Sulfonate (Pfos) And Ethanol On Fatty Liver Disease Using A Modified Niaaa Model., Tyler Charles Gripshover

Electronic Theses and Dissertations

Perfluoroalkyl Substances (PFAS) are a family of man-made, surfactant-like compounds that are a major environmental contaminant. A multitude of studies have indicated that PFAS are able to induce fatty liver disease and modulate lipid metabolism. However, the distinct mechanism of PFAS influence on the liver and metabolism disruption remains to be elucidated. On the other hand, it is well documented that alcohol consumption has various adverse health impacts including fatty liver disease and subsequent progression to more adverse liver states. To date, there are no published studies on whether PFAS and alcohol can jointly exacerbate fatty liver progression or interact …

Geographic And Occupational Mobility Of Small-Scale Fishers Of Lake Malawi: An Exploratory Study Of Water, Sanitation, And Hygiene Access, Malawi., Rochelle H. Holm, Tikhala Chakalamba, Bwighane Ngasama, Fanuel Kapute

Faculty and Staff Scholarship

The livelihood of small-scale fishers on the world’s freshwater lakes cuts across the Sustainable Development Goal (SDG) 6, which covers water and sanitation, and SDG 8 on economic growth. The aim of this study was to examine the nature and extent of fishers’ mobility patterns and access to improved sanitation facilities, safe drinking water, and handwashing practices while at work and home for two fishing camps in Malawi. The study used key informant interviews, questionnaires, water quality testing, and an observational checklist, followed by interviews on fishers’ occupational migration. Many fishers (85%; 51/60) live and work in fishing camps with …

Wastewater Sample Site Selection To Estimate Geographically Resolved Community Prevalence Of Covid-19: A Sampling Protocol Perspective., R. Yeager, R. H. Holm, K. Saurabh, J. L. Fuqua, D. Talley, A. Bhatnagar, T. Smith

Faculty and Staff Scholarship

Wastewater monitoring for virus infections within communities can complement conventional clinical surveillance. Currently, most SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) clinical testing is voluntary and inconsistently available, except for a few occupational and educational settings, and therefore likely underrepresents actual population prevalence. Randomized testing on a regular basis to estimate accurate population-level infection rates is prohibitively costly and is hampered by a range of limitations and barriers associated with participation in clinical research. In comparison, community-level fecal monitoring can be performed through wastewater surveillance to effectively surveil communities. However, epidemiologically defined protocols for wastewater sample site selection are lacking. …

Assessing The Role Of Chronic Arsenite Exposure In Disrupting The Egfr Signaling Axis., Christine Kim

Electronic Theses and Dissertations

Chronic arsenic exposure is a risk factor for the development of pulmonary diseases, including lung cancer, but the exact mechanism is not yet fully understood. Many previous studies have relied on acute arsenic exposure (i.e. 1-10 uM arsenic for 24 hours) to study arsenic toxicological effects. However, acute exposure does not reflect the levels or duration of arsenic associated with environmental exposure, or drinking of contaminated well water. This dissertation differentiates the effects of acute versus chronic arsenic exposures on the EGFR signaling axis and suggests possible mechanisms for chronic arsenic-induced pulmonary diseases. The EGFR is a receptor tyrosine kinase …

Identifying The Cardiovascular Effects Of Multiple Pollutants., Katlyn Elizabeth Mcgraw

Electronic Theses and Dissertations

Cardiovascular disease (CVD) is the leading cause of death from environmental exposures. Although exposure to PM_2.5 is an established risk factor for CVD, the contribution of other hazardous pollutant exposure to CVD is less clear. Overall, this work aimed to examine the effect of pollutants with lesser documented effects on cardiovascular disease using a multi-pronged approach to exposure assessment. The three aims were to examine the relationship between county-level toxic chemical releases and CVD mortality in the contiguous United States between 2002 and 2012, to assess the relationship between individual-level VOC metabolites and vascular function, and to build multipollutant …

Impact Of Sampling Depth On Pathogen Detection In Pit Latrines., Drew Capone, Petros Chigwechokha, Francis L. De Los Reyes, Rochelle H. Holm, Benjamin B. Risk, Elizabeth Tilley, Joe Brown

Faculty and Staff Scholarship

Wastewater based epidemiology (WBE) is increasingly used to provide decision makers with actionable data about community health. WBE efforts to date have primarily focused on sewer-transported wastewater in high-income countries, but at least 1.8 billion people in low-and middle-income countries (LMIC) use onsite sanitation systems such as pit latrines and septic tanks. Like wastewater, fecal sludges from such systems offer similar advantages in community pathogen monitoring and other epidemiological applications. To evaluate the distribution of enteric pathogens inside pit latrines–which could inform sampling methods for WBE in LMIC settings unserved by sewers–we collected fecal sludges from the surface, mid-point, and …

How A Low-Cost Method For Cumulative Water-Sampling Shows Need For Improvement Of Legal Public-Contact Standards In The United States, Samuel C. Kessler

Grawemeyer Colloquium Papers

Across the world, it is estimated that 4.5 billion people live near water sources “impaired” for use or contact. Standards for human-interaction are established by international organizations such as the WHO, and legislative bodies from national to local levels with jurisdiction over the quality of our waterways to ensure public & environmental health. Standards are often assessed from “grab-samples” taken from a waterbody at a certain time, with a minimum number analyzed. Water-quality standards in the United States are enforced under the Clean Water Act (CWA) via the Environmental Protection Agency (EPA), applying to “waters of the United States” (WOTUS). …

A Qualitative Study Of Nimbyism For Waste In Smaller Urban Areas Of A Low-Income Country, Mzuzu, Malawi., Rochelle H. Holm, Brighton A. Chunga, Adrian Mallory, Paul Hutchings, Alison Parker

Faculty and Staff Scholarship

When waste management infrastructure is built, there can be resistance from the local affected populations, often termed the Not in My Backyard (NIMBY) phenomenon. This study aims to understand the forms of resistance that may develop in such contexts, focusing on 2 solid waste and 1 liquid waste management site within Mzuzu City, Malawi. At the newest solid waste site, community resistance had grown to the extent that the site was reportedly destroyed by the local community. Interviews and observations of the sites are complemented by examining historic and recent satellite images. It was found that, at the new solid …

A Review Of The Financial Value Of Faecal Sludge Reuse In Low-Income Countries., Adrian Mallory, Rochelle Holm, Alison Parker

Faculty and Staff Scholarship

Faecal sludge reuse could promote responsible waste management and alleviate resource shortages. However, for this reuse to be carried out at scale, it needs to be financially viable. This paper reviews the financial values of resource recovery from 112 data points from 43 publications from academic and grey literature. The results found 65% of the existing literature is projected rather than being based on observed data from products in practice, with limited studies providing actual experiences of revenue in practice. Some of the estimates of the potential value were ten times those observed in data from operating businesses. Reasons for …

Re-Evaluating The Strength Of Pit-Latrine Faecal Sludge From Dynamic Cone Penetrometer Test Data., Yasmine Shafiq, Stuart Haigh, Rochelle Holm, Alison Parker

Faculty and Staff Scholarship

In 2017, 55% of the global population were without safely managed sanitation services. On-site sanitation solutions, such as pit latrines, provide the majority of sanitation coverage across developing countries. Appropriate technologies are required in order to safely empty these latrines without damage to people or the environment. The design of appropriate emptying technologies can be hampered by a lack of knowledge of the mechanical properties of the waste, such as its strength. This paper will develop a calibration for a dynamic cone penetrometer to give accurate measurements of faecal sludge strength against a standard scale, rendering existing data comparable. It …

N-Acetyltranserase 2 (Nat2) Genotype Polymorphism In Cryopreserved Human Hepatocytes And Chinese Hamster Ovary (Cho) Cells., Mariam Refaat Zaky Habil

Electronic Theses and Dissertations

Arylamine N-acetyltransferases, NAT1 and NAT2, catalyze the detoxification and/or activation of drugs and aromatic amine carcinogens. Single nucleotide polymorphisms or SNPs result in different human NAT2 genotypes thus dividing the population into rapid, intermediate, and slow acetylators. We hypothesize allelic variants of NAT2 genotype will decrease levels of N-acetylation, cytotoxicity, oxidative stress, DNA adduct formation, and mutagenesis compared to the reference allele NAT2*4. Cryopreserved human hepatocytes expressing different NAT2 genotypes and NER-deficient Chinese hamster ovary (CHO) cells transfected with human CYP1A2 and human NAT2*4, NAT2*5B or NAT2*7B have been used to investigate N-acetylation of different xenobiotics. In …

Tobacco Product-Derived Aldehydes: Effects On Circulating Angiogenic Cells & Implications For Cardiovascular Disease., Jordan B. Lynch

Electronic Theses and Dissertations

Cardiovascular disease (CVD) is the leading cause of death worldwide. Tobacco smoke is the most significant modifiable risk factor in CVD development and contains numerous toxic compounds, including aldehydes, which have been linked to CVD. Formaldehyde, acetaldehyde, acrolein, and crotonaldehyde have been identified as significant contributors to cigarette-induced health effects, but the mechanism of these effects is not well understood. These aldehydes are also found in aerosols produced by e-cigarettes (e-cigs). The goal of this dissertation was to explore the systemic, hematological, and endothelium-related effects of exposure to tobacco products and constituent aldehydes and to identify potential mechanisms of injury. …

Dual Role Of Antimicrobial Peptide Cathelicidin In Alcohol-Associated Liver Disease., Fengyuan Li

Electronic Theses and Dissertations

Patients with alcohol-associated liver disease (ALD) have high morbidity and mortality in its severe forms. One of the major features in different forms of ALD is the altered gut microbiota. Antimicrobial peptides (AMPs) play a crucial role in maintaining gut microbiota homeostasis. LL-37 (known as CRAMP in mouse) is the sole member of the human cathelicidin family and has piqued great research interest for its dual role in modulating microbiota and the immune response in metabolic diseases. Inflammasome activation is an important component of the liver pathophysiology in ALD and requires two signals for its full activation to induce the …

Volatile Organic Compound Exposure And Cardiometabolic Syndrome Risk In A Nationally Representative Cohort., Stacey Lane Konkle

Electronic Theses and Dissertations

BACKGROUND: The relative importance of environmental exposures such as volatile organic compounds (VOCs) is one of the paramount public health priorities of our time, yet is presently unstudied. VOCs are ubiquitous in the environment and have been associated with numerous adverse health effects, including a number of cardiovascular and metabolic effects that are components of Cardiometabolic Syndrome (CMS). OBJECTIVES: To examine the relationship between CMS and individual-level exposures to VOCs, measured as urinary metabolites of VOCs (UM-VOCs), in a nationally representative sample. METHODS: Associations between urinary biomarkers of exposure to 19 parent VOCs and CMS were assessed using the National …

Tobacco-Derived Aldehydes: Platelet Activation, Thrombosis, And The Role Of Trpa1., Andre Dwayne Richardson

Electronic Theses and Dissertations

Cigarette smoking is the single largest risk factor for cardiovascular disease (CVD) pathophysiology. Numerous researchers have shown potential associations between aldehydes in tobacco-derived aerosols from mainstream cigarette smoke (MCS) or electronic cigarettes (e-cigs) and their cardiotoxicity by damaging blood vessel endothelium. The severity of exposure to these toxicants can furthermore lead to adverse cardiovascular outcomes such as myocardial infarctions, stroke, coronary and peripheral artery disease, or atherosclerosis due to blood clots, a pro-thrombotic event. However, the mechanisms by which levels of harmful and potentially harmful constituents (HPHCs) such as aldehydes induce thrombosis are not well-known. Of specific interest, evidence has …

The Role Of Slc7a11 In Controlling Extracellular And Intracellular Redox Environments Of Lung Fibroblasts - Potential Targets For Intervention In Aging And Idiopathic Pulmonary Fibrosis., Yuxuan Zheng

Electronic Theses and Dissertations

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by extracellular matrix deposition by fibroblasts. Aging and oxidative stress increase the susceptibility to IPF. Redox couples, cysteine/cystine (Cys/CySS) and glutathione/glutathione disulfide (GSH/GSSG), and their redox potentials (E_h) quantify oxidative stress. Fibroblasts from old mice maintain more oxidized extracellular E_h(Cys/CySS) than young mice. Microarray shows down-regulation of Slc7a11 potentially mediates this age-related oxidation. Slc7a11 is the key component of system X_c^-, an antiporter that imports CySS and exports glutamate. The first aim of this dissertation is to investigate the mechanistic link between Slc7a11 …