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PubMed1997

The expression of regulated endocrine-specific protein of 18 kDa in peptidergic cells of rat peripheral endocrine tissues and in blood.

We examined the cellular localization of regulated endocrine-specific protein of 18 kDa (RESP18) and mRNA in peripheral endocrine tissues. In situ hybridization and immunocytochemistry identified RESP18 mRNA in most cells of the anterior and intermediate pituitary, with RESP18 protein apparent in many anterior pituitary cells but very few intermediate pituitary cells. In the adrenal medulla and superior cervical ganglion, RESP18 mRNA co-localized with dopamine beta-mono-oxygenase and neuropeptide Y. In the thyroid, RESP18 mRNA was localized to C-cells. RESP18 mRNA was expressed in most of the cells of the pancreatic islets, co-localizing with insulin, glucagon, and somatostatin. No RESP18 mRNA or protein was detected in the adrenal cortex, ovary, neural lobe of the pituitary, parathyroid, exocrine pancreas, thyroid follicular cells, placenta, mammary tissue, liver, lung, or atria. As in the intermediate lobe of the pituitary, high levels of RESP18 mRNA in the pancreatic islets and adrenal medulla did not always correlate with immunodetectable RESP protein, suggesting that post-transcriptional mechanisms are important in controlling RESP18 expression. Western blot analyses identified 18 kDa RESP and higher molecular weight isoforms of RESP in most tissues and in plasma. Subcellular fractionation of the anterior pituitary identified 18 kDa RESP18 in fractions enriched in endoplasmic reticulum and secretory granules, with the higher molecular weight isoforms of RESP18 concentrated in fractions enriched in secretory granules. The broad neuroendocrine distribution of RESP18 suggests that it subserves an important function in the secretory pathway that is common to the production of many secreted peptides.

Adrenal Glands↗
PubMed1992

Repeated maternal separation in the neonatal rat: cellular mechanisms contributing to brain growth sparing.

Separation of neonates from their dam has been shown to evoke acutely a variety of biochemical responses, typified by depression of ornithine decarboxylase (ODC) activity. In the current study where rat pups were removed from their nursing dams for 6 h, ODC activities in the liver, heart, kidney and lung were markedly suppressed, but the enzyme in the brain was not altered during the early postnatal ages. These data suggest that the brain was protected from maternal separation insults, a homeostatic response mediated in part, by an increase of circulating corticosterone and glycogen mobilization from peripheral tissues, particularly the liver. In addition, we examined whether these responses were extended to pups who were subject to repeated episodes of maternal deprivation, and whether this stress paradigm might be associated with corresponding changes of cellular growth and maturation. Pups were removed from their dams for 6 h daily beginning at 4 days of age until weaning at 21 days. Plasma corticosterone levels of the deprived pups were elevated significantly at the end of each stress episode but returned to basal (control) levels subsequently. The repeating stress paradigm did not influence the magnitude of this hormonal response at the ensuing ages. Consistent with findings observed in the single episodes of stress, ODC activities in the peripheral tissues were significantly depressed in pups subject to repeated maternal deprivation, but the enzyme appeared to recover to control levels 18 h after each insult. In contrast, brain ODC activity did not exhibit any change throughout the period examined. Moreover, while ontogenetic gains of DNA and protein in the peripheral tissues of the deprived rats lagged slightly but consistently behind those of controls, these macromolecules in the brain were not affected appreciably. These results thus suggest that brain growth was, by and large, spared from insults associated with repeated maternal separation; but this stressful paradigm did produce marked, though reversible biochemical and physiological responses in the peripheral tissues of neonates, which cumulatively led to a lag of cellular development.

Animals↗
PubMed1990

Pharmacokinetics of 2-nitroimidazole hypoxic cell radiosensitizers in rodent peripheral nervous tissue.

The concentrations of seven 2-nitroimidazoles--including misonidazole, etanidazole (SR-2508), pimonidazole (Ro 03-8799), desmethylmisonidazole (Ro 05-9963), RK28, RP170, and KU2285--were measured in the sciatic nerves of C3H/He mice using reverse-phase high-performance liquid chromatography. Drug exposure to the peripheral nervous system was highest for misonidazole, followed by desmethylmisonidazole, etanidazole, pimonidazole and RK28. The lower drug exposure of pimonidazole and RK28 seemed to be related to their lower hydrophilicity. The apparent biological half-lives of the compounds in the peripheral nerves were correlated to their hydrophilicity: the more hydrophilic the compound, the longer the apparent biological half-life in the peripheral nervous tissue of the mice. Measurement of drug exposure in the rodent peripheral nervous system, rather than in the brain, was a better indicator for estimating the occurrence of clinical peripheral neuropathy by 2-nitroimidazoles.

Animals↗
PubMed1989

Lymphatic subpopulations and their transition in myocardial tissue and peripheral blood of patients with biopsy-proven myocarditis.

To determine abnormal immune regulation in biopsy-proven active and healed myocarditis cases, lymphatic subpopulations in myocardial tissue and peripheral blood were studied. Among 53 cases examined, 19 were active myocarditis (M) and 34 were healing or healed (HM). Five cases of myocarditis were studied sequentially. The percentages of pan T-cells, B-cells, helper/inducer T-cells (Th/i), suppressor/cytotoxic T-cells (Ts/c), etc per total marker positive cells were calculated by use of monoclonal antibodies. In myocardial tissue, the percentage of Th/i was significantly lower in HM than M (p less than 0.01). The helper/suppressor ratio (OKT4/8) in peripheral blood was 2.43 +/- 0.43 (mean +/- SE) in M, 1.61 +/- 0.19 in HM and 1.34 +/- 0.12 in age-matched controls. In 5 progressive studied cases of M, there was a decrease of the helper/suppressor ratio at 1 to 6 months after the myocarditis. It was concluded that subsidence of the immune reaction in myocardium is related to the healing process of myocarditis and may suggest improved prognosis.

Adolescent↗
PubMed1979

Large interindividual variations in metabolism of benzo(alpha)pyrene by peripheral lung tissue from lung cancer patients.

A very large variation (44-fold) was observed in the ability of short-term organ cultures of peripheral lung tissue from lung-cancer patients to metabolize the environmental carcinogen benzo(alpha)pyrene to organic solvent-soluble metabolites. The amounts of benzo(alpha)pyrene (2 microM) metabolized ranged from little (1%) to almost total (96.2%) metabolism within 24 h of culture. Previous work by Kellerman et al. (1973) has suggested a relationship between susceptibility to lung cancer and the indicibility of aryl hydrocarbon hydroxylase activity in cultured human lymphocytes. The metabolic fate of carcinogenic polycyclic aromatic hydrocarbons in the respiratory tract in vivo is undoubtedly more closely mimicked by short-term organ culture of human lung than by cultured lymphocytes. Thus the very wide interindividual variation observed in pulmonary metabolism of benzo(alpha)pyrene in this study and the large variations in covalent binding to human bronchial DNA observed by Harris et al. (1976) strongly suggest that there may be little basis for screening humans for variations in lymphocyte aryl hydrocarbon hydroxylase activity as a means of assessing their susceptibility to lung cancer.

Aged↗
PubMed2006

Tissue-engineered peripheral nerve grafting by differentiated bone marrow stromal cells.

Bone marrow stromal cells are multipotential stem cells that contribute to the differentiation of tissues such as bone, cartilage, fat and muscle. In the experiment, we found that bone marrow stromal cells can be induced to differentiate into cells expressing characteristic markers of Schwann cells, such as S-100 and glial fibrillary acidic protein, promoting peripheral nerve regeneration. Tissue-engineered bioartificial nerve grafting of rats by differentiated bone marrow stromal cells was applied for bridging a 10 mm-long sciatic nerve defect. Twenty-eight inbred strains of female F344 rats weighing 160 approximately 200 g were randomly divided into four nerve grafting groups, with seven rats in each group. Differentiated bone marrow stromal cell-laden group: poly(lactic-co-glycolic) acid tubes with an intrinsic framework were seeded with syngeneic bone marrow stromal cells which were induced for 5 days; Schwann cell-laden group: poly(lactic-co-glycolic) acid tubes with an intrinsic framework were seeded with syngeneic Schwann cells; acellular group: poly(lactic-co-glycolic) acid tubes were only filled with an intrinsic framework; autografts group. Three months later, a series of examinations was performed, including electrophysiological methods, walking track analysis, immunohistological staining of nerves, immunostaining of S-100 and neurofilament, and axon counts. The outcome indicated that bone marrow stromal cells are able to differentiate into Schwann-like cells and Schwann-like cells could promote nerve regeneration. Bone marrow stromal cells may be potentially optional seed cells for peripheral nerve tissue engineering because of abilities of promoting axonal regeneration.

Animals↗
PubMed2001

Quantitative mRNA analysis of five C-terminal splice variants of the human 5-HT4 receptor in the central nervous system by TaqMan real time RT-PCR.

5-HT4 receptors mediate several physiological effects of 5-HT, particularly in the central nervous system (CNS), heart and gut. Recently, several C-terminal splice variants of the human 5-HT4 (h5-HT4) receptor have been described, namely h5-HT4(a), h5-HT4(b), h5-HT4(c), h5-HT4(d) and h5-HT4(g). Previous tissue distribution data suggest some degree of specificity in the mRNA expression patterns of the different h5-HT4 receptor splice variants. However, comparison of the mRNA expression profiles of these splice variants is difficult due to the non-quantitative methods used, and in addition, there is very limited data on the expression of each splice variant in human CNS subregions. In the present study we used a single technique, TaqMan real time quantitative RT-PCR, to investigate the mRNA distribution of 5-HT4 receptor C-terminal splice variants in multiple human CNS and peripheral tissues. Using a primer/probe set that amplified all 5-HT4 splice variants (5-HT4pan), the highest CNS expression of 5-HT4 receptor mRNA was observed in basal ganglia, amygdala and hippocampus, consistent with previous studies. h5-HT4(a), h5-HT4(b), h5-HT4(c) and h5-HT4(g) were predominantly expressed in various CNS tissues, compared to most peripheral tissues, but there were differences in expression levels and distribution patterns of each variant. The distribution profile and expression levels observed for the 5-HT4(b) splice variant were virtually identical to that obtained with the 5-HT4pan primer/probe set, whilst the other splice variants were expressed at much lower levels and with different expression patterns obtained with both 5-HT4(b) and 5-HT4pan primer/probe sets. Highest levels of 5-HT4(g) were observed in the hypothalamus and cortex, whilst the 5-HT4(a) variant was highest in the amygdala. 5-HT4(c) expression was highest in the pituitary gland whilst 5-HT4(d) mRNA was only detected in the small intestine at very low levels and not in the CNS. In conclusion, we have shown quantitative differences in the mRNA distribution profiles of the 5-HT4 receptor C-terminal splice variants in human CNS subregions as well as peripheral tissues. In addition, our data suggests that the h5-HT4(b) variant is the most predominant form of the 5-HT4 receptor in humans.

Alternative Splicing↗
PubMed1994

The disposition of (R)-alpha-methylhistamine, a histamine H3-receptor agonist, in rats.

Using a modified HPLC method with a fluorescence spectrophotometer and a weak cation exchanger, it was possible to separate (R)-alpha-methylhistamine (alpha-methylhistamine) from histamine in plasma and various tissues. The assay was used to study the disposition and pharmacokinetic analysis of alpha-methylhistamine after a bolus intravenous administration to rats. After rapid intravenous administration (12.6 mg kg-1), the plasma concentration declined biexponentially with a half-life of 1.3 min in the elimination phase. The area under the plasma concentration-time curve and total body clearance were 130 micrograms min mL-1 and 97 mL min-1 kg-1, respectively. After administration, alpha-methylhistamine was immediately transferred to various tissues. The concentration was high in the kidney, lung, and liver (kidney > lung > liver), but low in the brain. The tissue-to-plasma concentration ratios in peripheral tissues were greater than 1, suggesting that the transfer of alpha-methylhistamine to peripheral tissues was due to a specialized transport mechanism or possibly to tissue binding. However, the finding that the tissue/plasma ratio in the brain was lower than unity suggests that the transport system in this tissue depends on a concentration gradient, and that alpha-methylhistamine crosses the blood-brain barrier in rats with difficulty.

Animals↗
PubMed1992

Lipoprotein receptors, plasma cholesterol metabolism, and the regulation of cellular free cholesterol concentration.

Classical concepts of the regulation of plasma cholesterol levels involve roles for the "forward" delivery of low density lipoprotein (LDL) cholesterol from the liver to the peripheral tissues, mediated by the LDL receptor, and a "reverse" delivery of cholesterol in the form of high density lipoprotein (HDL) from the peripheral tissues to the liver. Candidate receptors for HDL in peripheral tissues and for chylomicrons in the liver have more recently been described, and a receptor of uncertain function recognizing chemically modified LDL has also been identified. The activities of all the well-characterized lipoprotein receptors, as well of major catalytic factors in plasma that regulate cholesterol esterification and cholesteryl ester transfer between lipoproteins, reflect the need to maintain plasma membrane free cholesterol level, and its direct and indirect effects within the membrane, within well-defined limits.

Amino Acid Sequence↗
PubMed2000

Changes in the motility, morphology, and F-actin architecture of human dendritic cells in an in vitro model of dendritic cell development.

An in vitro model has been developed for analyzing the two developmental phases of human dendritic cell (DC) migration. Employing the age of the culture and the addition of GM-CSF, IL-4, and serum to regulate cellular phenotype, and glass coated with acid-precipitated human plasma proteins to facilitate persistent DC translocation, the model produces three sequential in vitro phenotypes with the following suggested in vivo counterparts: (1) DCs recently isolated from blood, which are highly polar and motile, and reflect the behavior of "undifferentiated" DCs that must extravasate from the blood stream and migrate into peripheral tissue; (2) large, nonmotile, stellate DCs, which reflect the highly "differentiated" signature phenotype of DCs in peripheral tissue, whose function is to capture foreign antigens; and (3) the large, motile "dedifferentiated" DCs, which reflect the behavior of "veiled cells" that have captured an antigen, retracted dendritic processes, migrated out of peripheral tissue, and are in the process of transporting a captured antigen to a proximal draining lymph node for presentation to T cells. Computer-assisted motion analysis of the three sequential phenotypes and fluorescent staining of F-actin reveal three unique behavioral states and unique cellular architecture consistent with inferred in vivo function. This in vitro model should serve as a starting point for elucidating the cues and molecular mechanisms involved in the regulation of DC differentiation and motility.

Actins↗
PubMed1984

Muscarinic cholinergic receptors in peripheral lung tissue of normal subjects and of patients with chronic obstructive lung disease.

Muscarinic cholinergic receptors have been identified and characterized by radioligand binding studies in human peripheral lung tissue. The tissue was obtained at thoracotomy of 12 patients, of whom four had chronic obstructive lung disease. The radioligand 1-quinuclidinyl [phenyl-4-3H]benzilate (3H-QNB) was used to label the muscarinic cholinergic receptors. Binding was saturable, protein dependent and showed a high affinity and stereospecificity. Specific binding could be inhibited by agonists and antagonists; molar inhibition constants determined for the agents used were of the same order of magnitude as those reported for 3H-QNB inhibition in various tissues of laboratory animals. Inhibition experiments with agonists resulted in Hill slopes which were significantly different from unity, indicating multiple binding sites. The stable GTP analogue guanyl-5'-imidodiphosphate had no effect on the Hill slopes of agonists or antagonists. The number of binding sites was significantly less in lung tissue from patients with chronic obstructive lung disease.

Aged↗
PubMed2000

Regulation of inflammation by collagen-binding integrins alpha1beta1 and alpha2beta1 in models of hypersensitivity and arthritis.

Adhesive interactions play an important role in inflammation by promoting leukocyte attachment and extravasation from the vasculature into the peripheral tissues. However, the importance of adhesion molecules within the extracellular matrix-rich environment of peripheral tissues, in which cells must migrate and be activated, has not been well explored. We investigated the role of the major collagen-binding integrins, alpha1beta1 and alpha2beta1, in several in vivo models of inflammation. mAb's against murine alpha1 and alpha2 were found to significantly inhibit effector phase inflammatory responses in animal models of delayed-type hypersensitivity (DTH), contact hypersensitivity (CHS), and arthritis. Mice that were alpha1-deficient also showed decreased inflammatory responses in the CHS and arthritis models when compared with wild-type mice. Decreased leukocyte infiltration and edema formation accompanied inhibition of antigen-specific models of inflammation, as nonspecific inflammation induced by croton oil was not inhibited. This study demonstrates the importance in vivo of alpha1beta1 and alpha2beta1, the collagen-binding integrins, in inflammatory diseases. The study also extends the role of integrins in inflammation beyond leukocyte attachment and extravasation at the vascular endothelial interface, revealing the extracellular matrix environment of peripheral tissues as a new point of intervention for adhesion-based therapies.

Animals↗
PubMedDate not supplied

[Aldosterone content of the blood and tissues in rats with an altered level of adrenergic activity].

The content of aldosterone (A) was studied in rat adrenal glands, blood plasma and peripheral tissues--in the myocardium, skeletal muscles, thymus and liver--1 h after the administration of alpha-adrenergic stimulator noradrenaline and beta-adrenergic stimulator isoprenaline and after simultaneous administration of alpha- and beta-blockers and a sympatholytic agent (pyrroxan, propranolol and bretylium tosylate respectively). Adrenergic stimulation did not change the level of A in the adrenal glands, raised its blood concentration and, to a greater extent, its level in the peripheral tissues. A marked increase in the blood concentration of A resulted from isoprenaline and its accumulation in tissues--from noradrenaline. A decrease in the level of adrenergic activity considerably lowered the A content in the adrenal glands, blood plasma and peripheral tissues excluding the myocardium where this value was higher than in the blood.

Adrenal Glands↗
PubMed2004

Sympathetic activation triggers endogenous opioid release and analgesia within peripheral inflamed tissue.

Stress induces analgesia by mechanisms within and outside the brain. Here we show that the sympathetic nervous system is an essential trigger of intrinsic opioid analgesia within peripheral injured tissue. Noradrenaline, injected directly into inflamed hind paws of male Wistar rats, produced dose-dependent antinociception, reversible by alpha(1)-, alpha(2)- and beta(2)-antagonists. alpha(1)-, alpha(2)- and beta(2)-adrenergic receptors were demonstrated on beta-endorphin-containing immune cells and noradrenaline induced adrenergic receptor-specific release of beta-endorphin from immune cell suspensions. This antinociceptive effect of noradrenaline was reversed by micro - and delta-opioid antagonists as well as by anti-beta-endorphin. Stress-induced peripheral analgesia was abolished by chemical sympathectomy and by adrenergic antagonists. These findings indicate that sympathetic neuron-derived noradrenaline stimulates adrenergic receptors on inflammatory cells to release beta-endorphin, which induces analgesia via activation of peripheral opioid receptors.

Adrenergic alpha-Antagonists↗
PubMed1995

Mechanisms of immune tolerance induction through the thymic expression of a peripheral tissue-specific protein.

A major process through which the immune system becomes tolerant to self proteins involves the deletion of self reactive cells in the thymus. However, T cells reactive to peripheral tissue-specific proteins can escape this deletion and become tolerized in the periphery by a variety of mechanisms. We report here, contrary to expectation, that the pancreas-specific protein, elastase I, is also expressed at a low level in the thymus, and that this thymic expression contributes to tolerance induction. To study the mechanism of this tolerance induction, we utilized a double transgenic mouse model. In these mice the expression of a model protein, SV40 T antigen, is directed by the elastase I promoter and hence parallels elastase I expression in the pancreas and thymus. These mice were crossed with mice transgenic for a TCR specific for T antigen, so the majority of thymocytes and T cells in these mice express the transgene. In double transgenic mice we find that thymic expression of T antigen results in anergic thymocytes which also show a reduction of Th1 activity with no decrease in Th2 activity. These functional characteristics persist in peripheral T cells, but there is also a depletion in the number of T antigen reactive T cells in lymph nodes. Chimeras were constructed which directly demonstrated that the thymus is the site of tolerance induction and that the tolerizing element is thymic epithelium. We propose that the loss of Th1 activity as a consequence of the thymic epithelium being encountered by tissue-specific proteins results in the functional tolerization of CTL in vivo, despite the fact that CTL are fully functional in vitro. In this way autoimmune destruction is contained. Thymic expression of peripheral proteins may therefore be an additional way in which tolerance to peripheral proteins can be achieved.

Animals↗
PubMed2004

Endorectal diffusion-weighted imaging in prostate cancer to differentiate malignant and benign peripheral zone tissue.

PURPOSE: To determine if the apparent diffusion coefficient (ADC) can discriminate benign from malignant peripheral zone (PZ) tissue in patients with biopsy-proven prostate cancer that have undergone endorectal diffusion-weighted imaging (DWI) of the prostate. MATERIALS AND METHODS: Ten patients with prostate cancer underwent endorectal magnetic resonance imaging (MRI) in addition to DWI. A two-dimensional grid was placed over the axial images, and each voxel was graded by a 4-point rating scale to discriminate nonmalignant from malignant PZ tissue based on MR images alone. ADC was then determined for each voxel and plotted for nonmalignant and malignant voxels for the entire patient set. Second, with the radiologist aware of biopsy locations, any previously assigned voxel grade that was inconsistent with biopsy data was regrouped and ADCs were replotted. RESULTS: For the entire patient set, without and with knowledge of the biopsy data, the mean ADCs for nonmalignant and malignant tissue were 1.61 +/- 0.27 and 1.34 +/- 0.38 x 10(-3) mm2/second (P = 0.002) and 1.61 +/- 0.26 and 1.27 +/- 0.37 x 10(-3) mm2/second (P = 0.0005), respectively. CONCLUSION: DWI of the prostate is possible with an endorectal coil. The mean ADC for malignant PZ tissue is less than nonmalignant tissue, although there is overlap in individual values.

Aged↗
PubMed1985

Residual complement activity after incubation with myelin isolated from both the central and peripheral nervous tissues.

The relative ability of isolated central and peripheral nervous system myelin to interact with the complement system of plasma proteins was studied. The myelin used was a highly pure form, devoid of contamination by any subcellular organelles or membranes. Residual complement activity was a linear function of increasing quantities of myelin from 10 to 40 micrograms of myelin protein. Central and peripheral nervous system myelin showed identical residual complement activity at various temperatures above 7 degrees C and also after various time periods of incubation. The results show that central and peripheral nervous system myelin show equal ability to interact with complement, in spite of their different origin and differences in morphology and protein composition.

Animals↗
PubMed1991

Effects of chondroitinase ABC on intrathecal and peripheral nerve tissue. An in vivo experimental study on rabbits.

The enzyme chondroitinase ABC has recently been suggested for use in chemonucleolysis. The effects of 200 U ml of chondroitinase ABC were studied on intrathecal and peripheral nerve tissue in rabbits. After the intrathecal (subarachnoid) application of 0.2 ml of either the diluent in the control group (N = 2) or chondroitinase in the study group (N = 4), no neurologic deficit was detected. Compared with the control group, no morphologic changes at the light microscopic level were induced in the spinal cord by chondroitinase. No neurophysiologic differences were detected between tibial nerves after exposure to 1 ml of the diluent (control, N = 8) or chondroitinase (the other leg) for 4 weeks, nor did the study group, compared with the control group, show any morphologic changes in the tibial nerves. Because the concentration of chondroitinase ABC tested was approximately 40 times higher than might be used clinically for chemonucleolysis, the present study indicates a wide margin of safety for unwanted side effects on nerve tissue.

Animals↗