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Biomedical subjects

Georg Wick

Publications and source records attributed to Georg Wick.

At least 19 recordsLinked to original sources
PubMed2007

Identification and dynamics of proteins adhering to the surface of medical silicones in vivo and in vitro.

Silicone has been used in medical practice as a paradigmatic implant material for decades despite significant detrimental side effects. Our targeted proteomics approach was aimed at identification of the proteins adsorbed to the surface of silicone because they have been characterized as key components in the onset and perpetuation of local immune reactions to silicone. The composition of the proteinacious film, the dynamics of protein deposition, and protein modifications after adsorption were analyzed both in vivo and in vitro. Differential analysis of protein deposition was performed, followed by protein identification with mass spectrometry, database matching, and Western blots. Thus far, we have identified the 30 most abundant proteins deposited on the surface of silicone, the largest known inventory of such proteins so far. Structural and extracellular matrix proteins predominated, followed by mediators of host defense, metabolism, transport, and stress related proteins. In addition, several biochemical modifications of fibronectin, vitronectin, and heat shock protein 60 were detected. Our analyses also revealed previously undetected proteins deposited on the surface of silicone. As tentative initiators and/or modulators of the response to silicone, they are therefore valuable candidates for prognosis and therapy.

Adsorption↗
PubMed2006

Isogentisin--a novel compound for the prevention of smoking-caused endothelial injury.

The best strategy in the fight against tobacco-induced diseases is prevention. However, more than one billion people around the world are smokers. Most of these people will develop or already suffer from tobacco-induced diseases. In this project, we screened 22 natural alpine plant extracts for their potential to protect human vascular endothelial cells from cigarette smoke-induced cell damage. Extracts from Gentiana lutea (Yellow Gentian) proved to be effective, and were therefore subjected to bio-guided fractionation. Although our analyses suggest that G. lutea contains several active principles, fractions containing isogentisin (1,3-dihydroxy-7-methoxyxanthone), and pure isogentisin, were most effective. In experiments addressing the nature of the mechanism of protection, we were able to show that isogentisin does not directly interfere with cigarette smoke chemicals. Addition of isogentisin to the cells as long as 4.5h after exposure to cigarette smoke chemicals protected endothelial cells from cell death. Finally, detailed analyses of intracellular oxidative stress and protein oxidation suggest that isogentisin promotes cell survival by activating cellular repair functions.

Apoptosis↗
PubMed2006

Identification of atherosclerosis-associated conformational heat shock protein 60 epitopes by phage display and structural alignment.

Autoimmune reactions to HSP60 are believed to play a key role during development of early atherosclerosis. Due to the high degree of phylogenetic conservation between microbial and human HSP60, bacterial infections might be responsible for inducing cross-reactivity to self HSP60, which is expressed on the surface of arterial endothelial cells stressed by classical atherosclerosis risk factors. Conformational epitopes recognized by polyclonal anti-mycobacterial HSP60 antibodies from subjects with atherosclerosis were identified using a phage displayed random library of cyclic constrained 7mer peptides. After five rounds of selection, DNA sequencing of strongly binding clones revealed that one peptide motif (CIGSPSTNC) was present in 64% of all clones, and a second motif (CSFHYQNRC) in 14%. Using a newly developed method for structural alignment of small constrained peptides onto a protein surface, we located the motif present in 14% of all clones on the surface of mycobacterial HSP60. The motif present in 64% of all clones was found on the surface of mycobacterial HSP60 as well as in the homologous region of human HSP60, which makes this epitope a promising candidate for further investigations on cross-reactive epitopes involved in early atherogenesis.

Amino Acid Sequence↗
PubMed2006

Cigarette smoke--an aging accelerator?

Cigarette smoking reduces life span by an average of 7 years, and tobacco consumption accounts for a shortening of disease free life by 14 years. The exact mechanisms by which smoking causes disease and death are generally not well understood, but evidence continues to mount that cigarette smoking exhausts cellular defense and repair functions, leading to an accumulation of damage e.g. mutations and malfunctioning proteins. In this review, we make an attempt to ascribe many of the deleterious effects of smoking on human health to a general principle, namely the acceleration of aging processes by cigarette smoke chemicals.

Aging↗
PubMed2006

Atherosclerosis research from past to present--on the track of two pathologists with opposing views, Carl von Rokitansky and Rudolf Virchow.

It is now clear that inflammation plays a key role in atherogenesis. As a matter of fact, signs of inflammation of atherosclerotic plaques have been observed for centuries and also constituted the basis for a fierce controversy in the 19th century between the prominent Austrian pathologist Carl von Rokitansky and his German counterpart, Rudolf Virchow. While the former attributed a secondary role to these inflammatory arterial changes, Virchow considered them to be of primary importance. We had the unique opportunity to address this controversy by investigating atherosclerotic specimens from autopsies performed by Carl von Rokitansky up to 178 years ago. Twelve atherosclerotic arteries originally collected between the years 1827 to 1885 were selected from the Collection Rokitansky of the Federal Museum of Pathological Anatomy, Vienna Medical University. Using modern sophisticated immunohistochemical and immunofluorescence techniques, it was shown that various cellular intralesional components, as well as extracellular matrix proteins, were preserved in the historic atherosclerotic specimens. Most importantly, CD3 positive cells were abundant in early lesions, thus, rather supporting Virchows's view, that inflammation is an initiating factor in atherogenesis. Furthermore, we hope to have opened a new and intriguing possibility to study various pathological conditions using valuable historical specimens.

Atherosclerosis↗
PubMed2006

Hydrogen peroxide-mediated necrosis induction in HUVECs is associated with an atypical pattern of caspase-3 cleavage.

Oxidative stress, continuously exerted during chronic inflammation, has been implicated as a major causative agent of cellular dysfunction and cell death. In the present study, we investigated the impact of oxidative stress on the mode of cell death in HUVECs using H2O2 as a model reagent. We found that the predominant form of cell death was necrosis. Necrosis induction was accompanied by a distinct mode of caspase-3 cleavage, yielding a 29-kDa fragment. While inhibition of caspases could not prevent the generation of the 29-kDa fragment, general protease inhibitors, such as leupeptin and LLNL, proved to be effective in inhibiting the distinct processing pattern of caspase-3. These results suggest that caspases can act as substrates for non-caspase proteases in cells primed for necrosis induction. Thus, the pattern of caspase-3 cleavage might reflect the proteolytic system engaged in the cell death machinery in HUVECs.

Amino Acid Chloromethyl Ketones↗
PubMed2006

Increased serum cadmium and strontium levels in young smokers: effects on arterial endothelial cell gene transcription.

OBJECTIVE: Metal constituents of tobacco have long been suspected to contribute to cardiovascular diseases. In this study, we determined the serum concentrations of aluminum, cadmium (Cd), cobalt, copper, iron, manganese, nickel, lead, strontium (Sr), and zinc of young nonsmokers, passive smokers, and smokers. METHODS AND RESULTS: Cd and Sr were found to be significantly increased in smokers compared with nonsmokers. The effects of these metals on primary arterial endothelial cells were then assessed using microarray technology and real-time polymerase chain reaction (RT-PCR). The data showed that Sr does not interfere with endothelial cell transcription. In contrast, the effects of Cd in amounts delivered to the human body by smoking were dramatic. CONCLUSIONS: Arterial endothelial cells responded to Cd exposure by massively upregulating metal and oxidant defense genes (metallothioneins) and by downregulating a number of transcription factors. In addition, the mRNA of the intermediate filament protein vimentin, crucial for the maintenance of cellular shape, was reduced. Surprisingly, a number of pro-inflammatory genes were downregulated in response to Cd. The present data suggest that by delivering Cd to the human body, smoking deregulates transcription, exerts stress, and damages the structure of the vascular endothelium; furthermore, in contrast to the effects of cigarette smoke as a whole, Cd seems to possess anti-inflammatory properties.

Adult↗
PubMed2006

An interstitial network of podoplanin-expressing cells in the human endolymphatic duct.

The human endolymphatic duct (ED) with encompassing interstitial connective tissue (CT) is believed to be important for endolymph resorption and fluid pressure regulation of the inner ear. The periductal CT cells are interconnected via numerous cellular extensions, but do not form vessel structures. Here we report that the periductal CT is populated by two distinct cell phenotypes; one expressing podoplanin, a protein otherwise found on lymph endothelia and on epithelia involved in fluid fluxes, and a second expressing a fibroblast marker. A majority of the interstitial cells expressed podoplanin but not the lymphatic endothelial cell markers hyaluronan receptor (LYVE-1) or vascular endothelial growth factor receptor-3 (VEGFR-3). The fibroblast marker positive cells were found close to the ED epithelium. In the mid- and distal parts of the ED, these cells were enriched under folded epithelia. Furthermore, subepithelial CT cells were found to express activated platelet derived growth factor (PDGF)-beta receptors. Cultured CT cells from human inner ear periductal and perisaccular explant tissues were identified as fibroblasts. These cells compacted a three-dimensional collagen lattice by a process that could be promoted by PDGF-BB, a factor involved in interstitial fluid pressure regulation. Our results are compatible with the notion that the periductal CT cells are involved in the regulation of inner ear fluid pressure. By active compaction of the periductal CT and by the formation of villous structures, the CT cells could modulate fluid fluxes over the ED epithelium as well as the longitudinal flow of endolymph in the ED.

Biomarkers↗
PubMed2006

Avian models with spontaneous autoimmune diseases.

Autoimmune diseases in human patients only become clinically manifest when the disease process has developed to a stage where functional compensation by the afflicted organ or system is not possible anymore. In order to understand the initial etiologic and pathogenic events that are generally not yet accessible in humans, appropriate animal models are required. In this respect, spontaneously developing models--albeit rare--reflect the situation in humans much more closely than experimentally induced models, including knockout and transgenic mice. The present chapter describes three spontaneous chicken models for human autoimmune diseases, the Obese strain (OS) with a Hashimoto-like autoimmune thyroiditis, the University of California at Davis lines 200 and 206 (UCD-200 and -206) with a scleroderma-like disease, and the amelanotic Smyth line with a vitiligo-like syndrome (SLV). Special emphasis is given to the new opportunities to unravel the genetic basis of these diseases in view of the recently completed sequencing of the chicken genome.

Animals↗
PubMed2006

Gene expression profiling of human endothelial cells exposed to 50-Hz magnetic fields fails to produce regulated candidate genes.

To address the question of a possible effect of magnetic fields (MF) at 50 Hz on living systems, gene expression analyses were performed on human primary vascular endothelial cells exposed to MF of various intensities compared to control cells. Exposure protocols included continuous exposure at a single intensity (10 and 700 microT), intermittent exposure at a single intensity (700 microT), and continuous exposure to a variable-intensity field (10-30 microT). The transcriptional response of the cells was investigated using oligonucleotide microarrays containing up to 30 000 unique features. Although in individual experiments genes were identified where the expression appeared to be affected by exposure to MF, none of these genes were regulated in the same manner in subsequent repetition experiments. This is the first report of a transcriptome-wide analysis of the effects of MF exposure on human cells. The lack of a reproducible effect of MF on the expression of any genes in our investigation adds further weight to the evidence that 50-Hz MF are not capable of interacting with biological systems and thus do not represent an endothelial stress factor.

Cell Culture Techniques↗
PubMed2005

Allergic rhinitis, asthma, and atherosclerosis in the Bruneck and ARMY studies.

BACKGROUND: Several diseases characterized by chronic inflammation and immune activation have been linked to enhanced risk for atherosclerosis. The potential association between allergies and atherosclerosis, however, remains to be defined. METHODS: The association between common allergic diseases (allergic rhinitis and asthma) and 5-year development and progression of carotid atherosclerosis (Bruneck Study) and high intima-media thickness in carotid and femoral arteries (Atherosclerosis Risk Factors in Male Youngsters [ARMY] study) was investigated. The Bruneck Study is a prospective population-based survey of 826 men and women aged 40 to 70 years; the ARMY study is a cross-sectional evaluation of 141 men aged 17 or 18 years. RESULTS: Subjects with allergic disorders were at a significantly increased risk for high intima-media thickness in the ARMY study (odds ratio, 2.5; 95% confidence interval, 1.1-5.5; P=.03) and for atherosclerosis development and progression in the Bruneck Study (odds ratio, 3.8; 95% confidence interval, 1.4-10.2; P=.007). The associations remained significant after multivariate adjustment for a broad array of established and potential vascular risk factors. When IgE levels were substituted for the clinical allergy variable, findings were confirmed in the Bruneck Study (adjusted odds ratio, 1.7; 95% confidence interval, 1.1-8.0), for a 1-SD increase in IgE level (P=.02). CONCLUSIONS: This study documents enhanced atherosclerosis among subjects with common allergic diseases. Our findings fit well with the emerging concept that key components of allergies, such as leukotrienes or mast cells, are active in human atherogenesis and further extend the growing list of immune system-mediated and chronic inflammatory disorders that have been linked with enhanced risk for atherosclerosis.

Adolescent↗
PubMed2005

Association of serum-soluble heat shock protein 60 with carotid atherosclerosis: clinical significance determined in a follow-up study.

BACKGROUND AND PURPOSE: Previous work has shown that soluble heat shock protein 60 (HSP60; sHSP60), present in circulating blood, is associated with carotid atherosclerosis. In the current evaluation, we tested the hypothesis that sHSP60 levels are associated with the progression of carotid arteriosclerosis, prospectively. METHODS: The association of sHSP60 with early atherogenesis (5-year development and progression of nonstenotic carotid plaques) was investigated as part of the population-based prospective Bruneck Study. The current study focused on the follow-up period between 1995 and 2000 and, thus, included 684 subjects. RESULTS: sHSP60 levels measured in 1995 and 2000 were highly correlated (r=0.40; P<0.001), indicating consistency over a 5-year period. Circulating HSP60 levels were significantly correlated with antilipopolysaccharide and anti-HSP60 antibodies. It was also elevated in subjects with chronic infection (top quintile group of HSP60, among subjects with and without chronic infection: 23.8% versus 17.0%; P=0.003 after adjustment for age and sex). HSP60 levels were significantly associated with early atherogenesis, both in the entire population (multivariate odds ratio, for a comparison between quintile group V versus I+II: 2.0 [1.2 to 3.5] and the subgroup free of atherosclerosis at the 1995 baseline: 3.8 [1.6 to 8.9]). The risk of early atherogenesis was additionally amplified when high-sHSP60 and chronic infection were present together. CONCLUSIONS: Our study provides the first prospective data confirming an association between high levels of sHSP60 and early carotid atherosclerosis. This possibly indicates an involvement of sHSP60 in activating proinflammatory processes associated with early vessel pathology.

Autoantigens↗
PubMed2005

Detection of HSP60 on the membrane surface of stressed human endothelial cells by atomic force and confocal microscopy.

The highly conserved and ubiquitous heat shock proteins (HSP) are essential for the cellular homeostasis and efficiently trigger cellular responses to stress conditions. Both microbial and human HSP act as dominant antigens in numerous infectious and autoimmune diseases such as atherosclerosis, inducing a strong immune-inflammatory response. In the present study, the surface localization of HSP60 on stressed and unstressed human umbilical venous endothelial cells (HUVECs) was investigated using sensitive high resolution microscopy methods and flow cytometry. Confocal laser scanning microscopy (CLSM) revealed an increase of HSP60 in the mitochondria and on the surface of heat-stressed living and fixed HUVECs compared to unstressed cells. Atomic force microscopy (AFM), which has developed as sensitive surface-probe technique in biology, confirmed the presence of HSP60 on the membrane of stressed cells at an even higher lateral resolution by detecting specific single molecule binding events between the monoclonal antibody AbII-13 tethered to AFM tips and HSP60 molecules on cells. The interaction force (force required to break a single AbII-13/HSP60 bond) was 59+/-2 pN, which correlated nicely to the 51+/-1 pN measured with isolated HSP60 attached to mica surfaces. Overall, we found clear evidence for the occurrence of HSP60 on the surface of stressed HUVECs in a very similar patchy distribution pattern in living and fixed cells. The relevance of our findings with respect to the role of HSP60 in atherogenesis is discussed.

Antibodies, Monoclonal↗
PubMed2005

Diminished transforming growth factor beta2 production leads to increased expression of a profibrotic procollagen alpha2 type I messenger RNA variant in embryonic fibroblasts of UCD-200 chickens, a model for systemic sclerosis.

OBJECTIVE: A procollagen alpha2(I) messenger RNA (mRNA) variant, with a 115-bp band and an expected band of 180 bp, was found to be increased during early, acute scleroderma-like disease in UCD-200 chickens. The present study investigated the influence of cytokines on the expression of these 2 proalpha2(I) mRNA variants. METHODS: Embryonic fibroblasts of UCD-200 chickens (UCD-200-CEF) and normal white leghorns (NWL-CEF) were grown in 3-dimensional collagen gels. Procollagen mRNA expression was analyzed by RNase protection assay, and proliferation was determined by (3)H-thymidine incorporation. Transforming growth factor beta1 (TGFbeta1) and TGFbeta2 were measured in culture supernatants by enzyme-linked immunosorbent assay. RESULTS: Compared with NWL-CEF, UCD-200-CEF expressed 7.2 times more of the smaller profibrotic proalpha2(I) mRNA variant. TGFbeta1 stimulated the proliferation of UCD-200-CEF, but not NWL-CEF. The 115 bp:180 bp ratio was increased by TGFbeta1 in both NWL-CEF and UCD-CEF. TGFbeta2 and TGFbeta3 reduced the expression of the profibrotic proalpha2(I) mRNA in UCD-200-CEF to the same levels observed in healthy control NWL-CEF. In culture supernatants, NWL-CEF produced 4.1 times more TGFbeta2 than that produced by UCD-CEF. Inhibition of endogenous TGFbeta2 in NWL-CEF resulted in the same 115 bp:180 bp ratio as seen in untreated UCD-CEF. CONCLUSION: TGFbeta2 reduces the expression of a profibrotic proalpha2(I) mRNA variant in UCD-200-CEF. The constitutive overproduction of this proalpha2(I) mRNA variant and the diminished synthesis of TGFbeta2 in untreated UCD-200-CEF suggest that TGFbeta2 can act as an antifibrotic cytokine and might be a key player during fibrosis onset. These results shed light on the contradictory observations regarding the role of TGFbeta2 in human systemic sclerosis.

Animals↗
PubMed2005

TCR signaling inhibits glucocorticoid-induced apoptosis in murine thymocytes depending on the stage of development.

Signaling by either the TCR or glucocorticoid receptor (GR) induces apoptosis in thymocytes. Interestingly, it has been shown previously that hybridoma T cells escape apoptosis induced by either TCR or GR when both of these receptors signal simultaneously. Whether such mutual antagonism is present in primary thymocytes was the subject of the present study. Both glucocorticoids (GC) and anti-TCR/CD28 (or anti-CD3/CD28) mAb induced apoptosis in total thymocytes. When these signals were present at the same time, GC-induced apoptosis was partially inhibited by TCR/CD3 signaling. Costimulation by anti-CD28 enhanced the inhibitory effects of anti-CD3 on GC-induced apoptosis about 30-fold. However, subset analysis revealed that most cells rescued from GC-induced apoptosis were mature CD4+ and CD8+ thymocytes, and these cells were resistant to TCR/CD3-induced apoptosis in the absence of GC. Similar results were obtained with mature splenic CD4+ and CD8+ T cells. TCR/CD3 signaling alone, while inducing apoptosis in CD4+(CD8+)TCRlow thymocytes, rescued a small subset of CD4+(CD8+)TCRlow thymocytes from GC-induced apoptosis. Thus, TCR signaling increasingly reverses GC-induced apoptosis as thymocyte development progresses. As GC are infinitely present in vivo, these findings support a model wherein TCR signaling may be required to prevent GC-induced apoptosis both under basal and immune challenging conditions.

Animals↗
PubMed2005

Metals in cigarette smoke.

Metals are vital for a huge number of physiological processes in the human body, but can also destroy health when the concentration is not within the physiologically favourable range. Cigarette smoking interferes with the carefully controlled metal homeostasis of the human body. This review focuses on the consequences of metal delivery to the human body by cigarette smoking and discusses the body's responses. The metal content of tobacco plants, smoke, the circulation, and various organs is discussed. Finally, we link individual cigarette smoke contained metals to the genesis of human diseases.

Humans↗
PubMed2005

Cigarette smoke metal-catalyzed protein oxidation leads to vascular endothelial cell contraction by depolymerization of microtubules.

Smoking is a significant risk factor for development of atherosclerosis. However, the pathophysiology of smoking-mediated vessel wall damage is not understood. With tools ranging from analytical chemistry to cell biology, we show that cigarette smoke contains metals that catalyze the direct oxidation of cellular proteins by smoke oxidants. Oxidation of cellular proteins causes a loss of microtubule function, culminating in microtubule depolymerization and proteasome-dependent degradation of alpha-tubulin. As a consequence of the microtubule collapse, cytoskeletal structures as well as intermediate filaments break down, leading finally to a contraction of vascular endothelial cells. We observed a smoke extract-induced, calpain-dependent degradation of the intracellular form of platelet-endothelial cell adhesion molecule 1/CD31, as well as a release of P-selectin/CD62P, IL-6, and IL-8 from endothelial cells into the supernatant. Increased levels of soluble CD62P and IL-6 are well known to be associated with smoking in humans. Increased permeability of the vascular endothelium is a crucial event in atherogenesis. This work highlights the compounds and mechanisms by which cigarette smoke induces leakiness of the vascular endothelium.

Acetylcysteine↗