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PubMed1999

Selective eosinophil transendothelial migration triggered by eotaxin via modulation of Mac-1/ICAM-1 and VLA-4/VCAM-1 interactions.

We have recently cloned eotaxin, a highly efficacious eosinophilic chemokine involved in the development of lung eosinophilia during allergic inflammatory reactions. To understand more precisely how eotaxin facilitates the specific migration of eosinophils, we have studied which adhesion receptors are essential for eotaxin action both in vivo and in vitro. Experiments using mice genetically deficient in adhesion receptors demonstrated that molecules previously reported to be involved in both leukocyte tethering/rolling (P-selectin and E-selectin) and in sticking/ transmigration (ICAM-1 and VCAM-1) are required for eotaxin action in vivo. To further elucidate the mechanism(s) involved in this process, we have used an in vitro transendothelial chemotaxis model. mAb neutralization studies performed in this system suggest that the integrins Mac-1 (CD11b/18), VLA-4 (alpha4beta1) and LFA-1 (CD11a/18) are involved in the transendothelial chemotaxis of eosinophils to eotaxin. Accordingly, the expression of these integrins on eosinophils is elevated by direct action of this chemokine in a concentration-dependent manner. Taken together, our results suggest that eotaxin-induced eosinophil transendothelial migration in vivo and in vitro relies on Mac-1/ICAM-1 and VLA-4NCAM-1 interactions, the latter ones becoming more relevant at later time points of the eotaxin-induced recruitment process.

Animals↗
PubMed1997

The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood.

Hematopoietic progenitor cells migrate in vitro and in vivo towards a gradient of the chemotactic factor stromal cell-derived factor-1 (SDF-1) produced by stromal cells. This is the first chemoattractant reported for human CD34+ progenitor cells. Concentrations of SDF-1 that elicit chemotaxis also induce a transient elevation of cytoplasmic calcium in CD34+ cells. SDF-1-induced chemotaxis is inhibited by pertussis toxin, suggesting that its signaling in CD34+ cells is mediated by seven transmembrane receptors coupled to Gi proteins. CD34+ cells migrating to SDF-1 include cells with a more primitive (CD34+/CD38- or CD34+/DR-) phenotype as well as CD34+ cells phenotypically committed to the erythroid, lymphoid and myeloid lineages, including functional BFU-E, CFU-GM, and CFU-MIX progenitors. Chemotaxis of CD34+ cells in response to SDF-1 is increased by IL-3 in vitro and is lower in CD34+ progenitors from peripheral blood than in CD34+ progenitors from bone marrow, suggesting that an altered response to SDF-1 may be associated with CD34 progenitor mobilization.

ADP-ribosyl Cyclase↗
PubMed2002

Folic acid treatment reduces chemokine release from peripheral blood mononuclear cells in hyperhomocysteinemic subjects.

Elevated plasma homocysteine concentration is an independent risk factor for cardiovascular disease. However, the mechanisms by which hyperhomocysteinemia induces vascular disease are uncertain. An early step in atherogenesis involves leukocyte migration into the arterial wall, a process regulated in part by chemokines. We hypothesized that homocysteine may exert its atherogenic effect in part through chemokine-mediated mechanisms, and in the present study, we examined the effects of folic acid supplementation for 6 weeks on chemokine levels in hyperhomocysteinemic individuals. Data showed the following: (1) Compared with control subjects, hyperhomocysteinemic subjects had elevated plasma levels of the CXC chemokines, epithelial neutrophil-activating peptide (ENA)-78 (P<0.05), and growth-regulated oncogene (GRO)alpha (P=0.088), and homocysteine was significantly correlated with ENA-78 and GROalpha. (2) During folic acid treatment, normalization of homocysteine levels was accompanied by a marked reduction in oxidized low density lipoprotein-stimulated release of CXC chemokines (ie, GROalpha, ENA-78, and interleukin-8) and CC chemokines (ie, monocyte chemoattractant peptide-1 and RANTES) in peripheral blood mononuclear cells from these individuals. (3) The oxidized low density lipoprotein-induced release of ENA-78 from peripheral blood mononuclear cells from control subjects was significantly reduced when cells were incubated in the presence of folic acid. These data may suggest that homocysteine exerts atherogenic effects in part by enhancing chemokine responses in cells involved in atherogenesis and that folic acid supplementation may downregulate these inflammatory responses.

Adult↗
PubMed2004

Polarized increase of calcium and nucleokinesis in tangentially migrating neurons.

Cortical interneurons originate from the ganglionic eminences and reach their final position in the cortex via tangential migratory routes. The mechanisms of this migration are poorly understood. Here we have performed confocal time-lapse analysis of cell movement in the intermediate zone of embryonic mouse cortical slices in order to directly visualize their mode of migration. Tangentially migrating neurons moved by nucleokinesis, characterized by active phases of discontinuous advances of the nucleus followed by periods of quiescence. Dissociated cells from the ganglionic eminences also showed nucleokinesis associated with an increase of intracellular calcium, [Ca(2+)](i) Calcium elevation was greatest in the proximal region of the leading process, a zone with a wide distribution of gamma-tubulin. General increases in [Ca(2+)](i) elicited by microperfussion with neurotransmitters did not elicit nucleokinesis. These results show that tangential migration uses nucleokinesis, a cell-intrinsic process in which calcium signalling is local, directional and highly regulated.

Animals↗
PubMed1997

Elevation of apolipoprotein E in the CSF of cattle affected by BSE.

The cerebrospinal fluid (CSF) of patients suffering from Creutzfeldt-Jakob disease (CJD) display two unique polypeptide chains by two-dimensional polyacrylamide gel electrophoresis (2-D PAGE). In the absence of a well-defined ante-mortem diagnostic test for bovine spongiform encephalopathy (BSE), spinal fluid samples of eight normal cows and eight cows known to carry BSE by post-mortem histological analysis were investigated to verify if equivalent polypeptides were present. Proteins with similar migration to human CJD polypeptides were not detected. But surprisingly, a cluster of polypeptide spots that was faint or not detected in normal bovine CSF samples was found to be elevated or massively increased in BSE CSF samples (more than 10-fold increase). These elevated polypeptide chains were identified as apolipoprotein E.

Amino Acid Sequence↗
PubMed2006

Interaction of human neutrophils with endothelial cells regulates the expression of endogenous proteins annexin 1, galectin-1 and galectin-3.

Annexin 1 (ANXA1), galectin-1 (Gal-1) and galectin-3 (Gal-3) proteins have been identified as important mediators that promote or inhibit leukocyte migration. The expression of these proteins was studied in human neutrophils and endothelial cells (ECs) during a transmigration process induced by IL-8. Upon neutrophil adhesion to EC, a significant increase in the cleaved ANXA1 (LCS3, raised against all ANXA1 isoforms) expression was detected in the plasma membrane of adhered neutrophils and ECs compared to intact ANXA1 isoform (LCPS1, against N-terminus of protein). Adherent neutrophils had elevated Gal-3 levels in the nucleus and cytoplasm, and ECs in their plasma membranes. In contrast, a decrease in the total amounts of Gal-1 was detected in migrated compared to non-migrated neutrophils. Therefore, ANXA1 and Gal-3 changed in their content and localization when neutrophils adhere to endothelia, suggesting a process of sensitive-balance between two endogenous anti- and pro-inflammatory mediators.

Annexin A1↗
PubMed1997

The involvement of immune reactions in cardiac damage during acute myocardial infarction: role of cell-mediated immune response.

This study was undertaken with the aim of investigating humoral and cell-mediated immune response in acute myocardial infarction (AMI) as possible mechanisms involved in the infarction enlargement. Twenty three patients with first AMI and 15 healthy volunteers were examined. Of the AMI patients, 14 had extensive infarction (group A), while 9 patients had small infarction (group B). Immunologic analyses were performed at admission, and repeated after 3, 7, 14 and 21 days of the acute event. Following parameters were tested: number of CD3+, CD4+, CD8+ and CD20+ cells; serum IgG, IgA, IgM, C3, C4, immune complex and anticardiac antibody levels; polymorphonuclear cell (PMN) function (chemotaxis, phagocytosis, metabolic activity); leukocyte migration in vitro in the presence of water-soluble homologous heart extract. It was demonstrated that the number of B cells, serum IgG, C3, immune complex and anticardiac antibody levels were elevated from 7th-14th days after AMI. Concerning these parameters, however, no significant differences were obtained between group A and group B of AMI patients. Chemotaxis and metabolic activity of peripheral blood PMN, but not phagocytosis, were enhanced during AMI, again changes of PMN did not correlate with the extension of infarction. In contrast, leukocyte migration inhibition in vitro revealed that only patients with extensive AMI have developed positive reaction during the first 14 days after the onset of the disease, while leukocyte inhibition reaction appeared in patients with nonextensive AMI not earlier than the 21st day after the infarction. These findings demonstrate generation of immune reactivity during AMI and indicate that humoral immune response seems more likely to be an epiphenomenon related to tissue necrosis, while cell-mediated immune reactions could influence the extensiveness of cardiac damage.

Acute Disease↗
PubMed2003

Acute outbreak of gnathostomiasis in a fishing community in Sinaloa, Mexico.

An increasing number of human cases of gnathostomiasis have been reported in Sinaloa, Mexico, most of whom have a custom of eating of raw fish dishes such as 'cebiche'. Here we report five adult patients, three women and two men, having an acute episode of vomiting and abdominal pain a few minutes after eating a dish of cebiche prepared from a spotted sleeper perch (Eleotris picta) fished from a nearby lake in southern Sinaloa. All five patients experienced acute throat pain, chest and joint pains, headache and fever. One patient, a 55-year-old male, was hospitalized with suspected pancreatitis and pneumonia. By 8-9 days later, all five patients developed between three and 12 edematous, migrating skin lesions on the back, abdomen, upper and lower extremities, face, eye and scalp. By ELISA, all of them were sero-positive to Gnathostoma doloresi antigen and had elevated IgE levels. Eosinophilia was found in two patients. These patients lived in an agricultural and fishing community. In this community we carried out a sero-epidemiological survey and study of living conditions in a random sample of 309 individuals distributed in 74 households. Frequent consumption of raw fish was reported in 36% of households, and 12 individuals had a clinical history of migrating skin lesions. The sero-prevalence to Gnathostoma antigens was 34.95%. Five fish species and four species of ichthyophagous birds collected from three lakes in the village and a nearby estuary were infected with the advanced third-stage larvae of G. binucleatum, a species found in Ecuador and Mexico. The results describe the first known outbreak of acute gnathostomiasis on the American continent.

Acute Disease↗
PubMed1987

Uterine motility of the sow during the oestrous cycle and early pregnancy.

With electromyography and strain gauges the uterine motility of the sow during the oestrous cycle and early pregnancy was studied. Special attention was paid to characterization of myometrial activity at the time of intra-uterine migration of blastocysts. From recordings of 4 animals (3 became pregnant) 3 types of electrical spiking activity (each could be correlated with an elevation of the strain gauge tension) were discerned. Two of them appeared regularly and were suitable for analysis: "High Voltage Slow Acticity" (with relative high amplitude and low frequency of spikes) and "Low Voltage Fast Activity" (with relative low aplitude and high frequency of spikes). The sexual status markedly influenced myometrial activity: during proestrus and oestrus only one type of electrical activity was present whereas the myoelectrical complex (an episode of this activity and the subsequent interval of inactivity) was shorter than 10 min. During dioestrus the myoelectrical complex was longer than 10 min and "High Voltage Slow Activity" (solely on the cervix and bifurcation) and "Low Voltage Fast Activity" occurred simultaneously in episodes which mainly appeared to originate on the bifurcation. The characteristics of uterine activity during pregnancy were similar to those of a cyclic sow until day 12. It was only on day 12 that gestation appeared from an increased frequency of myoelectrical complexes. It is concluded that "Low Voltage Fast Activity" as it was found on the uterine horn at days 8-9 might be involved in the process of intra-uterine migration of blastocysts. In cyclic and in pregnant animals the patterns of "Low Voltage Fast Activity" were similar. Therefore, the occurrence of "Low Voltage Fast Activity" is independent of the actual presence of blastocysts. It seems to be exhibited in dependence on the ovarian hormones.

Animals↗
PubMed1994

Immunohistochemical insights into sickle cell retinopathy.

Dynamic vaso-occlusive and vaso-proliferative events occur in sickle cell retinopathy. Using streptavidin peroxidase immunohistochemistry, we investigated changes in distribution and relative levels of components in the fibrinolytic system and growth factors in retina and choroid from 2 sickle cell patients: a 20 month old SS patient and a 54 year old SC patient. Antigen localization in the sickle cell patients was compared to localization from 2 non-sickle cell, non-diabetic control subjects. In the fibrinolytic system, tissue plasminogen activator (tPA) localization and immunoreactivity were comparable in all eyes, but plasminogen activator inhibitor-1 (PAI-1) immunoreactivity was elevated within the walls of retinal vessels in the sickle cell tissue. Immunoreactive fibrin was often observed within the lumen of retinal and choroidal vessels and in choroidal neo-vascularization (CNV) in sickle cell subjects. Blood vessels containing fibrin generally exhibited elevated PAI-1 immunoreactivity. Von Willebrand's factor (vWf) and basic fibroblast growth factor (bFGF) immunoreactivity in sickle cell patients were elevated in choriocapillaris and the walls of some retinal vessels. Transforming growth factor-beta 1 (TGF-beta 1) immunoreactivity was significantly lower in sickle cell choriocapillaris than in controls. In chorioretinal pigmented lesions of the SC patient, bFGF and TGF-beta 1, beta 2, and beta 3 immunoreactivity was present within migrating retinal pigment epithelial (RPE) cells. Our interpretation of the data presented in this case study is that fibrin deposition within retinal and choroidal vessels of sickle cell subjects may occur due to elevated PAI-1 activity. Moreover, vaso-occlusions of choroidal vessels may influence the expression of growth factors in choriocapillaris endothelium, which could stimulate formation of choroidal neovascularization. Finally, fibrosis and gliosis in and near chorioretinal pigmented lesions may be stimulated by RPE production of bFGF and TGF-beta's.

Aged↗
PubMed1994

Electric field-directed fibroblast locomotion involves cell surface molecular reorganization and is calcium independent.

Directional cellular locomotion is thought to involve localized intracellular calcium changes and the lateral transport of cell surface molecules. We have examined the roles of both calcium and cell surface glycoprotein redistribution in the directional migration of two murine fibroblastic cell lines, NIH 3T3 and SV101. These cell types exhibit persistent, cathode directed motility when exposed to direct current electric fields. Using time lapse phase contrast microscopy and image analysis, we have determined that electric field-directed locomotion in each cell type is a calcium independent process. Both exhibit cathode directed motility in the absence of extracellular calcium, and electric fields cause no detectable elevations or gradients of cytosolic free calcium. We find evidence suggesting that galvanotaxis in these cells involves the lateral redistribution of plasma membrane glycoproteins. Electric fields cause the lateral migration of plasma membrane concanavalin A receptors toward the cathode in both NIH 3T3 and SV101 fibroblasts. Exposure of directionally migrating cells to Con A inhibits the normal change of cell direction following a reversal of electric field polarity. Additionally, when cells are plated on Con A-coated substrata so that Con A receptors mediate cell-substratum adhesion, cathode-directed locomotion and a cathodal accumulation of Con A receptors are observed. Immunofluorescent labeling of the fibronectin receptor in NIH 3T3 fibroblasts suggests the recruitment of integrins from large clusters to form a more diffuse distribution toward the cathode in field-treated cells. Our results indicate that the mechanism of electric field directed locomotion in NIH 3T3 and SV101 fibroblasts involves the lateral redistribution of plasma membrane glycoproteins involved in cell-substratum adhesion.

Animals↗
PubMed2004

17-Beta estradiol and 4-nonylphenol delay smolt development and downstream migration in Atlantic salmon, Salmo salar.

The effect of 17-beta estradiol (E2) and 4-nonylphenol (4-NP) on smoltification and downstream migration of Atlantic salmon was studied in an integrated laboratory and field study. In a stock of hatchery-raised 1-year-old salmon, smoltification progressed from February until late May as judged by increased gill Na+, K+ -ATPase activity and 24 h sea water (SW)-tolerance. Starting late March, three groups of 150 fish were each given 6 serial injections over 20 days of 2 microg/g body weight E2, 120 microg/g 4-NP dissolved in peanut oil or peanut oil (4 microl/g) as control. After the last injection, all fish were individually tagged (Passive Integrated Transponder tags) and a non-lethal gill biopsy was taken. Two days later (8 April), 100 fish per group were transported to the field site and released into a small stream. Smolt migration was registered by measuring arrival time at a trap downstream of the release site. Serum vitellogenin levels increased several-fold in both male and female E2- and 4-NP-treated fish. Overall, E2- and 4-NP-treatment impaired smolting as judged by elevated condition factor, reduced gill Na+, K+ -ATPase activity and alpha-subunit Na+, K+ -ATPase mRNA level, reduced muscle water content and increased mortality following 24 h SW-challenge. After release, control fish initiated downstream migration immediately, with 50% of the total number of migrants appearing in the trap within 10 days. E2- and 4-NP-treated fish appeared in the trap with a delay in comparison to controls of 6 and 8 days, respectively. After the smolt run, no fish were registered by electro-fishing upstream of the trap. The total number of fish reaching the trap and thus post-release survival was in the order control (81%), E2 (53%), 4-NP (12%). Representatives from all treatment groups held under simulated natural conditions in the laboratory survived 100% through the migration period, suggesting that a combination of behavioural and in-stream factors (predation by herons) may contribute to the differential mortality. The study indicates that short-term exposure to natural and environmental estrogens may impair smolt development and survival and delay subsequent downstream migration in Atlantic salmon.

Analysis of Variance↗
PubMed2004

23Na magnetic resonance imaging for the determination of myocardial viability: the status and the challenges.

The determination of the extent of the non-viable tissue after myocardial infarction has a major impact on further treatment of patients. During acute myocardial infarction, total sodium content of the tissue is elevated. This is caused by discontinuation of ion homeostasis, edema formation and membrane rupture. The situation is a different one in the chronic phase of scar formation, where cell migration causes changes in the ratio of extra- and intracellular volume. The accumulation of sodium causes an increase in the signal in (23)Na magnetic resonance imaging. The differences in intra- and extracellular sodium concentration modulate total sodium content and can be used as a natural, intrinsic contrast. In animal experiments, (23)Na magnetic resonance imaging allows the non-invasive determination of infarct size. As neither stunned nor hibernating tissue shows elevated total sodium content of the tissue, the method is able to discriminate viable and non-viable tissue. A small number of initial clinical studies show promising results for the use of this technique in humans. The development of (23)Na magnetic resonance imaging and the current status of the application are described.

Animals↗
PubMed2006

Gut myoelectrical activity induces heat shock response in Escherichia coli and Caco-2 cells.

The heat shock response is associated with the intracellular expression of a number of highly conserved heat shock proteins (Hsps). According to their molecular size, Hsps have been divided into several groups, which are strongly conserved and show high homology between the species, e.g., Hsp70, MW 70 kDa (Lindquist & Craig, 1998; Morimoto, 1998; Jolly & Morimoto, 2000; Zylicz et al. 2001). In all organisms the Hsp expression under stress conditions is regulated at transcriptional level, e.g., in humans by the heat shock transcription factor Hsf1 (Morimoto, 1998; Wu, 1995), while in Escherichia coli by replacement of the sigma factor sigma(70) in RNA polymerase by the sigma factor sigma(32) (Gross, 1987). The Hsps allow cell survival under stress conditions by renaturating of denaturated proteins, protecting of stress-labile proteins, preventing protein aggregation (chaperone functions), and by degradation of damaged proteins (protease activities) (Lindquist & Craig, 1988; Morimoto, 1998; Jolly & Morimoto, 2000). They have also many housekeeping functions under non-stressful conditions during the cell cycle, growth, development, and differentiation (Morimoto, 1998). Among a number of plausible inducing factors already studied, extremely low artificial electromagnetic fields have been shown to induce stress response in various cells, such as expression of sigma(32) mRNA (Cairo et al. 1998) and induction of DnaJ and DnaK proteins in Eschericha coli (Chow & Tung, 2000); expression of hsp-16 gene in Caenorhabditis elegans (Miyakawa et al., 2001); induction of heat shock transcription factor Hsf1 and Hsp70, Hsp90 and Hsp27 in human cells (Lin et al. 1997; Lin et al. 1998; Goodman & Blank, 1998; Pipkin et al. 1999). Nevertheless, the role of endogenous electromagnetic fields, i.e., generated by electrically active cells within a body remains controversial. Heat shock proteins (Hsps) protect cells against various environmental and endogenous stressors. Cytoprotection caused by Hsps involves tolerance induced by one agent against other, more severe agents. We have found that exposure of prokaryotic (Escherichia coli) and eukaryotic (Caco-2) cells to an electrical field (EF) connected with a myoelectrical migrating complex (MMC) generated by the small intestine smooth muscle induces the heat shock response. Using Western blot analysis, we have detected an elevated level of sigma factor 32 in E. coli cells exposed to MMC-related EF, and confocal microscopy indicated an increased level of the inducible form of Hsp70 protein in EF-stimulated Caco-2 cells. Additionally, we have found that this induced level of Hsp70 protected the Caco-2 cells against apoptosis caused by camptothecin. Our observations suggest that the myoelectrical activity of the gut may induce heat shock mechanisms in the cells of gut epithelium as well as in gastrointestinal micro-organisms.

Action Potentials↗
PubMed1995

Osteopontin and beta 3 integrin are coordinately expressed in regenerating endothelium in vivo and stimulate Arg-Gly-Asp-dependent endothelial migration in vitro.

Osteopontin is an Arg-Gly-Asp (RGD)-containing acidic glycoprotein postulated to mediate cellular adhesion and migration in a growing number of normal and pathological conditions through interaction with integrin molecules. In this report, we have investigated the potential contributions of osteopontin and one of its receptors, the alpha v beta 3 integrin, to endothelial regenerative processes by using both in vivo and in vitro models. In vivo, uninjured rat arterial endothelium had undetectable levels of osteopontin and beta 3-integrin mRNA by in situ hybridization. After balloon catheter denudation, osteopontin mRNA levels correlated temporally and spatially with active endothelial proliferation and migration, with the highest levels observed at the wound edge between 8 hours and 2 weeks after injury, declining to uninjured levels at 6 weeks, when regeneration was complete. Osteopontin protein levels, as determined by immunocytochemistry, paralleled the time course of mRNA expression. Likewise, beta 3-integrin mRNA and protein levels were substantially elevated in regenerating endothelial cells but were not detectable in uninjured or healed endothelium. In vitro, rat smooth muscle cell-derived and bacterial expressed mouse recombinant osteopontins both stimulated the adhesion and directed migration of bovine aortic endothelial cells through interactions with the alpha v beta 3 receptor. Structural mutants of osteopontin confirmed the importance of the RGD domain for both adhesion and migration of endothelial cells through alpha v beta 3. These data suggest important roles for osteopontin and beta 3 integrin in regenerating endothelium.

Animals↗
PubMed2004

Involvement of the CXCL12/CXCR4 pathway in the advanced liver disease that is associated with hepatitis C virus or hepatitis B virus.

Chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infection is accompanied by inflammation and fibrosis eventually leading to cirrhosis. The chemokine CXCL12 is involved in chronic inflammatory conditions. The role of the CXCL12/CXCR4 pathway in HCV- and HBV-associated liver inflammation and fibrosis was therefore studied. The levels and tissue localization of CXCL12 in liver and plasma of HCV and HBV patients were tested using immunohistochemistry and ELISA. The expression and function of CXCR4 on liver-infiltrating lymphocytes (LIL) were tested by FACS and transwell migration assays. We found that CXCL12 is expressed by bile duct epithelial cells in normal liver tissue. Bile duct proliferation and liver fibrosis in chronic HCV and HBV infection result in the anatomical re-distribution of CXCL12 in the liver. Moreover, CXCL12 is up-regulated in the endothelium of neo-blood-vessels formed in active inflammatory foci and is significantly elevated, compared with controls, in the plasma of patients with advanced liver fibrosis. Complementing these observations were others indicating that over 50% of LIL express CXCR4 and, in response to CXCL12, migrated and adhered to fibronectin. These observations suggest an important role for the CXCL12/CXCR4 pathway in recruitment and retention of immune cells in the liver during chronic HCV and HBV infection.

Cell Adhesion↗
PubMed1998

Gap junction-mediated cell-cell communication modulates mouse neural crest migration.

Previous studies showed that conotruncal heart malformations can arise with the increase or decrease in alpha1 connexin function in neural crest cells. To elucidate the possible basis for the quantitative requirement for alpha1 connexin gap junctions in cardiac development, a neural crest outgrowth culture system was used to examine migration of neural crest cells derived from CMV43 transgenic embryos overexpressing alpha1 connexins, and from alpha1 connexin knockout (KO) mice and FC transgenic mice expressing a dominant-negative alpha1 connexin fusion protein. These studies showed that the migration rate of cardiac neural crest was increased in the CMV43 embryos, but decreased in the FC transgenic and alpha1 connexin KO embryos. Migration changes occurred in step with connexin gene or transgene dosage in the homozygous vs. hemizygous alpha1 connexin KO and CMV43 embryos, respectively. Dye coupling analysis in neural crest cells in the outgrowth cultures and also in the living embryos showed an elevation of gap junction communication in the CMV43 transgenic mice, while a reduction was observed in the FC transgenic and alpha1 connexin KO mice. Further analysis using oleamide to downregulate gap junction communication in nontransgenic outgrowth cultures showed that this independent method of reducing gap junction communication in cardiac crest cells also resulted in a reduction in the rate of crest migration. To determine the possible relevance of these findings to neural crest migration in vivo, a lacZ transgene was used to visualize the distribution of cardiac neural crest cells in the outflow tract. These studies showed more lacZ-positive cells in the outflow septum in the CMV43 transgenic mice, while a reduction was observed in the alpha1 connexin KO mice. Surprisingly, this was accompanied by cell proliferation changes, not in the cardiac neural crest cells, but in the myocardium- an elevation in the CMV43 mice vs. a reduction in the alpha1 connexin KO mice. The latter observation suggests that cardiac neural crest cells may have a role in modulating growth and development of non-neural crest- derived tissues. Overall, these findings suggest that gap junction communication mediated by alpha1 connexins plays an important role in cardiac neural crest migration. Furthermore, they indicate that cardiac neural crest perturbation is the likely underlying cause for heart defects in mice with the gain or loss of alpha1 connexin function.

Animals↗
PubMed1989

Relationship between DNA fragmentation and apoptosis in the programmed cell death in the rat prostate following castration.

Previous studies have demonstrated that the rapid involution of the rat ventral prostate following castration involves the death of the androgen-dependent epithelial cells present within the gland and that this death is the result of a series of discrete biochemical steps. The degradation of genomic DNA into nucleosomal-sized fragments is an early event in this process and is catalyzed by calcium magnesium-dependent endonuclease activity. The morphologic correlation of the involution process involves a series of structural changes which are collectively referred to as apoptosis. The apoptotic process describes the earliest apparent signs of morphologic change exhibited by the dying cells through their eventual complete destruction and deletion from the tissue. The temporal relationship between these recently described biochemical events and the morphologic changes of the apoptotic process were compared in the present study, in order to test the cause versus effect nature of DNA fragmentation in the programmed death of androgen dependent prostatic cells following castration. These studies demonstrated that the early elevation of the Ca+2 Mg+2-dependent endonuclease activity and the fragmentation of DNA into nucleosomal oligomers occurs within prostatic glandular epithelial cells and probably does not involve the direct participation of extraprostatic cells which may subsequently migrate into the gland. Once the DNA is initially cleaved into the nucleosomal oligomers, the subsequent participation of lysosomal enzymes act in a less restricted fashion to degrade both the nucleosomal DNA as well as the cytoplasmic elements and the cell becomes morphologically apoptotic. As the elevations in Ca+2 Mg+2-dependent endonuclease activity and DNA fragmentation are initiated at a time well before the cell is morphologically dead, as defined by apoptosis, these changes in DNA metabolism must not be the consequences of cell death but instead are early causal events in an active process of programmed cell death.

Animals↗