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Biomedical subjects

Z Nevo

Publications and source records attributed to Z Nevo.

At least 19 recordsLinked to original sources
PubMed1992

Neuropeptidergic innervation of intramuscular hemangiomas.

Intramuscular hemangiomas are idiopathic lesions which are either tumoral or developmental in origin. A close association of abnormal blood vessels with nerve fibers is found and may suggest that nerves have a primary inciting role in the development of these lesions. In the current study, the number of nerve fibers in different zones around the tumors, as well as the type of neuropeptides present in these fibers, was quantitatively assessed by computer-assisted image analysis of immunohistochemical staining of histological slides. The number of nerve fibers as determined by positive staining by anti-protein S-100 antibodies was found to be elevated in the immediate vicinity of the abnormal blood vessels. The density of the nerve fibers rapidly declined with increasing distance from the hemangiomas, reaching normal values at distances of over 2 mm. Furthermore, hemangiomas contain a significantly higher number of calcitonin gene-related peptide (CGRP), substance P, and Met-enkephalin-positive fibers. The most significant rise in number is that of CGRP-positive fibers. This neuropeptide is a known mitogen, which could be responsible for the growth of the hemangiomatous blood vessels. Substance P is a nociceptive neurotransmitter and its presence can explain the pain which often accompanies even tiny intramuscular hemangiomas.

Adolescent↗
PubMed1992

Hyperosmotic activation of the Na(+)-H+ exchanger in a rat bone cell line: temperature dependence and activation pathways.

1. The hyperosmotic activation of the Na(+)-H+ exchanger was studied in an osteoblast-like rat cell line (RCJ 1.20). The activation was monitored by recording the intracellular pH (pHi) changes employing double excitation of the pH-sensitive fluorescent dye 2'7'-bis(carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester (BCECF-AM). 2. Exposure of the cells to a hyperosmotic HCO(3-)-free medium at 37 degrees C produced an initial cytosolic acidification of 0.05 pH units followed by a lag period and an alkalinization overshoot of about 0.2 pH units, without a concomitant change of the free cytosolic calcium [Ca2+]i by the use of Fura-2 calcium-sensitive probes. This response was completely inhibited by amiloride (0.33 mM) or by Na+ depletion from the external medium and insensitive to the extracellular Cl- replacement, indicating the involvement of a Na(+)-H+ exchanger in the hyperosmotic response. 3. Hyperosmotic stimuli (200 moSM sucrose) applied in the temperature range of 17-37 degrees C demonstrated a shortening of the lag period preceding alkalinization and an increased rate of proton extrusion upon temperature elevation. The biochemical reaction underlying the lag period and the proton extrusion resulted in apparent activation energies of 19 and 29 kcal mol-1, respectively, as calculated from the appropriate Arrhenius plots. 4. Stimulation of the exchanger under isosmotic conditions by 25 nM 4 beta-phorbol 12-myristate 13-acetate (PMA) and 0.1 mM vanadate resulted in an amiloride-sensitive pHi increase of about 0.08 pH units. The hyperosmotic stress was additive to the stimulatory effects of these agents, suggesting an independent hyperosmotic activation pathway. 5. The hyperosmotic activation of the Na(+)-H+ exchanger was independent of cAMP, cGMP, cytosolic Ca2+ and protein kinase C. Thus, none of the classical transduction mechanisms seem to be involved directly in the hyperosmotic activation of the antiporter. 6. The pHi response induced by the hyperosmotic stress was abolished by two calmodulin inhibitors, W-7 and chlorpromazine (50% inhibition, Ki at 28 and 20 microM, respectively), 20 microM cytochalasin B, but not by 10 microM colchicine. The results suggest the involvement of actin and calmodulin-like structural elements of the cytoskeleton in the transduction process leading to the activation of the Na(+)-H+ exchanger.

Animals↗
PubMed1992

Devascularization of the anterior cruciate ligament by synovial stripping in rabbits. An experimental model.

In rabbits, synovial stripping of the anterior cruciate ligament was performed, and histologic and mechanical changes were followed up to 2 months. The operation did not immediately affect the strength of the ligament or its histological structure. However, a gradual deterioration of mechanical properties, associated with collagen necrosis and an ineffectual reparative response, was evident. Thus, synovial stripping of the ligament with the attendant concomitant devascularization leads to ligamentary insufficiency despite the lack of structural damage to the ligament by the contusion itself.

Animals↗
PubMed1991

Regulation of the Na+/H+ exchanger under conditions of abolished proton gradient: isosmotic and hyperosmotic stimulation.

Activation of the Na+/H+ exchanger following isosmotic and hyperosmotic stimuli was investigated in an osteoblast cell line (RCJ 1.20). The pH dependence of the transporter activity was studied under conditions of abolished proton gradient (pHi = pHo) across the membrane. The isotonic response is Na+o dependent, increases towards higher pH-values, displaying a sigmoidal dependence on pHi = o (Hill coefficient approximately 1.8) and is controlled by pHo. The greater than first order dependence on pH suggests that H+o inhibits the exchange beyond the rate expected from competition with the Na+o alone. This may be due to the existence of an external H+ regulatory site with a negative cooperative effect on the intra- or extracellular transport site. The hyperosmotic activation is Na+o independent, parallels the sigmoidal pH dependence of the isosmotic stimulus (Hill coefficient approximately 2.0) and is mediated through an increase of the Vmax without a change in the intracellular proton sensitivity.

Animals↗
PubMed1990

Decrease in the basal levels of cytosolic free calcium in chondrocytes during aging in culture: possible role as differentiation-signal.

Cell- and matrix-related parameters, which characterize the aging and differentiation process of cartilage in vivo, were measured in cultured chick epiphyseal chondrocytes during maintenance in a suspension culture for 34 days. A gradual decrease in the rates of proliferation and an increase in the size of the cells were observed. Ultrastructural examination revealed increased vacuolization and appearance of glycogen-storing pools. The rate of proteoglycan synthesis gradually increased. Age-related changes in the composition of the proteoglycan consisted of an increase in the ratio of keratan sulfate/chondroitin sulfate. The results indicate that the process of aging in culture resembles maturation and differentiation of cartilage tissue in vivo. The levels of cytosolic free calcium ions ([Ca2+]i) were measured in fura-2-loaded cells during the course of aging in culture. A gradual decrease in [Ca2+]i was observed. In 5-day cultures, a value of 184 nM [Ca2+]i was measured; this value decreased to 61 nM in 34-day cultures. On the basis of the present data and the previous results, which showed that cartilage-derived growth factors caused a decrease in [Ca2+]i, concomitantly with enhancing differentiation, whereas factors which elevated [Ca2+]i caused an increase in proliferation and a decrease in proteoglycan synthesis, we suggest a model for control of chondrocyte differentiation and aging. The model suggests that the rate of differentiation may be paced by changes in steady-state levels of [Ca2+]i.

Animals↗
PubMed1990

Regenerating hyaline cartilage in articular defects of old chickens using implants of embryonal chick chondrocytes embedded in a new natural delivery substance.

Partial and full thickness defects were created mechanically in articular cartilage and subchondral bone of the tibiotarsal joint condyles of 3-year-old chickens. The wounds were then repaired using embryonal chick chondrocytes embedded in a new biocompatible, hyaluronic acid-based delivery substance. Controls were similarly operated on but received either no treatment or implants of the delivery substance only. Animals were killed from 1 week to 6 months postoperatively. Sections from the two groups were examined and compared macroscopically, histologically, and histochemically. Results of 6-month follow-up showed that only the defects of the experimental chickens were completely filled with reparative hyaline cartilage tissue, with no signs of inflammation or immunologic rejection. Initially the entire defect cavity, whether partial thickness or full thickness up to the deep regions in the subchondral bone, was filled with cartilaginous reparative tissue. Relatively rapid maturation occurred under the tidemark; chondrocytes hypertrophied, were invaded with vascular elements and ossified. In the superficial areas, the reparative tissue remained cartilaginous and matured as typical hyaline cartilage tissue. These results indicate that aged chicken cartilage and its accompanying thin and spongy osteoporotic bone offer a favorable host environment for embryonal cell implants.

Animals↗
PubMed1989

Fate of allogeneic embryonal chick chondrocytes implanted orthotopically, as determined by the host's age.

Chondrocytes derived from chick embryos can be successfully implanted in defects of adult chick articular cartilage surfaces. Such implants thrive in their implantation site and create a new articular surface. The chondrocytes mature and hypertrophy in the orthotopic site without invoking an immune response. Eventually a steady state is reached in which mature chondrocytes resurface the defect while in the deeper areas spongy bone replaces the hypertrophic chondrocytes. Time schedules of these repair events have been studied in hosts of different ages. We compared 4-month-old chicks with 3-year-old chickens. The embryonal chondrocytes implanted in the latter group underwent an accelerated aging process. The defects were completely filled-up after 1 month as compared with 2-3 months in the younger age group. Endochondral ossification in the older group was evident as early as 2 months post implantation and was completed after 6 months. This contrasts with the situation in the younger group where the chondrocytes only began to hypertrophy after 6 months. At this stage endochondral ossification was hardly seen at all. A unique response to the cartilaginous implants is seen in the old group only in the vicinity of the reparative tissue, accumulation of hematopoietic centers. This study seem to indicate that the host's environment affects the "biological clock", i.e. rate and degree of aging of the implanted cells, as well as their matrices.

Age Factors↗
PubMed1988

Slowing down aging of cultured embryonal chick chondrocytes by maintenance under lowered oxygen tension.

Cultured epiphyseal-chondrocytes from embryonic chick may serve as a useful in vitro model to study aging processes in cartilage. The accelerated aging process in cultured chondrocytes is completed within a month and is manifested by typical changes in both cellular and extracellular compartments. Under common maintenance conditions, cells show a gradual loss of replicative capacity, increase in the rate of proteoglycan synthesis and age-dependent changes in the structure and composition of proteoglycan. An environmental factor--reduced oxygen tension--was found to slow down aging processes and preserve the young features of chondrocytes for a longer duration in culture. Cultures maintained under lower oxygen tension had higher proliferation rate, smaller cell size, lower rate of proteoglycan synthesis, and lower content of keratan sulfate side chains in the proteoglycan. In addition higher concentrations of free cytosolic calcium [Ca2+]in as compared to control cultures, was found. It is suggested that the increased proliferation rate and the decrease in proteoglycan synthesis caused by low oxygen tension may be signalled by the higher [Ca2+]in in these cells.

Animals↗
PubMed1987

Murine macrophage heparanase: inhibition and comparison with metastatic tumor cells.

Circulating macrophages and metastatic tumor cells can penetrate the vascular endothelium and migrate from the circulatory system to extravascular compartments. Both activated murine macrophages and different metastatic tumor cells (B16-BL6 melanoma; ESb T-lymphoma) attach, invade, and penetrate confluent vascular endothelial cell monlayer in vitro, by degrading heparan sulfate proteoglycans in the subendothelial extracellular matrix. The sensitivity of the enzymes from the various sources degrading the heparan sulfate proteoglycan was challenged and compared by a series of inhibitors. Activated macrophages demonstrate a heparanase with an endoglycosidase activity that cleaves from the [35S]O4 = -labeled heparan sulfate proteoglycans of the extracellular matrix 10 kDa glycosaminoglycan fragments. The macrophages do not store the heparanase intracellularly but it is instead found pericellularly and requires a continuous cell-matrix contact at the optimal pH for maintaining cell growth. The degradation of [35S]O4 = -labeled extracellular matrix proteoglycans by the macrophages' heparanase is significantly inhibited in the presence of heparan sulfate (10 micrograms/ml), arteparon (10 micrograms/ml), and heparin at a concentration of 3 micrograms/ml. In contrast, other glycosaminoglycans such as hyaluronic acid, dermatan sulfate, and chondroitin sulfate as well as the specific inhibitor of exo-beta-glucuronidase D-saccharic acid 1,4-lactone failed to inhibit the degradation of sulfated proteoglycans in the subendothelial extracellular matrix. Degradation of this heparan sulfate proteoglycan is a two-step sequential process involving protease activity followed by heparanase activity. However, the following antiproteases--alpha 2-macroglobulin, antithrombin III, leupeptin, and phenylmethylsulfony fluoride (PMSF)--failed to inhibit this degradation process, and only alpha 1-antitrypsin inhibited the heparanase activity. B16-BL6 metastatic melanoma cell heparanase, which is also a cell-associated enzyme, was inhibited by heparin to the same extent as the macrophage heparanase. On the other hand, heparanase of the highly metastatic variant (ESb) of a methylcholanthrene-induced T lymphoma, which is an extracellular enzyme released by the cells to the incubation medium, was more sensitive to heparin and arteparon than the macrophages' heparanase, inhibited at concentrations of 1 and 3 micrograms/ml, respectively. These results may indicate the potential use of heparin or other glycosaminoglycans as specific and differential inhibitors for the formation in certain cases of blood-borne tumor metastasis.

Animals↗
PubMed1987

Use of cultured embryonal chick epiphyseal chondrocytes as grafts for defects in chick articular cartilage.

Full-thickness defects in articular cartilage were repaired with cultured homologous embryonic chick epiphyseal chondrocytes embedded in a biological resorbable immobilization vehicle (BRIV). This graft was successfully transplanted in mechanically induced defects in the surface of condylar articular cartilage of the tibiotarsal joint of four-month-old roosters. Healing of the defects was observed macroscopically, histologically, and histochemically and with the use of biochemical analyses for six months. Chondrocyte proliferation was seen 48 hours after implantation, and a hyaline cartilage matrix surrounding the cells was present two weeks later. Within eight weeks, the defects were completely filled with hyaline cartilage, which integrated smoothly with the neighboring cartilage without the formation of fibrous tissue at the interface. The cell content and rate of proteoglycan synthesis remained high for four months, then declined slowly to the level of the surrounding cartilage. Six months after transplantation, the cartilaginous tissue in the wound at levels below the ossification front showed penetration by vascular elements and young bone trabeculae at the margins of the reparative tissue. No signs of immunogenic rejection of the implants were observed. These results may be related to the employment of a capable source of cells, i.e., cultured chondrocytes characterized by a high mitotic rate and an early stage of development. The transplanted cells grew well and maintained their initial rate of proliferation, with definite maturation and transformation. The resulting cartilage was structurally reorganized according to the host pattern and under the influence of multitudinous environmental conditions. The articular zone preserved its cartilaginous phenotype, whereas the subchondral regions were transformed into bone.

Animals↗
PubMed1985

Decrease in cytosolic free Ca2+ and enhanced proteoglycan synthesis induced by cartilage derived growth factors in cultured chondrocytes.

Cartilage-derived growth factors, enhance proteoglycan synthesis in cultured chick-embryo chondrocytes, and have almost no effect on cell proliferation. Addition of cartilage derived growth factors to cartilage cells loaded with the fluorescent Ca2+ indicator quin 2, caused a rapid, concentration dependent decrease in cytoplasmic free Ca2+. This decrease persisted also in Ca2+-free medium, indicating that it is not mediated by a decrease in the passive permeability of cell membrane to Ca2+. Addition of the Ca2+ ionophore A23187, with or without cartilage derived factors, caused an increase in cytoplasmic free Ca2+ together with inhibition of proteoglycan synthesis and enhanced cell proliferation. The results may indicate that whereas cell proliferation in chondrocytes is signaled by an increase in cytoplasmic Ca2+ ([Ca2+]in), proteoglycan synthesis is signaled by a decrease in [Ca2+]in. The data lead to suggesting a mechanism for antagonistic regulation of cell proliferation and the expression of the differentiated state.

Animals↗
PubMed1985

Arthritis induced by a T-lymphocyte clone that responds to Mycobacterium tuberculosis and to cartilage proteoglycans.

Adjuvant arthritis characterized by chronic inflammation of the joints of rats is induced by immunization to Mycobacterium tuberculosis. To learn how autoimmune arthritis may be caused by a microbial antigen, we isolated a T-lymphocyte clone specific for M. tuberculosis antigens that was strongly arthritogenic. We now report that the clone recognized, in addition to M. tuberculosis antigens, antigens present in human synovial fluid, medium of chondrocyte cultures, and proteoglycans purified from cartilage. These observations indicate that the target antigen for the arthritogenic clone resides in the proteoglycan component of cartilage. As this arthritogenic clone shows specificity for both a M. tuberculosis antigen and a cartilage constituent we conclude that disease is probably caused by antigenic cross-reactivity. Thus, an autoimmune disease may be triggered by structural mimicry between antigens in the environment and self-antigens in the individual.

Animals↗
PubMed1979

Growth factors.

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Animals↗
PubMed1979

Fetal bone grafts do not elicit allograft rejection because of protecting anti-Ia alloantibodies. Implications to the immune survival of fetuses in allogeneic mothers.

In a previous study we showed that allografts of BN fetal bone, unlike allografts of adult bone, are not rejected by allogeneic recipients of the Lewis strain in spite of the existence of major histocompatibility complex (MHC) incompatibility between donors and hosts. In the present study, we analyzed the relationships existing between the host and fetal tissue that determine graft survival. We found that (1) the fetal BN graft, unlike adult grafts, induces in Lewis recipients a vigorous humoral response consisting mainly in the production of IgG antibody that seems to be directed against antigens of Ia-like specificities. (2) The BN rats are genetically defective in their capacity to respond to determinants and thus are not capable of producing anti-Ia antibodies; in accordance, Lewis fetal bone grafts are rejected by the BN recipients. (3) Chondrocytes isolated from fetal mouse bones do express Ia antigenic determinants. We suggest that the survival of an allogeneic fetal graft in an immunologically intact recipient depends on an active and selective immune response directed against the Ia components associated with the MHC on the embryonic and fetal cells. On the basis of these notions, we propose that the capacity of Ia determinants expressed on cells of the embryo, to elicit anti-Ia and IgG alloantibodies in the pregnant mother, determines the capacity of the embryo to escape rejection by the histoincompatible mother.

Animals↗