Biomedical subjects

M Eckhardt

Publications and source records attributed to M Eckhardt.

At least 19 recordsLinked to original sources

PubMed2001

The effect of 1,3-diaryl-[1H]-pyrazole-4-acetamides on glucose utilization in ob/ob mice.

This article provides evidence of a new class of compounds, 1,3-diaryl-[1H]-pyrazole-4-acetamides, initially identified from their ability to increase glucose transport in an adipocyte and muscle cell line and ultimately demonstrating dramatic glucose lowering in ob/ob mice, a diabetic animal model. The lead compound, 1, possessed some behavioral-like effects which were removed by structural variation during the course of this investigation. Specifically, 11g (R1 = meta-CF(3), Ar2 = 4'biphenyl, R3 = diethylamide) illustrated the potency of this series with ED(50) values for glucose lowering in ob/ob mice of 3.0 mg/kg/day. Concomitant with its effect on glucose lowering, 11g also caused a 50% reduction in insulin levels consistent with an agent that increases whole body insulin sensitivity. 11g showed favorable pharmacokinetic data with acceptable absorption, negligible metabolism, and good duration of action. 11g demonstrated no appreciable adipogenic effect through PPAR gamma agonism, a characteristic of the thiazolidinediones (TZD), and so represents a potentially new class of agents for the treatment of diabetes.

Acetamides↗

PubMed2001

[Malignant melanoma of the ciliary body. A diagnostic problem].

BACKGROUND: Ciliary body melanoma is often diagnosed too late and therefore has a poor prognosis. The circular infiltration of the iridocorneal angle by malignant cells can lead to secondary glaucoma, often misdiagnosed as pigmentary glaucoma. MATERIAL AND METHODS: In a 40-year-old patient the diagnosis "atypical pigmentary glaucoma" was made due to elevated intraocular pressure and pigmentation of the iridocorneal angle; no changes were present in the iris. In a second case pronounced pigmentation of the chamber angle and secondary glaucoma led to the clinical diagnosis of a ring melanoma and resulted in enucleation of the globe. RESULTS: In the first case, increasing pigmentation of the chamber angle over 4 weeks led to the presumed diagnosis of a ring melanoma. Histopathological evaluation confirmed the diagnosis of a ring melanoma of the ciliary body. In the second case histology revealed retinal detachment with intraocular bleeding without intraocular melanoma. The pigmentation in the lower part of the chamber angle was due to hemosiderosis. CONCLUSION: Diagnosis of ciliary body melanomas may be difficult in some cases due to its similarity to other eye diseases. The differential diagnosis of malignant melanoma of the ciliary body should be considered in cases of unilateral pigmentary glaucoma.

Adult↗

PubMed2001

The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose transporter.

Leukocyte adhesion deficiency II (LAD II) is characterized by the lack of fucosylated glycoconjugates, including selectin ligands, causing immunodeficiency and severe mental and growth retardation. No deficiency in fucosyltransferase activities or in the activities of enzymes involved in GDP-fucose biosynthesis has been found. Instead, the transport of GDP-fucose into isolated Golgi vesicles of LAD II cells appeared to be reduced. To identify the gene mutated in LAD II, we cloned 12 cDNAs from Caenorhabditis elegans, encoding multi-spanning transmembrane proteins with homology to known nucleotide sugar transporters, and transfected them into fibroblasts from an LAD II patient. One of these clones re-established expression of fucosylated glycoconjugates with high efficiency and allowed us to identify a human homolog with 55% identity, which also directed re-expression of fucosylated glycoconjugates. Both proteins were localized to the Golgi. The corresponding endogenous protein in LAD II cells had an R147C amino acid change in the conserved fourth transmembrane region. Overexpression of this mutant protein in cells from a patient with LAD II did not rescue fucosylation, demonstrating that the point mutation affected the activity of the protein. Thus, we have identified the first putative GDP-fucose transporter, which has been highly conserved throughout evolution. A point mutation in its gene is responsible for the disease in this patient with LAD II.

Amino Acid Sequence↗

PubMed2001

Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance.

Obesity and dysfunctional energy partitioning can lead to the development of insulin resistance and type 2 diabetes. The antidiabetic thiazolidinediones shift the energy balance toward storage, leading to an increase in whole-body adiposity. These studies examine the effects of pioglitazone (Pio) on adipose tissue physiology, accumulation, and distribution in female Zucker (fa/fa) rats. Pio treatment (up to 28 days) decreased the insulin-resistant and hyperlipidemic states and increased food consumption and whole-body adiposity. Magnetic resonance imaging (MRI) analysis and weights of fat pads demonstrated that the increase in adiposity was not only limited to the major fat depots but also to fat deposition throughout the body. Adipocyte sizing profiles, fat pad histology, and DNA content show that Pio treatment increased the number of small adipocytes because of both the appearance of new adipocytes and the shrinkage and/or disappearance of existing mature adipocytes. The remodeling was time dependent, with new small adipocytes appearing in clusters throughout the fat pad, and accompanied by a three- to fourfold increase in citrate synthase and fatty acid synthase activity. The appearance of new fat cells and the increase in fat mass were depot specific, with a rank order of responsiveness of ovarian > retroperitoneal > subcutaneous. This differential depot effect resulted in a redistribution of the fat mass in the abdominal region such that there was an increase in the visceral:subcutaneous ratio, as confirmed by MRI analysis. Although the increased adiposity is paradoxical to an improvement in insulin sensitivity, the quantitative increase of adipose mass should be viewed in context of the qualitative changes in adipose tissue, including the remodeling of adipocytes to a smaller size with higher lipid storage potential. This shift in energy balance is likely to result in lower circulating free fatty acid levels, ultimately improving insulin sensitivity and the metabolic state.

Adipocytes↗

PubMed2000

Molecular defects that cause loss of polysialic acid in the complementation group 2A10.

Polysialic acid (PSA) is a dynamically regulated posttranslational modification of the neural cell adhesion molecule (NCAM), which modulates NCAM binding functions. PSA biosynthesis is catalyzed by two polysialyltransferases, ST8SiaII and ST8SiaIV. The catalytic mechanisms of these enzymes are unknown. In Chinese hamster ovary cells, ST8SiaIV is responsible for PSA expression. In the complementation group 2A10, the ST8SiaIV gene is disrupted. Investigating the molecular defects in this complementation group, seven clones with missense mutations in ST8SiaIV were found. Mutations cause replacement of amino acids that are highly conserved in alpha2,8-sialyltransferases. To verify the physiological relevance of identified mutations, identical amino acid substitutions were introduced into epitope-tagged variants of hamster ST8SiaIV and murine ST8SiaII and recombinant proteins were tested in vivo and in vitro. None of these constructs reconstituted PSA synthesis in 2A10 cells, although the proteins were expressed and with the exception of the cysteine variants ST8SiaIV-C356F and ST8SiaII-C371F correctly targeted to the Golgi apparatus. Interestingly, two mutations (ST8SiaIV-R277G and -M333V and the corresponding mutants ST8SiaII-R292G and -M348V) could be partially rescued if tested in vitro. Although these mutants were negative for autopolysialylation, partial reconstitution of both auto- and NCAM polysialylation was achieved in the presence of NCAM. The data presented in this study suggest a functional link between auto- and NCAM polysialylation.

Amino Acid Sequence↗

PubMed2000

Mice deficient in the polysialyltransferase ST8SiaIV/PST-1 allow discrimination of the roles of neural cell adhesion molecule protein and polysialic acid in neural development and synaptic plasticity.

Functional properties of the neural cell adhesion molecule (NCAM) are strongly influenced by polysialylation. We used gene-targeting to generate mice lacking ST8SiaIV/PST-1, one of the polysialyltransferases responsible for addition of polysialic acid (PSA) to NCAM. Mice homozygous for the null mutation reveal normal development of gross anatomical features. In contrast to NCAM-deficient mice, olfactory precursor cells in the rostral migratory stream express PSA and follow their normal pathway. Furthermore, delamination of mossy fibers in the hippocampal CA3 region, as found in NCAM-deficient mice, does not occur in ST8SiaIV mutants. However, during postnatal development these animals show a decrease of PSA in most brain regions compared to wild-type animals. Loss of PSA in the presence of NCAM protein but in the absence of obvious histological changes allowed us to directly address the role of PSA in synaptic plasticity. Schaffer collateral-CA1 synapses, which express PSA in wild types, showed impaired long-term potentiation (LTP) and long-term depression (LTD) in adult mutants. This impairment was age-dependent, following the time course of developmental disappearance of PSA. Contrary to NCAM mutant mice, LTP in ST8SiaIV mutants was undisturbed at mossy fiber-CA3 synapses, which do not express PSA in wild-type mice. The results demonstrate an essential role for ST8SiaIV in synaptic plasticity in hippocampal CA1 synapses, whereas PSA produced by different polysialyltransferase or polysialyltransferases at early stages of differentiation regulates migration of neural precursor cells and correct lamination of mossy fibers. We suggest that NCAM but not PSA is likely to be important for LTP in the hippocampal CA3 region.

Aging↗

PubMed2000

Binding of Clostridium botulinum C2 toxin to asparagine-linked complex and hybrid carbohydrates.

Clostridium botulinum C2 toxin is a binary toxin composed of an enzymatic subunit (C2I) capable of ADP-ribosylating actin and a binding subunit (C2II) that is responsible for interaction with receptors on eukaryotic cells. Here we show that binding of C2 toxin depends on the presence of asparagine-linked carbohydrates. A recently identified Chinese hamster ovary cell mutant (Fritz, G., Schroeder, P., and Aktories, K. (1995) Infect. Immun. 63, 2334-2340) was found to be deficient in N-acetylglucosaminyltransferase I. C2 sensitivity of this mutant was restored by transfection of an N-acetylglucosaminyltransferase I cDNA. C2 toxin sensitivity was reduced after inhibition of alpha-mannosidase II. In contrast, Chinese hamster ovary cell mutants deficient in sialylated (Lec2) or galactosylated (Lec8) glycoconjugates showed an increase in toxin sensitivity compared with wild-type cells. Our results show that the GlcNAc residue linked beta-1,2 to the alpha-1,3-mannose of the asparagine-linked core structure is essential for C2II binding to Chinese hamster ovary cells.

Animals↗

PubMed2000

Synthesis pattern of matrix metalloproteinases (MMPs) and inhibitors (TIMPs) in human explant organ cultures after treatment with latanoprost and dexamethasone.

PURPOSE: To determine changes in production of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in the ciliary body, the trabecular meshwork and the retinal pigment epithelium induced by both prostaglandins and corticosteroids. METHODS: Explant organ cultures were removed by a scleral incision 3 mm posterior to the limbus. Retinal pigment epithelium was grown to confluence. Organ and cell cultures were treated with latanoprost and/or dexamethasone for 72 h. The activity of MMP-2, -3 and -9 was assessed using zymography. The synthesis pattern of MMPs and TIMP-1 and -2 was identified using immunostaining. RESULTS: Treatment of explant organ cultures with 10 micrograms/ml of latanoprost induced a mean upregulation of MMP-2 by 36%, MMP-3 by 112% and MMP-9 by 156% as seen by zymography. Dexamethasone 500 nm reduced the amounts of secreted MMP-2 by 13%, MMP-3 by 69%. MMP-9 was not detectable in the media of corticosteroid-treated explant organ cultures. The addition of 10 micrograms/ml of latanoprost to dexamethasone-treated cultures increased MMP-2 by 14%, MMP-3 by 43% and MMP-9 by 49%. Using immunohistochemistry we found staining with antibodies against MMP-2, -3, -9 and TIMP-1 and -2 within the ciliary body, and only to a lesser degree in the trabecular meshwork. Latanoprost treatment caused an increase of 29% in MMP-2 (p < 0.0001), 98% in MMP-3 (p < 0.0001) and 108% in MMP-9 (p < 0.0001). Dexamethasone reduced the staining for MMP-2 by 32% (p < 0.0001), for MMP-3 by 33% (p < 0.0001) and for MMP-9 by 83% (p < 0.0001). Almost no change in staining for MMPs was detectable in the trabecular meshwork. Neither latanoprost treatment nor dexamethasone induced significant changes (p < 0.93) in the secretion of TIMPs. In the media of non-treated retinal pigment epithelium (RPE) cells the only MMP detected was MMP-2. RPE cells in culture did not respond to either treatment with a change in their MMP secretion. CONCLUSION: We detected a profound upregulation of both MMP-3 and MMP-9 and a mild induction of MMP-2 through latanoprost in the ciliary body, but not the trabecular meshwork or RPE cells. Corticosteroids, on the other hand, downregulated MMP expression in both tissues. This inhibiting effect of corticosteroids on MMP production was reversed by latanoprost.

Aged↗

PubMed2000

Effects of pioglitazone on promoting energy storage, not expenditure, in brown adipose tissue of obese fa/fa Zucker rats: comparison to CL 316,243.

Recent advances in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) include the use of thiazolidinediones (TZDs), agents that enhance insulin action, in part, through an activation of adipose tissue peroxisome proliferator-activated receptor gamma. Current evidence also indicates that these agents upregulate uncoupling protein 1 (UCP1) gene expression in brown adipocytes and increase interscapular brown adipose tissue (IBAT) mass in rodents, suggestive of a thermogenic component to their mechanism of action. In the present study, the TZD pioglitazone (PIO) and the beta3-adrenoceptor agonist CL 316,243 (CL), were used to determine whether the antidiabetic effects of PIO, like those of CL, may, in part, be mediated by an increase in either IBAT thermogenesis or whole-body energy expenditure. Treatment of obese, insulin resistant fa/fa Zucker rats with PIO for 10 days resulted in a 2- to 3-fold increase in IBAT mass, due largely to an increase in adipocyte size and number, and increased fatty acid biosynthesis. However, unlike the effects of CL, the PIO-induced IBAT changes were not associated with an increase in UCP1 expression or whole-body energy expenditure. In contrast to CL, PIO substantially increased body weight gains over the 10-day treatment period by increasing feeding efficiency. These data suggest that, unlike CL, the actions of PIO in the obese Zucker rat does not include increased energy expenditure, but rather strengthens its role as an adipogenic and lipogenic agent, which promotes energy storage.

Adipose Tissue, Brown↗

PubMed1999

Membrane topology of the mammalian CMP-sialic acid transporter.

Nucleotide sugar transporters form a family of distantly related membrane proteins of the Golgi apparatus and the endoplasmic reticulum. The first transporter sequences have been identified within the last 2 years. However, information about the secondary and tertiary structure for these molecules has been limited to theoretical considerations. In the present study, an epitope-insertion approach was used to investigate the membrane topology of the CMP-sialic acid transporter. Immunofluorescence studies were carried out to analyze the orientation of the introduced epitopes in semipermeabilized cells. Both an amino-terminally introduced FLAG sequence and a carboxyl-terminal hemagglutinin tag were found to be oriented toward the cytosol. Results obtained with CMP-sialic acid transporter variants that contained the hemagglutinin epitope in potential intermembrane loop structures were in good correlation with the presence of 10 transmembrane regions. This building concept seems to be preserved also in other mammalian and nonmammalian nucleotide sugar transporters. Moreover, the functional analysis of the generated mutants demonstrated that insertions in or very close to membrane-spanning regions inactivate the transport process, whereas those in hydrophilic loop structures have no detectable effect on the activity. This study points the way toward understanding structure-function relationships of nucleotide sugar transporters.

Amino Acid Sequence↗

PubMed1999

Complete capsulorhexis opening occlusion despite capsular tension ring implantation.

An 89-year-old woman and an 86-year-old woman had continuous curvilinear capsulorhexis, phacoemulsification, and implantation of a silicone plate-haptic intraocular lens. Because of presumed weak zonules (high age, pseudoexfoliation), a poly(methyl methacrylate) capsular tension ring was also implanted. Despite this, both patients reported deterioration in visual acuity that was the result of complete occlusion of the anterior capsule opening by fibrotic tissue 4 and 3 months postoperatively, respectively.

Aged↗

PubMed1998

Mutants of the CMP-sialic acid transporter causing the Lec2 phenotype.

Chinese hamster ovary (CHO) mutants belonging to the Lec2 complementation group are unable to translocate CMP-sialic acid to the lumen of the Golgi apparatus. Complementation cloning in these cells has recently been used to isolate cDNAs encoding the CMP-sialic acid transporter from mouse and hamster. The present study was carried out to determine the molecular defects leading to the inactivation of CMP-sialic acid transport. To this end, CMP-sialic acid transporter cDNAs derived from five independent clones of the Lec2 complementation group, were analyzed. Deletions in the coding region were observed for three clones, and single mutants were found to contain an insertion and a point mutation. Epitope-tagged variants of the wild-type transporter protein and of the mutants were used to investigate the effect of the structural changes on the expression and subcellular targeting of the transporter proteins. Mutants derived from deletions showed reduced protein expression and in immunofluorescence showed a diffuse staining throughout the cytoplasm in transiently transfected cells, while the translation product derived from the point-mutated cDNA (G189E) was expressed at the level of the wild-type transporter and co-localized with the Golgi marker alpha-mannosidase II. This mutation therefore seems to directly affect the transport activity. Site-directed mutagenesis was used to change glycine 189 into alanine, glutamine, and isoleucine, respectively. While the G189A mutant was able to complement CMP-sialic acid transport-deficient Chinese hamster ovary mutants, the exchange of glycine 189 into glutamine or isoleucine dramatically affected the transport activity of the CMP-sialic acid transporter.

Animals↗

PubMed1998

Mammalian cytidine 5'-monophosphate N-acetylneuraminic acid synthetase: a nuclear protein with evolutionarily conserved structural motifs.

Sialic acids of cell surface glycoproteins and glycolipids play a pivotal role in the structure and function of animal tissues. The pattern of cell surface sialylation is species- and tissue-specific, is highly regulated during embryonic development, and changes with stages of differentiation. A prerequisite for the synthesis of sialylated glycoconjugates is the activated sugar-nucleotide cytidine 5'-monophosphate N-acetylneuraminic acid (CMP-Neu5Ac), which provides a substrate for Golgi sialyltransferases. Although a mammalian enzymatic activity responsible for the synthesis of CMP-Neu5Ac has been described and the enzyme has been purified to near homogeneity, sequence information is restricted to bacterial CMP-Neu5Ac synthetases. In this paper, we describe the molecular characterization, functional expression, and subcellular localization of murine CMP-Neu5Ac synthetase. Cloning was achieved by complementation of the Chinese hamster ovary lec32 mutation that causes a deficiency in CMP-Neu5Ac synthetase activity. A murine cDNA encoding a protein of 432 amino acids rescued the lec32 mutation and also caused polysialic acid to be expressed in the capsule of the CMP-Neu5Ac synthetase negative Escherichia coli mutant EV5. Three potential nuclear localization signals were found in the murine synthetase, and immunofluorescence studies confirmed predominantly nuclear localization of an N-terminally Flag-tagged molecule. Four stretches of amino acids that occur in the N-terminal region are highly conserved in bacterial CMP-Neu5Ac synthetases, providing evidence for an ancestral relationship between the sialylation pathways of bacterial and animal cells.

Amino Acid Sequence↗

PubMed1998

Intraocular pressure difference in Goldmann applanation tonometry versus Perkins hand-held applanation tonometry in overweight patients.

OBJECTIVE: To analyze the increase in intraocular pressure (IOP) caused by anatomic and physiologic factors in overweight patients when using Goldmann applanation tonometry. DESIGN: A prospective cohort study. PARTICIPANTS: Seventy average-weight individuals who had no difficulties with IOP measurements at the slit lamp and 12 obese patients with suspected glaucoma who could position the head at the slit lamp only with great effort participated. INTERVENTION: The authors compared IOP values between slit-lamp-mounted Goldmann applanation tonometry and Perkins hand-held tonometry. MAIN OUTCOME MEASURE: The difference in Goldmann and Perkins IOP measurements was examined. RESULTS: In the group of obese patients, the mean IOP was 20.9+/-2.28 mmHg (mean +/- standard deviation; range, 18-26 mmHg) for the right eye and 21.4+/-3.16 mmHg (range, 16-28 mmHg) for the left eye when determined by Goldmann tonometry and 16.3+/-2.39 mmHg (range, 13-20 mmHg) for the right eye and 16.3+/-2.42 (range, 11-19 mmHg) for the left eye when determined by Perkins tonometry. The mean decrease was 4.5+/-1.3 mmHg (range, 3-7 mmHg) for the right eye and 4.9+/-1.9 mmHg (range, 2-9 mmHg) for the left eye. In the control group, the mean difference between the two types of tonometers for the right eye was 0.34+/-0.69 mmHg and for the left eye was 0.33+/-0.82 mmHg. Patients who had a falsely elevated IOP on Goldmann tonometry had an average body mass index of 34+/-3.82 (range, 28.5-41.9); most were female (5:1 ratio). CONCLUSION: The authors believe simultaneous breath-holding and thorax compression, with subsequent increase in venous pressure, may be a causative factor for transitory elevations of IOP. Perkins tonometry in obese patients may help avoid a false diagnosis of glaucoma caused by transitory elevations in IOP.

Adult↗

PubMed1998

Polysialic acid: three-dimensional structure, biosynthesis and function.

Polysialic acid is a unique cell surface polysaccharide found in the capsule of neuroinvasive bacteria and as a highly regulated post-translational modification of the neural cell adhesion molecule. Recent progress has been achieved in research on both the physicochemical properties of polysialic acid and the biosynthetic pathways leading to polysialic acid expression in bacteria and mammals.

Animals↗

PubMed1998

Serum polysialylated neural cell adhesion molecule in childhood neuroblastoma.

Neuroblastoma cells express the polysialylated form of the neural cell adhesion molecule (NCAM), which normally becomes restricted to a few neural tissues after embryogenesis. In this study, we investigated serum levels of polysialylated NCAM in 14 children with different grades and stages of neuroblastoma using an immunoluminescence assay, and compared the results to 269 healthy control subjects. Simultaneously, the polysialylated NCAM content of the tumours was determined by immunohistochemistry. Serum levels were dramatically elevated (more than sixfold) in children with advanced stages and fatal courses of disease, whereas children with differentiated tumour types and limited disease had low or normal levels. Serum concentrations correlated with the polysialylated NCAM content of the tumours, and they decreased during successful therapy. We therefore suggest polysialylated NCAM to be a useful marker monitoring childhood neuroblastoma.

Biomarkers, Tumor↗

PubMed1998

Genomic organization of the murine polysialyltransferase gene ST8SiaIV (PST-1).

Polysialic acid (PSA) is an important regulator of cellular interactions. Two enzymes (ST8SiaII and ST8SiaIV) are capable of synthesizing PSA. In the present study, the gene encoding the murine ST8SiaIV (PST-1) has been isolated and characterized. In contrast to the ST8SiaII (STX) gene which contains six exons and spans about 80 kb, the ST8SiaIV gene comprises only five exons spanning over at least 55 kb. However, alignment of the two genes revealed that exon-intron boundaries of exons 2-5 of ST8SiaIV and exons 3-6 of ST8SiaII are located at identical sites. Differences are restricted to the 5'-region encoded by one exon in the case of ST8SiaIV, whereas the corresponding region of ST8SiaII is interrupted by a very long intron. 5'-RACE analysis of the ST8SiaIV transcript using mRNA from AtT20 cells identified two transcription start sites at positions -324 and -204 relative to the translation start codon. The promoter region of ST8SiaIV lacks TATA- and CAAT-like sequences and is enriched in G+C (60%). The promoter contains putative Sp1, AP-1, AP-2, and PEA3 binding sites, as well as a purine- and a pyrimidine-rich region. Luciferase reporter gene assays demonstrated that the region between nucleotides -443 and -162 is sufficient to direct gene expression. The induction of luciferase activity was 30- and 10-fold in the PSA-positive AtT20 and CHO cells, but only 5- and 7-fold in the PSA-negative NIH-3T3 cells and in a PSA-negative subline of AtT20. Thus, although decreased in activity in PSA-negative cell lines, the basal promoter is not sufficient for the strong cell-type and tissue specific regulation of the ST8SiaIV gene, suggesting regulatory elements in the more upstream 5'-region.

Amino Acid Sequence↗

PubMed1998

Pathogenesis of acute radiation effects in the urinary bladder. Experimental results.

PURPOSE: The present review summarizes experimental studies of the pathogenesis of acute radiation-induced changes in urinary bladder function. MATERIAL AND METHODS: Transurethral cystometry was used for longitudinal assessment of bladder function in mice. With this technique, radiation-induced changes in storage capacity can be quantified. In histological studies, changes in urothelial cell density and in urothelial protein expression during the acute radiation response were determined. Acetylsalicylic acid (ASA) was used for the treatment of acute functional changes. RESULTS: The histological studies did not reveal any systematic fluctuations in urothelial cell density during the time of the acute radiation response. However, characteristic changes in the expression of proteins associated with urothelial cell function, differentiation and cell contact were observed, which correlated with the functional impairment. By local or systematical application of ASA, a significant restoration of bladder function compared to placebo treatment could be achieved. CONCLUSION: Acute functional radiation effects in the urinary bladder are not based on urothelial denudation. However, changes in protein expression indicate an impairment of the urothelial barrier function. The results of ASA treatment demonstrate that prostaglandins are involved in the response. Alterations in urothelial or endothelial prostaglandin metabolism may be primarily radiation-induced or secondary because of the impaired urothelial barrier.

Animals↗