Histology and histopathology Vol.20, nº 3 (2005)

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http://hdl.handle.net/10201/177478

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Open Access
Detection of transforming growth factor-a and epidermal growth factor receptor mRNA and immunohistochemical localization of the corresponding proteins in the canine uterus during the estrous cycle
(Murcia : F. Hernández, 2005) Tamada, H.; Tominaga, M.; Kida, K.; Kawate, N.; Inaba, T.; Matsuyama, S.; Sawada, T.
Uterine expression of the epidermal growth factor (EGF) family of growth factors has not been studied in the dog. The present study looks at the presence of mRNA transcripts and immunohistochemical localization for transforming growth factor-a (TGF-a), which is the potent EGF family member, and for EGF receptor (EGF-R) in the canine uterus during the estrous cycle. The reverse transcriptase-polymerase chain reaction together with sequencing of the products confirmed the presence of their mRNA transcripts in the endometrium throughout the estrous cycle. Immunohistochemical analysis found clear positive staining for TGF-a and EGF-R in the luminal and glandular epithelia at proestrus and estrus. Immunoreactivity decreased at the early stage of diestrus. In the mid stage of diestrus, clear staining for TGF-a was again found in the glands of the luminal region, and staining for EGF-R was observed in all glands. Very little staining was seen at anestrus for either TGF-a or EGF-R. These results suggest that TGF-a expressed in the uterus may be involved in regulating growth, differentiation and regression in the endometrial epithelial cells during the estrous cycle in the dog.
Open Access
Thymidylate synthase predicts for clinical outcome in invasive breast cancer
(Murcia : F. Hernández, 2005) Yu, Z.; Sun, J.; Zhen, J.; Zhang, Q.; Yang, Q.
Thymidylate synthase (TS) is a major target of 5-fluorouracil (5-FU) and dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme in the degradation of 5-FU. Whether TS or DPD could be used as valuable parameters for 5-FU sensitivity in clinical patients are largely unknown. We analyzed TS and DPD expression in breast carcinomas to evaluate the clinicopathological significance of these enzymes in patients with invasive breast cancer receiving 5-FUbased chemotherapy. A total of 197 patients with invasive ductal carcinoma were included in our study. Both the TS and DPD expression were analyzed using immunohistochemical method for all the surgical samples. Sixty-three out of 197 (31.97%) patients are positive for TS expression, and 77 out of 197 (39.09%) patients are positive for DPD expression. TS expression was not correlated with DPD expression. Patients with TS-positivity had aggressive phenotype including large tumor size, low differentiation and nodal metastasis. DPD expression is not related with phenotype or prognosis. Multivariate analysis demonstrated that TS expression was an independent prognostic factor for both disease-free and overall survival. The current study demonstrated that TS but not DPD expression was associated with both progression and prognosis in breast cancer receiving 5-FU-based chemotherapy. TS expression in the primary tumor might be useful as a predictive parameter for the efficacy of 5-FU-based chemotherapy for breast cancer.
Open Access
Immunological and molecular aspects of liver fibrosis in chronic hepatitis C virus infection
(Murcia : F. Hernández, 2005) Giannelli, G.; Antonaci, S.
Chronic C hepatitis represents a major health problem worldwide, mainly because progression of the tissue damage leads to the development of cirrhosis and hepatocellular carcinoma. In this review we discuss the molecular mechanisms underlying the development of liver fibrosis. In particular we consider some immunologic aspects that regulate the interaction between HCV and the host immune defense. Reflections are made about the roles played by the host capacity to respond to the viral infection during therapy and the consequences of the deposition of extracellular matrix (ECM) proteins leading to the development of fibrosis. The involvement of inflammatory cytokines in regulating the proteolytic remodeling of the liver and the ECM turn-over is essential for the activation of hepatic stellate cells (HSCs), that have an important role in the progression of liver fibrosis. Finally, we analyze one of the aspects involved in the activation of the HSCs, namely the proteolytic remodeling of the surrounding environment.
Open Access
Novel oncogene HCCR: its diagnostic and therapeutic implications for cancer
(Murcia : F. Hernández, 2005) Chung, Y.J.; Kim, J.W.
Identification of robust diagnostic and therapeutic target molecules for human malignancy is still an important issue. If we identify novel proteins which play a stem-line role for cellular transformation or aggravation of malignancy, it could give us a clue to diagnose a tumor in an earlier stage and to develop more reliable therapeutic tools. For this purpose, we have screened abnormally expressed genes in various human cancers by differential display RT-PCR. One of the overexpressed genes was a human cervical cancer oncogene (HCCR). HCCR was not only identified in cervical cancer tissues, but also found to be overexpressed in various human malignancies such as leukemia/lymphoma, breast, kidney, stomach, colon, liver and ovarian cancer. This molecule appeared to be a negative regulator of p53. In this paper, we discuss the biological functions of HCCR molecules and its implications for early diagnosis and future development of therapeutic devices of cancer.
Open Access
The diverse signaling network of EGFR, HER2, HER3 and HER4 tyrosine kinase receptors and the consequences for therapeutic approaches
(Murcia : F. Hernández, 2005) Zaczek, A.; Brandt, B.; Bielawski, K.P.
The HER family of receptor tyrosine kinase couples binding of extracellular growth factor ligands to intracellular signal transduction pathways, contributing in this fashion to the ability of the cell to respond correctly to its environment. The HER family and its ligands are critically involved in the carcinogenesis of the mammary gland. Abnormal function of the members of HER family resulting in receptor hyper-activation (due to gene amplification, protein overexpression or abnormal transcriptional regulation) has been linked with breast cancer prognosis. It is also extensively studied as the predictive factor and target for therapy. There are clinical indications supporting the concept that none of the receptors: EGFR, HER2, HER3 and HER4 can be considered as the stand-alone receptor in breast cancer development and clinical course of the disease. There is a growing body of evidence that cooperation between them contributes to more aggressive tumor phenotype and influences the response to therapy. This underlines the importance of quantification of all HER family members and indicates the urgent need for implementation of methods that can efficiently and reliably examine four HER receptors as a whole panel in breast cancer patients.
Open Access
Clinicopathologic and prognostic significance of cyclooxygenase-2 expression in endometrial carcinoma
(Murcia : F. Hernández, 2005) Lambropoulou, M.; Alexiadis, G.; Limberis, V.; Nikolettos, N.; Tripsianis, G.
Backgroud: Endometrial carcinoma is the most common malignancy of the female genital tract in the Western world. COX-2 is highly expressed in endometrial carcinoma, but there is controversy regarding its clinical role and its possible prognostic role. COX-2 expression was determined by immunohistochemistry and was correlated to standard clinicopathologic variables in a series of primary untreated endometrial carcinoma patients. COX-2 as an accurate predictor of the disease was also analyzed. Methods: One-hundred and ten cases of primary untreated endometrial carcinoma hosts who were admitted to the Department of Obstetrics and Gynecology, University General Hospital of Alexandroupolis, were investigated. Immunohistochemistry was performed using rabbit polyclonal antiserum against human COX-2. Results: Twenty-eight patients (25.5%) were scored as COX-2 positive. A statistically significant association was found between COX-2 overexpression and FIGO stage (p=0.010). A positive correlation was also found with histological grade (p=0.019) and myometrial invasion (p=0.026). No significant association was found with histologic type of the tumor (p=0.164). COX-2 positive patients had a significant association with sort survival (p=0.028). Conclusions: COX-2 expression is an independent clinicopathologic factor and an independent prognostic factor in endometrial carcinoma. It could be used to plan treatment modalities for hosts.
Open Access
Bruton’s Tyrosine Kinase is involved in innate and adaptive immunity
(Murcia : F. Hernández, 2005) Brunner, C.; Müller, B.; Wirth, T.
Btk is a cytoplasmic tyrosine kinase, which is mainly involved in B cell receptor signalling. Gene targeting experiments revealed that Btk is important for B cell development and function. However, Btk is not only expressed in B cells, but also in most other haematopoietic lineages except for T cells and plasma cells. Recently we found that Btk is involved in Toll-like receptor signalling. Toll-like receptors play an important role in innate immunity. They are highly expressed on mast cells, macrophages and dendritic cells, which are essential for the recognition and consequently for the elimination of microbial pathogens. Therefore Btk might play an important role for the function of immunocompetent cells of innate as well as adaptive immunity.
Open Access
Metalloproteinase expression by control and telomerase immortalized human endometrial endothelial cells
(Murcia : F. Hernández, 2005) Krikun, G.; Mor, G.; Huang, J.; Schatz, F.; Lockwood, C.J.
Vascular endothelial cells play a critical role in the maintenance of endometrial homeostasis. Indeed many pathological conditions causing abnormal endometrial bleeding including progestin only contraception, hormone replacement therapy, endometrial polyps, myomas, hyperplasia and cancer are associated with aberrant angiogenesis. Critical to the process of angiogenesis is the breakdown of the surrounding tissues by matrix metalloproteases (MMPs). In addition to the cells surrounding the endometrial endothelial cells, the endothelial cells themselves produce their own panel of MMPs. We now characterize the specific MMPs that are expressed by endothelial cells derived from human endometrium. These include MMP-1, MMP-2 and MMP-10 but not MMP-3. In addition, in order to successfully carry out consistent, homogeneous and sufficient numbers of studies we investigated the in vitro expression of the MMPs with both freshly isolated, early passaged endometrial endothelial cells (HEECs) as well as with newly telomerase immortalized HEECs (T-HEECs). The latter were karyotypically normal and expressed classic endothelial cell endpoints such as tubulogenesis on matrigel and expression of the endothelial cell markers CD-31 (PECAM), von Willebrand’s factor, and the Tie-2 receptors. The levels of MMP expression as well as that of the metalloprotease inhibitors TIMP-1 and TIMP-2 were similar in parent and immortalized endothelial cells.
Open Access
Consistent lack of CD34-positive stromal cells in the stroma of malignant breast lesions
(Murcia : F. Hernández, 2005) Kuroda, Naoto; Jin, Y.L.; Hamauzu, T.; Toi, M.; Miyazaki, E.; Hiroi, Makoto; Moriki, T.; Enzan, H.
To examine the distribution of CD34-positive and ASMA-positive stromal cells in various breast lesions, we performed immunohistochemical assays (using a streptavidin-biotin immunoperoxidase technique) of tissue specimens, obtained by excisional biopsy and partial or total mastectomy, from 62 patients with breast lesions. Specimens were obtained from 64 lesions as follows: fibrocystic disease (n=12), intraductal papilloma (n=4), fibroadenoma (n=17), invasive lobular carcinoma (n=6), invasive ductal carcinoma (n=20) and invasive micropapillary carcinoma (n=5). In normal breast tissue (controls), CD34-positive spindle cells were abundant in the intralobular stroma, but no ASMApositive stromal cells were identified except myoepithelial cells. Small to large numbers of CD34- positive cells were observed in the stroma of 29 of 33 benign diseases. In all invasive carcinomas (lobular, ductal and micropapillary), no CD34-positive stromal cells were observed in the stroma. In the stroma of benign lesions, the number of ASMA-positive stromal cells was various, but the stroma of all invasive breast cancers contained ASMA-positive stromal cells. The present results indicate that disappearance of CD34- positive stromal cells consistently occurs in the stroma of invasive carcinoma of the breast, irrespective of histological type and may be associated with the presence of ASMA-positive stromal cells.
Open Access
Immunohistochemical localization of senescence marker protein-30 (SMP30) in the submandibular gland and ultrastructural changes of the granular duct cells in SMP30 knockout mice
(Murcia : F. Hernández, 2005) Ishii, K.; Tsubaki, T.; Fujita, K.; Ishigami, A.; Maruyama, N.; Akita, M.
Senescence Marker Protein-30 (SMP30) is a calcium-regulating protein that decreases in an androgen-independent manner as aging occurs. An enzyme-labeled antibody technique has demonstrated that SMP30 localized to the ducts (granular, intercalated, and striated ducts) of mouse submandibular glands. Immunoelectronmicroscopy demonstrated that the granular duct cells were strongly positive for SMP30, but that pillar cells in the granular duct were negative for the protein. In SMP30-knockout (KO) mice, the granular ducts were smaller in diameter. Swelling of mitochondria in the granular duct cells was observed; however, this phenomenon was not observed in the pillar cells. After administration of a-isoproterenol, a betaadrenergic stimulant, a large numbers of small secretory granules were present in the granular duct cells and an expansion of the rough endoplasmic reticulum in SMP30-wild type (WT) mice; in contrast, little change was observed in SMP30-KO mice. These results suggest that SMP30 may be closely related to a signal transduction pathway in the granular duct cells of submandibular glands.
Open Access
Expression of muscarinic acetylcholine receptors (M1-, M2-, M3- and M4-type) in the neuromuscular junction of the newborn and adult rat
(Murcia : F. Hernández, 2005) García, N .; Santafe, M.; Salmon, I.; Lanuza, M.A.; Tomas, J.
Using intracellular recording and immunohistochemistry, we studied the presynaptic muscarinic autoreceptor subtypes controlling ACh release in the neuromuscular junctions of the newborn (3-6 days postnatal) and adult (30-40 days) rat. In the Levator auris longus muscles of both newborn and adult rats, acetylcholine release was modified by the M1- receptor selective antagonists pirenzepine (10 µM) and MT-7 (100 nM) and by the M2-receptor selective antagonists methoctramine (1 µM) and AF-DX 116 (10 µM). The M4-receptor selective antagonists tropicamide (1 µM) and MT-3 (100 nM) can also modify the neurotransmitter release in certain synapses of the newborn muscles. The neurotransmitter release was not altered by the M3-receptor selective antagonist 4-DAMP (1 µM) in the adult or newborn rats. However, we directly demonstrate by immunocytochemistry the presence of these receptors in the motor endplates and conclude that M1-, M2-, M3- and M4-type muscarinic receptors are present in all the neuromuscular junctions of the rat muscle both in newborn and adult animals. These receptors may be located in the perisynaptic glial cell as well as at the nerve terminals.
Open Access
Unusual circular annulate lamellae in hepatocytes of Torpedo marmorata
(Murcia : F. Hernández, 2005) Haggag, A.; Gilloteaux, J.
This report describes an unusual morphology of annulate lamellae (AL) in the hepatocytes of Torpedo marmorata Risso. These Als and fragments are detected amidst the main glycogen and lipid deposits. AL cisterns are circumscribed by parts of the smooth endoplasmic reticulum. Based on the finding of these unusual annular ALs, accompanied by other subcellular lesions such as a number of membranous whorls and altered mitochondria. These findings can concur and support other authors’ observations suggesting that these adult hepatocytes transient changes reflect that this species could be exposed to local, natural or likely human coastal seabed pollutants.
Open Access
Decreased density of ß1-adrenergic receptors in preneoplastic and neoplastic liver lesions of F344 rats
(Murcia : F. Hernández, 2005) Cardani, R.; Zavanella, T.
There is some evidence that rodent hepatocarcinogenesis is accompanied by changes in the adrenergic responsiveness of liver cells to catecholamines. In this study, immunohistochemical expression of ß1-adrenergic receptors (ß1-ARs) has been examined in spontaneous and chemically induced preneoplastic and neoplastic liver lesions of female and male Fischer 344 rats. An antibody specific for ß1-AR subtype was used. The study was carried out on archival formalin-fixed and paraffin-embedded livers from rats used in a previous study of hepatocarcinogenesis. One control group given distilled water by gavage, and two experimental groups, one initiated with a single dose of diethylnitrosamine (DEN) and one initiated with DEN and continuously treated with phenobarbital (PB) were examined. Rats were sacrificed after 2, 4, 8 and 21 months of experimentation. All types of liver putative preneoplastic lesions examined (basophilic, glycogenretaining, or mixed cell foci) show a lower density of ß1- ARs than the surrounding normal liver parenchyma, either in control and in DEN-treated or DEN+PB-treated rats. No immunostaining is detectable in several altered cell foci. Hepatocellular adenomas and hepatocellular carcinomas also show a very low density of ß1-ARs, extensive areas completely devoid of ß1-ARs being mingled with areas showing a weak immunostaining.
Open Access
Dynamics of bone marrow changes in patients with chronic idiopathic myelofibrosis following allogeneic stem cell transplantation
(Murcia : F. Hernández, 2005) Thiele, J.; Kvasnicka, H.M.; Dietrich, H.; Stein, G.; Hann, M.; Kaminski, A.; Rathjen, N.; Metz, K.A.; Beelen, D.W.; Ditschkowski, M.; Zander, A.; Kroeger, N.
Scant knowledge exists about the dynamics of fibro-osteosclerotic bone marrow (BM) lesions and regeneration of hematopoiesis following allogeneic peripheral stem cell transplantation (SCT) in chronic idiopathic myelofibrosis. Therefore, an immunohistochemical and morphometric study was performed on BM biopsies in 20 patients before and at standardized intervals (days 30 through 384) following SCT. In responding patients, a total regression of the pretransplant increased fibrosis was completed in the posttransplant period after about six months, while the extent of osteosclerosis did not change significantly during observation time. The quantity of CD61+ megakaryocytes including precursors was strikingly variable after SCT and, by using planimetric methods, atypical microforms exhibiting a dysplastic aspect could be demonstrated. These anomalies may be responsible for posttransplant thrombocytopenia. CD34+ progenitor cells were increased before transplantation, however, their number declined rapidly to normal values in responding patients. Nucleated erythroid precursors revealed a decreased amount before and after SCT accounting for anemia. Large clusters of this cell lineage indicated an initial hematopoietic reconstitution comparable with the expansion of the neutrophil granulopoiesis. Proliferative activity and apoptosis showed an increase until one year after SCT that implied a still regenerating hematopoiesis in keeping with an enhanced cell turnover.
Open Access
Role of prostaglandin E2 receptor subtypes in ovarian follicle growth in the rat in vivo. Correlation with interleukin-8 and neutrophils
(Murcia : F. Hernández, 2005) El-Nefiawy, N.; Abdel-Hakim, K.; Kanayama, N.; Terao, T.
This study was conducted to elucidate the role of three of prostaglandin E2 (PGE2) receptor subtype (EP2, EP3, and EP4) agonists in the process of follicular growth. The influence of these agonists on ovarian expression of intimately related factors to follicle development (neutrophils and interleukin-8 (IL- 8)) was also investigated. Immature female Wistar rats were injected once with these agonists and killed 48 hours later. Another group of rats were injected pregnant mare serum gonadotrophin. For evaluation of follicle growth, morphometric assessment of antral and ovulatory follicles was performed in serial ovarian sections. The study demonstrated that, EP2 and EP4 agonists showed the maximum follicle counts and diameters versus the control. EP2 and EP4 agonists mimicked PMSG induced follicle growth. Injection of the three agonists induced neutrophil infiltration into theca layer. EP4 agonist showed the most intense ovarian neutrophil accumulation. In addition, dense ovarian IL-8 expression was observed only after EP4 agonist injection. Conclusions: Our data suggests that: 1) EP2 and EP4 receptors are the key PGE2 receptors engaged in follicle growth. 2) Ovarian IL-8 expression and neutrophil infiltration are chiefly mediated via the EP4 receptor. EP2 and EP4 receptor agonists may be candidates for promising reagents that induce follicle maturation in clinical or agricultural fields. This knowledge could provide numerous targets for manipulation of fertility.
Open Access
Cellular distribution of growth hormone-releasing hormone receptor in human reproductive system and breast and prostate cancers
(Murcia : F. Hernández, 2005) Gallego, R.; Pintos, E.; Garcia-Caballero, Tomas; Raghay, K.; Boulanger, L.; Beiras, Andres; Gaudreau, P.; Morel, G.
Growth hormone releasing hormone receptor (GHRH-R) mRNA and protein was first localized to the anterior pituitary gland, consequent with the action of its ligand on GH synthesis and release. Subsequent studies found GHRH-R also expressed in the hypothalamus and in systemic tissues including those of the reproductive system. In the present work, we studied the distribution of GHRH-R in human reproductive system of males and females by immunohistochemical method. GHRH-R immunostaining was localized in male reproductive system: Leydig cells, Sertoli and basal germ cells of the seminiferous tubules and prostate secretory cells. GHRH-R immunostaining was also demonstrated in the ovary: oocytes, follicular cells, granulosa, thecal and corpus luteum cells. Endometrial glands, placenta and normal mammary glands also showed GHRH-R immunostaining. Our results demonstrate the localization of GHRH-R in the reproductive system, which may mediate the direct action of GHRH in these tissues. Moreover, GHRH-R was demonstrated in prostate and breast carcinomas, opening a variety of possibilities for the use of GHRH antagonists in the treatment of prostatic and mammary tumors.
Open Access
Nuclear reprogramming and adult stem cell potential
(Murcia : F. Hernández, 2005) Corti, S.; Locatelli, F.; Papadimitriou, D.; Strazzer, S.; Bonato, S.; Comi, G.P.
Cell-based therapy may represent a new strategy to treat a vast array of clinical disorders including neurodegenerative diseases. Recent observations indicate that adult somatic stem cells have the capacity to contribute to the regeneration of different tissues, suggesting that differentiative restrictions are not completely irreversible and can be reprogrammed. Cell fusion might account for some changed phenotype of adult cells but it seems to be biologically irrelevant for its extreme rarity. Other experimental evidences are compatible with the hypothesis of wide multipotency of well-defined stem cell populations, but also with transdifferentiation and/or dedifferentiation. Further studies on nuclear reprogramming mechanisms are necessary to fulfil the promise for developing autologous cellular therapies.
Open Access
Muscle-derived stem cells in tissue engineering: defining cell properties suitable for construct design
(Murcia : F. Hernández, 2005) Buján, J.; Pascual, G.; Corrales, C.; Gómez-Gil, V.; Rodríguez, M.; Bellón, J.M.
The terms construct or tissue equivalent refer to neotissue produced by tissue engineering techniques. The elements forming the construct are scaffolds on which cells are “recreated” to form an enginnered-tissue sensitive to certain cell signals. The ability of the cells to expand and differentiate on the scaffold is determined by properties such as fixation, adhesion, proliferation and migration. Among the cell types that seem to be most promising for designing constructs are tissue-residing, or adult, stem cells, which show two main features: a capacity to differentiate into many cell lineages and the power of self-renewal. These features make them good candidates for cell replacement therapies. Here, we report the identification, isolation and culture of muscle stem cells aimed at establishing the ideal culture in terms of defining when the cultured cell population would show optimal characteristics for transfer to the scaffold to obtain a particular construct. Stem cells harvested from the dorsal muscle of white New Zealand rabbits were cultured in vitro and characterized 5 to 14 days after the start of culture. Fibroblasts obtained from the same experimental animal served as controls. The stem cells were examined by light and scanning electron microscopy. For stem cell identification, we used the antibodies anti-m-cadherin, anti-CD34 and anti-Myf-5. The markers of muscle differentiation used were: antivimentin, anti-a-actin, anti-desmin and anti-myosin. The expression profiles of the different markers of muscle differentiation and TGFß1 in the cell cultures were confirmed by Western blotting. Proliferation rates were determined by monitoring tritiated thymidine incorporation. The thymidine incorporation rate was substantially higher for the population of undifferentiated cells than for control fibroblasts obtained from the same animal. During the first five days of culture, most cells were negative for all the markers examined, with the exception of m-cadherin, CD34 and Myf-5, although discrete signs of vimentin expression started to emerge. After 14 days of culture, the adult stem cells showed vimentin (94.2%) and desmin (33.8%) expression yet scarce labeling for myosin (16.2%) and a-actin (8.3%). Control fibroblasts showed intense labeling for vimentin (99.3%) and a-actin (62.2%), while less than 2% of the population expressed myosin (0.9%) and desmin (1.6%). After two weeks of culture, muscle-derived stem cells show good proliferative and adhesion properties as they initiate differentiation. These conditions seem ideal for obtaining the desired construct.
Open Access
Immunohistochemical investigation of amyloid ß-protein (Aß) in the brain of aged cats
(Murcia : F. Hernández, 2005) Brellou, G.; Vlemmas, I.; Lekkas, S.; Papaioannou, N.
To clarify the immunohistochemical features of amyloid deposits and cerebral amyloid angiopathy (CAA), the distribution of the amyloid ß-protein subtypes Aß40, Aß42, Aß43 and Aß precursor protein (APP) were examined in the brains of fourteen aged cats (7.5-21 year-old). Two types of plaques were detected. The first type was characterized by Aß positive antigenic material and detected in the cortical layers of the frontal and parietal lobes of all examined cats. The second type was characterized by diffuse positive immune staining representing diffuse plaques, which were detected only in the very aged cats (17-21 years old) and distributed throughout the cortical layers of the parietal lobes. Vascular amyloid and the amyloid deposits were strongly positive-stained with the antibody Aß42. APP was exhibited in neurons and axons while the staining was stronger in the very aged cats (17-21 years old). Our findings suggest that the feline forms a spontaneous model for understanding the early changes of normal brain aging and the early stage of amyloid ‚-protein deposition.
Open Access
Chronic a1-adrenoreceptor blockade produces age-dependent changes in rat thymus structure and thymocyte differentiation
(Murcia : F. Hernández, 2005) Plecas-Soloravic, B.; Hristic-Zivkovic, I.; Radojevic, K.; Kosec, D.; Leposavic, G.
In order to examine the influence of chronic a1-adrenergic receptor (a1-AR) blockade on the thymus structure and T-cell maturation, peripubertal and adult male rats were treated with urapidil (0.20 mg/kg BW/d; s.c.) over 15 consecutive days. Thymic structure and phenotypic characteristics of the thymocytes were assessed by stereological and flow cytometry analysis, respectively. In immature rats, treatment with urapidil reduced the body weight gain and, affecting the volume of cortical compartment and its cellularity decreased the organ size and the total number of thymocytes compared to age-matched saline-injected controls. The percentage of CD4+8- single positive (SP) thymocytes was decreased, while that of CD4-8+ was increased suggesting, most likely, a disregulation in final steps of the positively selected cells maturation. However, a1- AR blockade in adult rats increased the thymus weight as a consequence of increase in the cortical size and cellularity. The increased percentage of most immature CD4-8- double negative (DN) cells associated with decreased percentage of immature CD4+8+ double positive (DP) thymocytes suggests a decelerated transition from DN to DP stage of T-cell development. As in immature rats, the treatment in adult rats evoked changes in the relative numbers of SP cells, but contrary to immature animals, favoring the maturation of CD4+8- over CD4-8+ thymocytes. These results demonstrate that: i) chronic blockade of a1-ARs affects both the thymus structure and thymocyte differentiation, ii) these effects are age-dependent, pointing out to pharmacological manipulation of a1-AR-mediated signaling as potential means for modulation of the intrathymic T-cell maturation.