Publications by authors named "Thomas Kampfrath"

28 Publications

  • Page 1 of 1

The 2018 AACC/SYCL PhD Clinical Chemist Compensation Survey.

J Appl Lab Med 2020 03;5(2):377-387

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Background: Doctoral level board-certified clinical chemists play an invaluable role in many facets of laboratory medicine and healthcare. However, information concerning their total compensation is sparse.

Content: A confidential self-reported compensation survey was conducted by the American Association for Clinical Chemistry's Society for Young Clinical Laboratorians (AACC SYCL) Core Committee from April 1 to April 17, 2018. Respondents provided information on geographic location, employment sector, gender, and years of experience to account for the influence of these variables on compensation. There were 199 respondents in total from the United States and Canada, however, only respondents employed in the United States with an earned doctoral degree and certification by the American Board of Clinical Chemistry (n = 133), were included in the full analysis. In comparison to compensation reported in AACC SYCL salary surveys conducted in 2010 and 2013, early career median salaries are trending upwards after correction for inflation.

Summary: This survey is the first to collect the gender of respondents, and identify a pay gap for some geographic groups. However, this gap could be due in part to a difference in the years of experience, since males were highly represented in the group with >20 years of experience (25 out of 35, 71%). Future studies on compensation trends within clinical chemistry that do not rely on self-report are needed to ensure accuracy and completeness of the dataset.
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http://dx.doi.org/10.1093/jalm/jfaa001DOI Listing
March 2020

Effects of Bilirubin Interference in the Roche Kinetic Alkaline Picrate Creatinine Assay.

J Appl Lab Med 2018 Jul;3(1):152-154

Department of Pathology and Laboratory Medicine, Santa Clara Valley Medical Center, San Jose, CA.

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http://dx.doi.org/10.1373/jalm.2017.025528DOI Listing
July 2018

Hybrid nanoparticles improve targeting to inflammatory macrophages through phagocytic signals.

J Control Release 2015 Nov 18;217:243-55. Epub 2015 Sep 18.

Division of Cardiovascular Medicine, Department of Medicine, University of Maryland, Baltimore, MD 21201, United States; Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH 43210, United States. Electronic address:

Macrophages are innate immune cells with great phenotypic plasticity, which allows them to regulate an array of physiological processes such as host defense, tissue repair, and lipid/lipoprotein metabolism. In this proof-of-principle study, we report that macrophages of the M1 inflammatory phenotype can be selectively targeted by model hybrid lipid-latex (LiLa) nanoparticles bearing phagocytic signals. We demonstrate a simple and robust route to fabricate nanoparticles and then show their efficacy through imaging and drug delivery in inflammatory disease models of atherosclerosis and obesity. Self-assembled LiLa nanoparticles can be modified with a variety of hydrophobic entities such as drug cargos, signaling lipids, and imaging reporters resulting in sub-100nm nanoparticles with low polydispersities. The optimized theranostic LiLa formulation with gadolinium, fluorescein and "eat-me" phagocytic signals (Gd-FITC-LiLa) a) demonstrates high relaxivity that improves magnetic resonance imaging (MRI) sensitivity, b) encapsulates hydrophobic drugs at up to 60% by weight, and c) selectively targets inflammatory M1 macrophages concomitant with controlled release of the payload of anti-inflammatory drug. The mechanism and kinetics of the payload discharge appeared to be phospholipase A2 activity-dependent, as determined by means of intracellular Förster resonance energy transfer (FRET). In vivo, LiLa targets M1 macrophages in a mouse model of atherosclerosis, allowing noninvasive imaging of atherosclerotic plaque by MRI. In the context of obesity, LiLa particles were selectively deposited to M1 macrophages within inflamed adipose tissue, as demonstrated by single-photon intravital imaging in mice. Collectively, our results suggest that phagocytic signals can preferentially target inflammatory macrophages in experimental models of atherosclerosis and obesity, thus opening the possibility of future clinical applications that diagnose/treat these conditions. Tunable LiLa nanoparticles reported here can serve as a model theranostic platform with application in various types of imaging of the diseases such as cardiovascular disorders, obesity, and cancer where macrophages play a pathogenic role.
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http://dx.doi.org/10.1016/j.jconrel.2015.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874242PMC
November 2015

Pregnant woman with markedly increased iron binding capacity.

Clin Chem 2015 May;61(5):779-80

Department of Pathology and Laboratory Medicine, Santa Clara Valley Medical Center, San Jose, CA.

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http://dx.doi.org/10.1373/clinchem.2014.234229DOI Listing
May 2015

Benzodiazepine in a urine specimen without drug metabolites.

Lab Med 2015 ;46(2):164-7

Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida.

Clinical History:

Patient: 41-year-old Hispanic woman. Chief Complaint: Pain in the neck, joints, and shoulders that started in August 2013. History of Present Illness: The patient has a history of psychiatric illness. Her primary care physician from an outside facility had prescribed alprazolam (Xanax) to treat her depression. The patient reported that in 2011 she experienced pain in the right side of her back and was diagnosed with sciatica. In addition, she was diagnosed with systemic lupus erythematosus (SLE) based on a positive finding for antinuclear antibodies (ANA) and double-stranded DNA (ds-DNA). She had not consulted a rheumatologist before this visit, nor had she received any medication for these conditions. Her recent history of symptoms included photosensitivity, painful aphthous ulcers, transient rashes, joint pain, myalgias, and bruising. The results of the most recent evaluation of her SLE serology revealed negative ANA and ds-DNA results. The current medications that the patient has been prescribed at Santa Clara Valley Medical Center include lamotrigine (Lamictal), sertraline (Zoloft), and gabapentin (Neurontin). In April 2014, the patient requested additional pain medication, such as hydrocodone/acetaminophen (Norco), during her physician visit. Consequently, as part of her pain management therapy agreement to ensure compliance,(1) she was subjected to a urine toxicology drug screening. At this time, her urine specimen, from an unwitnessed collection, tested positive for benzodiazepines using the Syva EMIT immunoassay (Siemens AG, Munich, Germany) at the cutoff of 200 ng/mL. However, results of a confirmatory test conducted via gas chromatography-mass spectrometry (GC/MS) did not identify any benzodiazepine metabolites in her urine but instead revealed the presence of a parent drug, alprazolam. Further, the same specimen tested positive for metronidazole. A visual inspection of the specimen revealed crystals on the bottom of the cup. In December 2013, this patient had tested positive for α-hydroxyalprazolam (an alprazolam metabolite; limit of detection, 10 ng/mL) and methamphetamine. At that time, she explained her positive urine-drug-test result by stating that "somebody had put something in my drink." Family history: Her father has been diagnosed with gout, knee osteoarthritis, and enlarged heart. Her brother has been diagnosed with clinical depression. Social history: Divorced; 3 children in the custody of their father; reported having smoked 0.5 packs of cigarettes per day for 20 years; denied any alcohol intake or illicit drug use.
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http://dx.doi.org/10.1309/LMIG49YDFSUNQ2YSDOI Listing
July 2016

Resolving a case of concurrent hepatitis B virus surface antigen (HBsAg) and surface antibody (HBsAb).

Clin Chim Acta 2014 Mar 4;430:171-2. Epub 2014 Feb 4.

Department of Pathology and Laboratory Medicine, University of Louisville, Louisville, KY, United States; Laboratory Service, Department of Veteran Affairs Medical Center, Robley Rex VA Medical Center, Louisville, KY, United States.

Background: In most cases, patients appear to recover from acute hepatitis B virus (HBV) infection and do not exhibit the surface antigen (HBsAg). Chronic carriers are positive for HBsAg but HBsAb is usually not present. After acute infection only HBsAb remains. The presence of both HBsAg and HBsAb is unusual.

Methods: We report on a patient whose results were analytically and clinically discrepant--positive for HBsAg and HBsAb on one testing platform but only HBsAg on another platform.

Results: Reasons for this result: 1) Interference from endogenous antibodies; 2) HBsAg is from one strain and HBsAb is from another: and 3) The presence of HBsAb and HBsAg. Growing evidence indicates that both may be present in many patients. Low HBsAb may be neutralized and not recognized by the solid-phase HBsAg in the assay. Likewise, low HBsAg may be neutralized by HBsAb. It remains unclear whether HBsAg is always cleared after acute infection.

Conclusions: Testing indicated that both HBsAb and HBsAb were present. The data shows that different testing platforms may produce different results depending on the kinetics, the exposure of the capture HBsAg and the extent of endogenous HBAg/HBsAb. We demonstrate a simple way to rule out test interference to presumptively identify true HBsAb.
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http://dx.doi.org/10.1016/j.cca.2014.01.016DOI Listing
March 2014

Undetected hypoglycemia in a patient receiving TPN.

Clin Chim Acta 2013 Sep 31;424:96-8. Epub 2013 May 31.

Department of Pathology and Laboratory Medicine, School of Medicine, University of Louisville, Louisville, KY, USA.

Case Report: A 58-year-old female was admitted to the hospital in a severely malnourished state. She was treated for Crohn's disease with total parental nutrition (TPN). The patient's blood glucose was monitored by point of care (POC) testing every 4h, and a specimen is also drawn daily for metabolic assessment. The POC blood glucose values were consistently much higher than the lab values. Humalog insulin (5 U) was given to the patient to decrease high blood glucose levels that developed following administration of TPN. The patient then became hypoglycemic as a result of this insulin treatment. POC glucose testing, performed every 4h, did not detect the iatrogenic hypoglycemia, while lab glucose results were not given close attention. The lab sample was always drawn 1-2h after insulin was given to the patient and resulted in a lower blood glucose value. In addition, the symptoms of hypoglycemia such as shaking and dizziness were masked by the patient's poor health status, supine position, and the continuously given TPN.

Conclusions: These findings highlighted the importance of the correct sampling time following insulin administration and the consideration of the lab results in addition to POC. The patient's insulin regimen was modified to prevent further hypoglycemic events.
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http://dx.doi.org/10.1016/j.cca.2013.05.023DOI Listing
September 2013

Aliskiren effect on plaque progression in established atherosclerosis using high resolution 3D MRI (ALPINE): a double-blind placebo-controlled trial.

J Am Heart Assoc 2013 May 17;2(3):e004879. Epub 2013 May 17.

Dorothy M. Davis Heart & Lung Research Institute and the Division of Cardiovascular Medicine, The Ohio State University, Columbus, OH 43210, USA.

Background: The renin-angiotensin system is well recognized as a mediator of pathophysiological events in atherosclerosis. The benefits of renin inhibition in atherosclerosis, especially when used in combination with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) are currently not known. We hypothesized that treatment with the renin inhibitor aliskiren in patients with established cardiovascular disease will prevent the progression of atherosclerosis as determined by high-resolution magnetic resonance imaging (MRI) measurements of arterial wall volume in the thoracic and abdominal aortas of high-risk patients with preexisting cardiovascular disease.

Methods And Results: This was a single-center, randomized, double-blind, placebo-controlled trial in patients with established cardiovascular disease. After a 2-week single-blind placebo phase, patients were randomized to receive either placebo (n=37, mean ± SD age 64.5 ± 8.9 years, 3 women) or 150 mg of aliskiren (n=34, mean ± SD age 63.9 ± 11.5 years, 9 women). Treatment dose was escalated to 300 mg at 2 weeks and maintained during the remainder of the study. Patients underwent dark-blood, 3-dimensional MRI assessment of atherosclerotic plaque in the thoracic and abdominal segments at baseline and on study completion or termination (up to 36 weeks of drug or matching placebo). Aliskiren use resulted in significant progression of aortic wall volume (normalized total wall volume 5.31 ± 6.57 vs 0.15 ± 4.39 mm(3), P=0.03, and percentage wall volume 3.37 ± 2.96% vs 0.97 ± 2.02%, P=0.04) compared with placebo. In a subgroup analysis of subjects receiving ACEI/ARB therapy, atherosclerosis progression was observed only in the aliskiren group, not in the placebo group.

Conclusions: MRI quantification of atheroma plaque burden demonstrated that aliskiren use in patients with preexisting cardiovascular disease resulted in an unexpected increase in aortic atherosclerosis compared with placebo. Although preliminary, these results may have implications for the use of renin inhibition as a therapeutic strategy in patients with cardiovascular disease, especially in those receiving ACEI/ARB therapy.

Clinical Trial Registration: URL: http://ClinicalTrials.gov Unique identifier: NCT01417104.
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http://dx.doi.org/10.1161/JAHA.112.004879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3698800PMC
May 2013

The new collaborative path in medical device development: the medical device innovation consortium.

Clin Biochem 2013 Oct 8;46(15):1320-2. Epub 2013 Apr 8.

Department of Pathology and Laboratory Medicine, University of Louisville, Louisville, KY 40292, USA. Electronic address:

The United States medical device market is the world's largest with over $100 billion in sales in 2011. Despite robust industry growth, the efficiency of the FDA approval process for moderate-risk (Class II) and high-risk devices (Class III) requiring 510(k) submission or pre-market approval (PMA) has been criticized. Recently, the FDA's Center for Devices and Radiological Health (CDRH) announced the creation of a Medical Device Innovation Consortium (MDIC), a public-private partnership (PPP) to share knowledge in regulatory science. Overarching goals include creating a forum for the exchange of ideas among the FDA, industry, and non-profit entities; providing monetary investments for project proposals prioritized by key working groups; and developing tools that support cost effective innovation, data-driven methodology, and implementation strategies. Clinical chemists and clinical laboratory scientists have several unique opportunities to contribute to the MDIC. These laboratory professionals have invaluable experience with the real-life performance of a variety of medical devices and their expertise can recognize unmet needs and contribute towards the acceleration of device development.
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http://dx.doi.org/10.1016/j.clinbiochem.2013.03.021DOI Listing
October 2013

Brief critical review: Statistical assessment of biomarker performance.

Clin Chim Acta 2013 Apr 18;419:102-7. Epub 2013 Feb 18.

Department of Pathology and Laboratory Medicine, University of Louisville, Louisville, KY, USA.

Introduction: Articles have suggested that C-statistics associated with receiver operator characteristic (ROC) curves are insufficiently sensitive compared to odds/risk ratios (OR/RR) defined by p-values. Some suggest reclassification techniques are more appropriate.

Methods: We review the concepts of p-values, OR/RR, and ROC curves. We construct a ROC curve, demonstrate parametric and nonparametric curves, and analyze a comparison of ROC curves.

Results: Using these illustrations, we show that the ROC curve is not simply a C-statistic but a continuum of sensitivity/specificity pairs over decision levels. We demonstrate that p-values provide little useful information about discrimination and that OR/RR is a limited expression of a sensitivity/specificity plot. We illustrate that low prevalence produces low positive predictive values, reclassification techniques are subject to the same rules of prevalence as other analysis, and that modifying the analysis can decrease the p-value comparing C-statistics without altering the sensitivity/specificity plot.

Conclusions: ROC curves provide both visual and statistical information to support entry into large-scale trials, determining decision levels and the use of testing in the absence of such trials. If the sensitivity/specificity plot shows little improvement at appropriate decision point(s), statistically significant-improvement in other "novel" statistical indices should be suspect.
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http://dx.doi.org/10.1016/j.cca.2013.02.006DOI Listing
April 2013

Distinct populations of innate CD8+ T cells revealed in a CXCR3 reporter mouse.

J Immunol 2013 Mar 21;190(5):2229-40. Epub 2013 Jan 21.

Department of Pathology, The Ohio State University Medical Center, Columbus, OH 43210, USA.

CXCR3, expressed mainly on activated T and NK cells, is implicated in a host of immunological conditions and can contribute either to disease resolution or pathology. We report the generation and characterization of a novel CXCR3 internal ribosome entry site bicistronic enhanced GFP reporter (CIBER) mouse in which enhanced GFP expression correlates with surface levels of CXCR3. Using CIBER mice, we identified two distinct populations of innate CD8(+) T cells based on constitutive expression of CXCR3. We demonstrate that CXCR3(+) innate CD8(+) T cells preferentially express higher levels of Ly6C and CD122, but lower levels of CCR9 compared with CXCR3(-) innate CD8(+) T cells. Furthermore, we show that CXCR3(+) innate CD8(+) T cells express higher transcript levels of antiapoptotic but lower levels of proapoptotic factors, respond more robustly to IL-2 and IL-15, and produce significantly more IFN-γ and granzyme B. Interestingly, CXCR3(+) innate CD8(+) T cells do not respond to IL-12 or IL-18 alone, but produce significant amounts of IFN-γ on stimulation with a combination of these cytokines. Taken together, these findings demonstrate that CXCR3(+) and CXCR3(-) innate CD8(+) T cells are phenotypically and functionally distinct. These newly generated CIBER mice provide a novel tool for studying the role of CXCR3 and CXCR3-expressing cells in vivo.
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http://dx.doi.org/10.4049/jimmunol.1201170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683850PMC
March 2013

Effects of a novel pharmacologic inhibitor of myeloperoxidase in a mouse atherosclerosis model.

PLoS One 2012 10;7(12):e50767. Epub 2012 Dec 10.

Department of Physiology, Hangzhou Normal University, Hangzhou, China.

Inflammation and oxidative stress play fundamental roles in the pathogenesis of atherosclerosis. Myeloperoxidase has been extensively implicated as a key mediator of inflammatory and redox-dependent processes in atherosclerosis. However, the effect of synthetic myeloperoxidase inhibitors on atherosclerosis has been insufficiently studied. In this study, ApoE(-/-) mice were randomized to low- and high-dose INV-315 groups for 16 weeks on high-fat diet. INV-315 resulted in reduced plaque burden and improved endothelial function in response to acetylcholine. These effects occurred without adverse events or changes in body weight or blood pressure. INV-315 treatment resulted in a decrease in iNOS gene expression, superoxide production and nitrotyrosine content in the aorta. Circulating IL-6 and inflammatory CD11b(+)/Ly6G(low)/7/4(hi) monocytes were significantly decreased in response to INV-315 treatment. Acute pretreatment with INV-315 blocked TNFα-mediated leukocyte adhesion in cremasteric venules and inhibited myeloperoxidase activity. Cholesterol efflux was significantly increased by high-dose INV-315 via ex-vivo reverse cholesterol transport assays. Our results suggest that myeloperoxidase inhibition may exert anti-atherosclerotic effects via inhibition of oxidative stress and enhancement of cholesterol efflux. These findings demonstrate a role for pharmacologic modulation of myeloperoxidase in atherosclerosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050767PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3519467PMC
June 2013

In vivo targeting of inflammation-associated myeloid-related protein 8/14 via gadolinium immunonanoparticles.

Arterioscler Thromb Vasc Biol 2012 Apr 2;32(4):962-70. Epub 2012 Feb 2.

Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, USA.

Objective: Myeloid-related protein (Mrp) 8/14 complex (is a highly expressed extracellularly secreted protein, implicated in atherosclerosis. In this study, we evaluated the feasibility of targeting Mrp in vivo through synthetic immuno-nanoprobes.

Methods And Results: Anti-Mrp-14 and nonspecific IgG-conjugated gadolinium nanoprobes (aMrp-) were synthesized and characterized. Pharmacokinetics and vascular targeting via MRI of the formulations were assessed in vivo in high fat-fed apolipoprotein E deficient (ApoE(-/-)), ApoE(-/-)/Mrp14(-/-) (double knockout) and chow-fed wild-type (C57BL/6) mice. Bone marrow-derived myeloid progenitor cells were isolated from both ApoE(-/-) and double knockout mice, differentiated to macrophages, and were treated with LPS, with or without Mrp8, Mrp14, or Mrp8/14; conditioned media was used for in vitro studies. Mrp-activated cells secreted significant amounts of proinflammatory cytokines, which was abolished by pretreatment with aMrp-NP. We show in vitro that aMrp-NP binds endothelial cells previously treated with conditioned media containing Mrp8/14. MRI following intravenous delivery of aMrp-NP revealed prolonged and substantial delineation of plaque in ApoE(-/-) but not double knockout or wild-type animals. Nonspecific IgG-conjugated gadolinium nanoprobe-injected animals in all groups did not show vessel wall enhancement. Flow-cytometric analysis of aortic digesta revealed that aMrp-NP present in Ly-6G(+), CD11b(+), CD11c(+), and CD31(+) cells in ApoE(-/-) but not in double knockout animals.

Conclusions: Targeted imaging with aMrp-NP demonstrates enhancement of plaque with binding to inflammatory cells and reduction in inflammation. This strategy has promise as a theranostic approach for atherosclerosis.
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http://dx.doi.org/10.1161/ATVBAHA.111.244509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348503PMC
April 2012

Pulmonary T cell activation in response to chronic particulate air pollution.

Am J Physiol Lung Cell Mol Physiol 2012 Feb 9;302(4):L399-409. Epub 2011 Dec 9.

Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, USA.

The purpose of this study was to investigate the effects of chronically inhaled particulate matter <2.5 μm (PM(2.5)) on inflammatory cell populations in the lung and systemic circulation. A prominent component of air pollution exposure is a systemic inflammatory response that may exaggerate chronic diseases such as atherosclerosis and insulin resistance. T cell response was measured in wild-type C57B/L6, Foxp3-green fluorescent protein (GFP) "knockin," and chemokine receptor 3 knockout (CXCR3(-/-)) mice following 24-28 wk of PM(2.5) or filtered air. Chronic PM(2.5) exposure resulted in increased CXCR3-expressing CD4(+) and CD8(+) T cells in the lungs, spleen, and blood with elevation in CD11c(+) macrophages in the lung and oxidized derivatives of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine in wild-type mice. CXCR3 deficiency decreased T cells in the lung. GFP(+) regulatory T cells increased with PM(2.5) exposure in the spleen and blood of Foxp3-GFP mice but were present at very low levels in the lung irrespective of PM(2.5) exposure. Mixed lymphocyte cultures using primary, PM(2.5)-treated macrophages demonstrated enhanced T cell proliferation. Our experiments indicate that PM(2.5) potentiates a proinflammatory Th1 response involving increased homing of CXCR3(+) T effector cells to the lung and modulation of systemic T cell populations.
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http://dx.doi.org/10.1152/ajplung.00261.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289266PMC
February 2012

Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis.

Circulation 2011 Nov 17;124(21):2338-49. Epub 2011 Oct 17.

Davis Heart & Lung Research Institute, 473 W 12th Avenue, Columbus, OH 43210, USA.

Background: Dipeptidyl-peptidase 4 (DPP-4) inhibitors are increasingly used to accomplish glycemic targets in patients with type II diabetes mellitus. Because DPP-4 is expressed in inflammatory cells, we hypothesized that its inhibition will exert favorable effects in atherosclerosis.

Methods And Results: Male LDLR(-/-) mice (6 weeks) were fed a high-fat diet or normal chow diet for 4 weeks and then randomized to vehicle or alogliptin, a high-affinity DPP-4 inhibitor (40 mg · kg(-1) · d(-1)), for 12 weeks. Metabolic parameters, blood pressure, vascular function, atherosclerosis burden, and indexes of inflammation were obtained in target tissues, including the vasculature, adipose, and bone marrow, with assessment of global and cell-specific inflammatory pathways. In vitro and in vivo assays of DPP-4 inhibition (DPP-4i) on monocyte activation/migration were conducted in both human and murine cells and in a short-term ApoE(-/-) mouse model. DPP-4i improved markers of insulin resistance and reduced blood pressure. DPP-4i reduced visceral adipose tissue macrophage content (adipose tissue macrophages; CD11b(+), CD11c(+), Ly6C(hi)) concomitant with upregulation of CD163. DPP-4 was highly expressed in bone marrow-derived CD11b(+) cells, with DPP-4i downregulating proinflammatory genes in these cells. DPP-4i decreased aortic plaque with a striking reduction in plaque macrophages. DPP-4i prevented monocyte migration and actin polymerization in in vitro assays via Rac-dependent mechanisms and prevented in vivo migration of labeled monocytes to the aorta in response to exogenous tumor necrosis factor-α and DPP-4.

Conclusion: DPP-4i exerts antiatherosclerotic effects and reduces inflammation via inhibition of monocyte activation/chemotaxis. These findings have important implications for the use of this class of drugs in atherosclerosis.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.111.041418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224594PMC
November 2011

Acute DPP-4 inhibition modulates vascular tone through GLP-1 independent pathways.

Vascul Pharmacol 2011 Jul-Sep;55(1-3):2-9. Epub 2011 Mar 10.

Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH, USA.

Evidence from both clinical and experimental studies indicates that Di-peptidyl peptidase-IV (DPP-4) inhibition may mediate favorable effects on the cardiovascular system. The objective of this study was to examine the acute effects of DPP-4 inhibition on vascular responses and to study the underlying mechanisms of alteration in tone. Aortic segments from C57BL/6 mice were treated with vasoconstrictors and exposed to various doses of alogliptin, a selective DPP-4 inhibitor. Vasodilator responses were evaluated using pathway specific antagonists to elucidate mechanisms of response. In parallel experiments, cultured human umbilical vein endothelial cells (HUVEC) were exposed to varying concentrations of alogliptin to evaluate the effects on candidate vasodilator pathways. Alogliptin relaxed phenylephrine and U46619 pre-constricted aortic segments in a dose dependent manner. Relaxation responses were not affected by the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin fragment 9-39 (88 ± 6 vs. 91 ± 2, p < 0.001). Vascular relaxation to alogliptin was significantly decreased by endothelial denudation, L-N(G)-monomethyl-arginine citrate (L-NMMA) and by the soluble guanylate cyclase inhibitor ODQ. DPP-4 inhibition induced relaxation was completely abolished by a combination of L-NMMA, charybdotoxin and apamin. Incubation of HUVECs with alogliptin resulted in eNOS and Akt phosphorylation (Ser(1177) and Ser(473) respectively) paralleled by a rapid increase in nitric oxide. Inhibition of Src kinase decreased eNOS and Akt phosphorylation, in contrast to a lack of any effect on insulin mediated activation of the eNOS-Akt, suggesting that alogliptin mediates vasodilation through Src kinase mediated effects on eNOS-Akt. DPP-4 inhibition by alogliptin mediates rapid vascular relaxation via GLP-1 independent, Src-Akt-eNOS mediated NO release and the activation of vascular potassium channels.
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http://dx.doi.org/10.1016/j.vph.2011.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845951PMC
January 2012

Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers.

PLoS One 2011 Jan 26;6(1):e16376. Epub 2011 Jan 26.

Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.

Background: The development of insulin resistance (IR) in mouse models of obesity and type 2 diabetes mellitus (DM) is characterized by progressive accumulation of inflammatory macrophages and subpopulations of T cells in the visceral adipose. Regulatory T cells (Tregs) may play a critical role in modulating tissue inflammation via their interactions with both adaptive and innate immune mechanisms. We hypothesized that an imbalance in Tregs is a critical determinant of adipose inflammation and investigated the role of Tregs in IR/obesity through coordinated studies in mice and humans.

Methods And Findings: Foxp3-green fluorescent protein (GFP) "knock-in" mice were randomized to a high-fat diet intervention for a duration of 12 weeks to induce DIO/IR. Morbidly obese humans without overt type 2 DM (n = 13) and lean controls (n = 7) were recruited prospectively for assessment of visceral adipose inflammation. DIO resulted in increased CD3(+)CD4(+), and CD3(+)CD8(+) cells in visceral adipose with a striking decrease in visceral adipose Tregs. Treg numbers in visceral adipose inversely correlated with CD11b(+)CD11c(+) adipose tissue macrophages (ATMs). Splenic Treg numbers were increased with up-regulation of homing receptors CXCR3 and CCR7 and marker of activation CD44. In-vitro differentiation assays showed an inhibition of Treg differentiation in response to conditioned media from inflammatory macrophages. Human visceral adipose in morbid obesity was characterized by an increase in CD11c(+) ATMs and a decrease in foxp3 expression.

Conclusions: Our experiments indicate that obesity in mice and humans results in adipose Treg depletion. These changes appear to occur via reduced local differentiation rather than impaired homing. Our findings implicate a role for Tregs as determinants of adipose inflammation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0016376PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3027666PMC
January 2011

Chronic fine particulate matter exposure induces systemic vascular dysfunction via NADPH oxidase and TLR4 pathways.

Circ Res 2011 Mar 27;108(6):716-26. Epub 2011 Jan 27.

Davis Heart & Lung Research Institute, Ohio State University College of Medicine, Columbus, OH 43210, USA.

Rationale: Chronic exposure to ambient air-borne particulate matter of < 2.5 μm (PM₂.₅) increases cardiovascular risk. The mechanisms by which inhaled ambient particles are sensed and how these effects are systemically transduced remain elusive.

Objective: To investigate the molecular mechanisms by which PM₂.₅ mediates inflammatory responses in a mouse model of chronic exposure.

Methods And Results: Here, we show that chronic exposure to ambient PM₂.₅ promotes Ly6C(high) inflammatory monocyte egress from bone-marrow and mediates their entry into tissue niches where they generate reactive oxygen species via NADPH oxidase. Toll-like receptor (TLR)4 and Nox2 (gp91(phox)) deficiency prevented monocyte NADPH oxidase activation in response to PM₂.₅ and was associated with restoration of systemic vascular dysfunction. TLR4 activation appeared to be a prerequisite for NAPDH oxidase activation as evidenced by reduced p47(phox) phosphorylation in TLR4 deficient animals. PM₂.₅ exposure markedly increased oxidized phospholipid derivatives of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC) in bronchioalveolar lavage fluid. Correspondingly, exposure of bone marrow-derived macrophages to oxPAPC but not PAPC recapitulated effects of chronic PM₂.₅ exposure, whereas TLR4 deficiency attenuated this response.

Conclusions: Taken together, our findings suggest that PM₂.₅ triggers an increase in oxidized phospholipids in lungs that then mediates a systemic cellular inflammatory response through TLR4/NADPH oxidase-dependent mechanisms.
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http://dx.doi.org/10.1161/CIRCRESAHA.110.237560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085907PMC
March 2011

A modified sesamol derivative inhibits progression of atherosclerosis.

Arterioscler Thromb Vasc Biol 2011 Mar 23;31(3):536-42. Epub 2010 Dec 23.

Davis Heart Lung Research Institute, Ohio State University, Columbus, OH 43210-1252, USA.

Objective: Sesamol, a phenolic component of lignans, has been previously shown to reduce lipopolysaccharide-induced oxidative stress and upregulate phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase pathways. In the present study, we synthesized a modified form of sesamol (INV-403) to enhance its properties and assessed its effects on atherosclerosis.

Methods And Results: Watanabe heritable hyperlipidemic rabbits were fed with high-cholesterol chow for 6 weeks and then randomized to receive high-cholesterol diet either alone or combined with INV-403 (20 mg/kg per day) for 12 weeks. Serial MRI analysis demonstrated that INV-403 rapidly reduced atherosclerotic plaques (within 6 weeks), with confirmatory morphological analysis at 12 weeks posttreatment revealing reduced atherosclerosis paralleled by reduction in lipid and inflammatory cell content. Consistent with its effect on atherosclerosis, INV-403 improved vascular function (decreased constriction to angiotensin II and increased relaxation to acetylcholine), reduced systemic and plaque oxidative stress, and inhibited nuclear factor-κB activation via effects on nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) phosphorylation with coordinate reduction in key endothelial adhesion molecules. In vitro experiments in cultured endothelial cells revealed effects of INV-403 in reducing IκBα phosphorylation via inhibition of IκB kinase 2 (IKK2).

Conclusions: INV-403 is a novel modified lignan derivative that potently inhibits atherosclerosis progression via its effects on IKK2 and nuclear factor-κB signaling.
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http://dx.doi.org/10.1161/ATVBAHA.110.219287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343762PMC
March 2011

Evidence that α-lipoic acid inhibits NF-κB activation independent of its antioxidant function.

Inflamm Res 2011 Mar 7;60(3):219-25. Epub 2010 Oct 7.

Davis Heart and Lung Research Institute, Colleges of Medicine and Public Health, The Ohio State University, Room 110, 473W 12th Avenue, Columbus, OH 43210-1252, USA.

Objective: α-Lipoic acid (LA) exerts beneficial effects in cardiovascular diseases though its antioxidant and/or anti-inflammatory functions. It is postulated that the anti-inflammatory function of LA results from its antioxidant function. In this study we tested whether inhibition of NF-κB by LA is dependent on its antioxidant function.

Methods: Human umbilical vein endothelial cells (HUVECs) were treated with tumor necrosis factor-α (TNFα) in the presence of various antioxidants, including LA, tiron, apocynin, and tempol. The activation of the nuclear factor-κB (NF-κB) signaling pathway was then analyzed.

Results: LA, but not other tested antioxidants, inhibited TNFα-induced inhibitor-kappaB-α (IκBα) degradation and VCAM-1 and COX2 expression in HUVECs. Although LA activated the phosphatidylinositol-3-kinase (PI3-kinase)/Akt pathway in HUVECs, inhibition of Akt by LY294002 did not affect inhibition of TNFα-induced IκBα degradation by LA. In transient co-transfection assays of a constitutively active mutant of IκB kinase-2 (IKK2), IKK2(EE), and a NF-κB luciferase reporter construct, LA dose-dependently inhibited IKK2(EE)-induced NF-κB activation in addition to inhibiting IKK activity in in vitro assays. Consistent with the effect on luciferase expression, LA inhibited IKK2(EE)-induced cyclo-oxygenase-2 (COX2) expression, suggesting that IKK2 inhibition by LA may be a relevant mechanism that explains its anti-inflammatory effects.

Conclusions: LA inhibits NF-κB activation through antioxidant-independent and probably IKK-dependent mechanisms.
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http://dx.doi.org/10.1007/s00011-010-0256-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832356PMC
March 2011

Effect of early particulate air pollution exposure on obesity in mice: role of p47phox.

Arterioscler Thromb Vasc Biol 2010 Dec 23;30(12):2518-27. Epub 2010 Sep 23.

Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus 43210, USA.

Objective: To evaluate the role of early-life exposure to airborne fine particulate matter (diameter, <2.5 μm [PM(2.5)]) pollution on metabolic parameters, inflammation, and adiposity; and to investigate the involvement of oxidative stress pathways in the development of metabolic abnormalities.

Methods And Results: PM(2.5) inhalation exposure (6 h/d, 5 d/wk) was performed in C57BL/6 mice (wild type) and mice deficient in the cytosolic subunit of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p47(phox) (p47(phox-/-)) beginning at the age of 3 weeks for a duration of 10 weeks. Both groups were simultaneously fed a normal diet or a high-fat diet for 10 weeks. PM(2.5)-exposed C57BL/6 mice fed a normal diet exhibited metabolic abnormalities after exposure to PM(2.5) or FA for 10 weeks. Consistent with insulin resistance, these abnormalities included enlarged subcutaneous and visceral fat contents, increased macrophage infiltration in visceral adipose tissue, and vascular dysfunction. Ex vivo-labeled and infused monocytes demonstrated increased adherence in the microcirculation of normal diet- or high-fat diet-fed PM(2.5)-exposed mice. p47(phox-/-) mice exhibited an improvement in parameters of insulin resistance, vascular function, and visceral inflammation in response to PM(2.5).

Conclusions: Early-life exposure to high levels of PM(2.5) is a risk factor for subsequent development of insulin resistance, adiposity, and inflammation. Reactive oxygen species generation by NADPH oxidase appears to mediate this risk.
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http://dx.doi.org/10.1161/ATVBAHA.110.215350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065931PMC
December 2010

Lipoic acid effects on established atherosclerosis.

Life Sci 2010 Jan 26;86(3-4):95-102. Epub 2009 Nov 26.

Davis Heart Lung Research Institute, College of Medicine, and Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio 43210-1252, USA.

Aims: Alpha-lipoic acid (LA) is a commonly used dietary supplement that exerts anti-oxidant and anti-inflammatory effects in vivo and in vitro. We investigated the mechanisms by which LA may confer protection in models of established atherosclerosis.

Main Methods: Watanabe heritable hyperlipidemic (WHHL) rabbits were fed with high cholesterol chow for 6 weeks and then randomized to receive either high cholesterol diet alone or combined with LA (20mg/kg/day) for 12 weeks. Vascular function was analyzed by myography. The effects of LA on T cell migration to chemokine gradients was assessed by Boyden chamber. NF-kappaB activation was determined by measuring translocation and electrophoresis migration shift assay (EMSA).

Key Findings: LA decreased body weight by 15+/-5% without alterations in lipid parameters. Magnetic Resonance Imaging (MRI) analysis demonstrated that LA reduced atherosclerotic plaques in the abdominal aorta, with morphological analysis revealing reduced lipid and inflammatory cell content. Consistent with its effect on atherosclerosis, LA improved vascular reactivity (decreased constriction to angiotensin II and increased relaxation to acetylcholine and insulin), inhibited NF-kappaB activation, and decreased oxidative stress and expression of key adhesion molecules in the vasculature. LA reduced T cell content in atherosclerotic plaque in conjunction with decreasing ICAM and CD62L (l-selectin) expression. These effects were confirmed by demonstration of a direct effect of LA in reducing T cell migration in response to CCL5 and SDF-1 and decreasing T cell adhesion to the endothelium by intra-vital microscopy.

Significance: The present findings offer a mechanistic insight into the therapeutic effects of LA on atherosclerosis.
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http://dx.doi.org/10.1016/j.lfs.2009.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075920PMC
January 2010

A mouse model of yellow fluorescent protein (YFP) expression in hematopoietic cells to assess leukocyte-endothelial interactions in the microcirculation.

Microvasc Res 2009 Dec 12;78(3):294-300. Epub 2009 Aug 12.

Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, 473 W. 12th Avenue, Room 110, Columbus, OH 43210, USA.

In this study, we describe the use of intravital microscopy in a transgenic mouse model expressing yellow fluorescent protein (YFP) under the control of a monocyte specific promoter c-fms (CD115) to track and quantify specific leukocyte subsets. Flow cytometry on peripheral and bone marrow leukocytes revealed that YFP was predominantly expressed by CD11a(+), CD11b(+), and CD14(+) monocytes. In the bone marrow, 67+/-4% of Ly6C(high) F4/80(+) cells were YFP(high) while 55+/-1% of Ly6C(low) F4/80(+) cells were YFP(low) supporting the use of c-fms(YFP) expression as a marker of monocyte lineage. 70+/-7% of CD11b(+) F4/80(+) Ly6C(+) ("triple positive") cells expressed YFP. To assess leukocyte-endothelial interactions in YFP(+) cells in c-fms(YFP+) mice, we evaluated leukocyte adhesion, rolling and local shear stress responses in the cremasteric endothelium 4 h following administration of TNFalpha. TNFalpha resulted in a five-fold increase in adhesion of YFP(+) cells to the endothelium and provided superior discriminative ability in assessing rolling and adhesion events when compared with bright field microscopy. Additionally, when compared with Rhodamine-6G labeled leukocytes or GFP(+) cells in mice transplanted with green fluorescent protein (GFP) positive bone marrow, the level of detail observed in the c-fms(YFP+) was greater, with both GFP(+) and YFP(+) cells demonstrating superior signal to noise compared to bright field microscopy. A weak positive linear correlation between wall shear stress and YFP(+) cell adhesion (r(2)=0.20, p<0.05) was seen in the cremasteric microcirculation. Taken together, these data demonstrate the use of c-fms(YFP+) mice in identifying distinct monocyte subsets and highlight the potential of this model for real-time monocyte-endothelial interactions using intravital microscopy.
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http://dx.doi.org/10.1016/j.mvr.2009.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073496PMC
December 2009

Ambient particulates alter vascular function through induction of reactive oxygen and nitrogen species.

Toxicol Sci 2009 Sep 30;111(1):80-8. Epub 2009 Jan 30.

Davis Heart & Lung Research Institute, Ohio State University, Columbus, Ohio 43210, USA.

Previous studies have shown a link between inhaled particulate matter (PM) exposure in urban areas and susceptibility to cardiovascular diseases. Although an oxidative stress pathway is strongly implicated, the locus of generation of reactive oxygen species (ROS) and the mechanisms by which these radicals exert their effects remain to be characterized. To test the hypothesis that exposure to environmentally relevant inhaled concentrated ambient PM (CAPs) enhances atherosclerosis through induction of vascular ROS and reactive nitrogen species. High-fat chow fed apolipoprotein E(-/-) mice were exposed to CAPs of less than 2.5 microm (PM(2.5)) or filtered air (FA), for 6 h/day, 5 days/week, for 4 months in Manhattan, NY. Atherosclerotic lesions were analyzed by histomorphometricly. Vascular reactivity, superoxide generation, mRNA expression of NADPH (nicotinamide adenine dinucleotide phosphate, reduced) oxidase subunits, inducible nitric oxide synthase, endothelial nitric oxide synthase, and GTP cyclohydrolase I were also assessed. Manhattan PM(2.5) CAPs were characterized by higher concentrations of organic and elemental carbon. Analysis of vascular responses revealed significantly decreased phenylephrine constriction in CAPs-exposed mice, which was restored by a soluble guanine cyclase inhibitor 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one. Vascular relaxation to A23187, but not to acetylcholine, was attenuated in CAPs mice. Aortic expression of NADPH oxidase subunits (p47(phox) and rac1) and iNOS were markedly increased, paralleled by increases in superoxide generation and extensive protein nitration in the aorta. The composite plaque area of thoracic aorta was significantly increased with pronounced macrophage infiltration and lipid deposition in the CAPs mice. CAPs exposure in Manhattan alters vasomotor tone and enhances atherosclerosis through NADPH oxidase dependent pathways.
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http://dx.doi.org/10.1093/toxsci/kfp004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726294PMC
September 2009

Ambient air pollution exaggerates adipose inflammation and insulin resistance in a mouse model of diet-induced obesity.

Circulation 2009 Feb 19;119(4):538-46. Epub 2009 Jan 19.

Wolfe Professor of Medicine and Radiology, Davis Heart and Lung Research Institute, Room 110, 473 W 12th Ave, Columbus, OH 43210-1252, USA.

Background: There is a strong link between urbanization and type 2 diabetes mellitus. Although a multitude of mechanisms have been proposed, there are no studies evaluating the impact of ambient air pollutants and the propensity to develop type 2 diabetes mellitus. We hypothesized that exposure to ambient fine particulate matter (<2.5 mum; PM(2.5)) exaggerates diet-induced insulin resistance, adipose inflammation, and visceral adiposity.

Methods And Results: Male C57BL/6 mice were fed high-fat chow for 10 weeks and randomly assigned to concentrated ambient PM(2.5) or filtered air (n=14 per group) for 24 weeks. PM(2.5)-exposed C57BL/6 mice exhibited marked whole-body insulin resistance, systemic inflammation, and an increase in visceral adiposity. PM(2.5) exposure induced signaling abnormalities characteristic of insulin resistance, including decreased Akt and endothelial nitric oxide synthase phosphorylation in the endothelium and increased protein kinase C expression. These abnormalilties were associated with abnormalities in vascular relaxation to insulin and acetylcholine. PM(2.5) increased adipose tissue macrophages (F4/80(+) cells) in visceral fat expressing higher levels of tumor necrosis factor-alpha/interleukin-6 and lower interleukin-10/N-acetyl-galactosamine specific lectin 1. To test the impact of PM(2.5) in eliciting direct monocyte infiltration into fat, we rendered FVBN mice expressing yellow fluorescent protein (YFP) under control of a monocyte-specific promoter (c-fms, c-fms(YFP)) diabetic over 10 weeks and then exposed these mice to PM(2.5) or saline intratracheally. PM(2.5) induced YFP cell accumulation in visceral fat and potentiated YFP cell adhesion in the microcirculation.

Conclusions: PM(2.5) exposure exaggerates insulin resistance and visceral inflammation/adiposity. These findings provide a new link between air pollution and type 2 diabetes mellitus.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.108.799015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3845676PMC
February 2009

Gadolinium-containing phosphatidylserine liposomes for molecular imaging of atherosclerosis.

J Lipid Res 2009 Nov 17;50(11):2157-63. Epub 2008 Nov 17.

Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH, USA.

Exteriorized phosphatidylserine (PS) residues in apoptotic cells trigger rapid phagocytosis by macrophage scavenger receptor pathways. Mimicking apoptosis with liposomes containing PS may represent an attractive approach for molecular imaging of atherosclerosis. We investigated the utility of paramagnetic gadolinium liposomes enriched with PS (Gd-PS) in imaging atherosclerotic plaque. Gd-PS-containing Gd-conjugated lipids, fluorescent rhodamine, and PS were prepared and characterized. Cellular uptake in RAW macrophages (fluorescent uptake of rhodamine) was studied on a fluorescence plate reader, while Gd-PS-induced alteration in T1 relaxivity was evaluated using a 1.5 T MRI scanner. RAW cells demonstrate PS-dependent uptake of across a range of concentrations (2, 6, 12, and 20%) in comparison to control liposomes with no PS (0%). In vivo performance of Gd-PS was evaluated in the ApoE(-/-) mouse model by collection of serial T1 weighted gradient echo MR images using an 11.7 T MRI system and revealed rapid and significant enhancement of the aortic wall that was seen for at least 4 h after injection. Gd-PS-enriched liposomes enhance atherosclerotic plaque and colocalize with macrophages in experimental atherosclerosis.
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http://dx.doi.org/10.1194/jlr.M800405-JLR200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2759821PMC
November 2009

Experimental hypoxia is a potent stimulus for radiotracer uptake in vitro: comparison of different tumor cells and primary endothelial cells.

Cancer Lett 2007 Aug 2;254(1):102-10. Epub 2007 Apr 2.

Institute of Radiopharmacy, Research Center Dresden-Rossendorf, Dresden, Germany.

Hypoxia causes upregulation of vascular endothelial growth factor (VEGF) which is a key regulator in tumor angiogenesis and essential for the proliferation of endothelial cells. Endothelial cells have been described to accumulate radiotracers like (18)F-FDG. However, the contribution of radiotracer uptake by endothelial cells to uptake measured in tumors by positron emission tomography (PET) is still unclear. In this study (18)F-FDG and (18)F-FMISO radiotracer uptake in various tumor and primary endothelial cells cultured at hypoxic conditions was investigated. Experimental hypoxia was confirmed by significant upregulation of VEGF mRNA. In comparison to normoxic conditions, cellular uptake of (18)F-FDG was significantly increased at hypoxic conditions in two of the tumor and all endothelial cells, whereas (18)F-FMISO uptake was only enhanced in tumor cell lines HT-29 and MCF-7. Our data showed a marked influence of experimental hypoxia on the metabolism and gene expression of tumor and endothelial cells in vitro. This indicates an important contribution of endothelial cells to (18)F-FDG radiotracer uptake in tumors and for the visualization of tumors by means of PET.
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http://dx.doi.org/10.1016/j.canlet.2007.02.016DOI Listing
August 2007