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PubMed1997

Fibroblast growth factor-2 potentiates vascular smooth muscle cell migration to platelet-derived growth factor: upregulation of alpha2beta1 integrin and disassembly of actin filaments.

Fibroblast growth factor-2 (FGF-2) has been implicated in vascular smooth muscle cell (SMC) migration, a key process in vascular disease. We demonstrate here that FGF-2 promotes SMC motility by altering beta1 integrin-mediated interactions with the extracellular matrix (ECM). FGF-2 significantly increased surface expression of alpha2beta1, alpha3beta1, and alpha5beta1 integrins on human SMCs, as assessed by flow cytometry. The greatest increase was for the collagen-binding alpha2beta1 integrin. Despite this, FGF-2 did not increase SMC adhesion to type I collagen but instead promoted SMC elongation and SMC motility. The latter was evaluated by using a microchemotaxis chamber and by digital time-lapse video microscopy. Although FGF-2 was not chemotactic for human SMCs, cells preincubated with FGF-2 displayed a 3.1-fold increase in migration to the undersurface of porous type I collagen-coated membranes and a 2.1-fold increase in migration speed on collagen. Furthermore, chemotaxis to platelet-derived growth factor-BB on collagen was significantly greater in SMCs exposed to FGF-2. FGF-2-induced elongation and migration on collagen were inhibited by a blocking anti-alpha2beta1 antibody; however, SMC adhesion to collagen was unaffected. SMC migration on fibronectin was also enhanced by FGF-2, although less prominently: migration through porous membranes increased 1.8-fold, and migration speed increased 1.3-fold. Also, FGF-2 completely disassembled the smooth muscle alpha-actin-containing stress fiber network contemporaneously with the change in integrin expression and cell shape. We conclude that (1) exogenous FGF-2 promotes SMC migration and potentiates chemotaxis to PDGF-BB; (2) the promigratory effect of FGF-2 is especially prominent on type I collagen and is mediated by upregulation of alpha2beta1 integrin; and (3) FGF-2 disassembles actin stress fibers, which may promote differential utilization of alpha2beta1 integrin for motility but not adhesion. This dynamic SMC-ECM interplay may be an important mechanism by which FGF-2 facilitates SMC motility in vivo.

Actin Cytoskeleton↗
PubMed1997

Effect of natriuretic peptide family on the oxidized LDL-induced migration of human coronary artery smooth muscle cells.

The migration of medial smooth muscle cells (SMCs) into the intima is proposed to be an important process of intimal thickening in atherosclerotic lesions. The present study examined the possible effect of a novel endothelium-derived relaxing peptide, C-type natriuretic peptide (CNP), on oxidized low-density lipoprotein (LDL)-induced migration of cultured human coronary artery SMCs by the Boyden's chamber method. The effect of CNP was compared with that of atrial and brain natriuretic peptides (ANP and BNP, respectively). Oxidized LDL stimulates SMC migration in a concentration-dependent manner between 20 and 200 micrograms/mL. This stimulation was chemotactic in nature but was not chemokinetic. By contrast, native LDL was without significant activity. CNP-22 clearly inhibited SMC migration stimulated with 200 micrograms/mL oxidized LDL in a concentration-dependent manner between 10(-9) and 10(-6) mol/L. ANP-(1-28) and BNP-32 also inhibited oxidized LDL-induced SMC migration at concentrations of 10(-7) and 10(-6) mol/L, but these effects were weaker than the effect of CNP-22. Such inhibition by these natriuretic peptides was paralleled by an increase in the cellular level of cGMP. Oxidized LDL-induced migration was significantly inhibited by a stable analogue of cGMP, 8-bromo-cGMP, or an activator of the cytosolic guanylate cyclase, sodium nitroprusside. These natriuretic peptides did not suppress the cell adhesion either in the absence or presence of oxidized LDL. These data indicate that oxidized LDL stimulates migration of human coronary artery SMCs and that natriuretic peptides, especially CNP, inhibit this stimulated SMC migration, at least in part, through a cGMP-dependent process. Taken together with the finding that oxidized LDL is present in the intima, CNP may play a role as a local antimigration factor during the process of intimal thickening in hypercholesterolemia-induced coronary atherosclerosis.

Cell Movement↗
PubMed2000

Vascular endothelial growth factor-stimulated actin reorganization and migration of endothelial cells is regulated via the serine/threonine kinase Akt.

Vascular endothelial growth factor (VEGF) induces endothelial cell proliferation, migration, and actin reorganization, all necessary components of an angiogenic response. However, the distinct signal transduction mechanisms leading to each angiogenic phenotype are not known. In this study, we examined the ability of VEGF to stimulate cell migration and actin rearrangement in microvascular endothelial cells infected with adenoviruses encoding beta-galactosidase (beta-gal), activation-deficient Akt (AA-Akt), or constitutively active Akt (myr-Akt). VEGF increased cell migration in cells transduced with beta-gal, whereas AA-Akt blocked VEGF-induced cell locomotion. Interestingly, myr-Akt transduction of bovine lung microvascular endothelial cells stimulated cytokinesis in the absence of VEGF, suggesting that constitutively active Akt, per se, can initiate the process of cell migration. Treatment of beta-gal-infected endothelial cells with an inhibitor of NO synthesis blocked VEGF-induced migration but did not influence migration initiated by myr-Akt. In addition, VEGF stimulated remodeling of the actin cytoskeleton into stress fibers, a response abrogated by infection with dominant-negative Akt, whereas transduction with myr-Akt alone caused profound reorganization of F-actin. Collectively, these data demonstrate that Akt is critically involved in endothelial cell signal transduction mechanisms leading to migration and that the Akt/endothelial NO synthase pathway is necessary for VEGF-stimulated cell migration.

Actins↗
PubMed1981

Effects of C5a on baboon alveolar macrophage migration.

The effect of C5a, a fragment of the fifth complement component, on alveolar macrophage migration was studied using a micropore method. Cells were obtained by broncho-pulmonary lavage, in vivo or in vitro, from control baboons and baboons taught to smoke cigarettes. Macrophage migration directly depended on the C5a concentration cells encountered. The highest C5a concentrations studied enhanced migration more than 20-fold. Cells from smokers exhibited greater migration than those from nonsmokers, and cells recovered in vivo exhibited greater migration than in vitro cells, but these differences were not significant. A gradient analysis suggested that C5a-induced migration was chemotactic, i.e., oriented; C5a enhanced migration more than N-formyl-methionyl-phenylalanine, and C5a without the C-terminal arginine lost over two thirds of its capacity to enhance migration. The observation that C5a induces alveolar macrophage chemotaxis established that alveolar macrophages are similar to other mononuclear phagocytes with respect to C5a-enhanced migratory responses, and demonstrated that complement components may participate in lung inflammatory reactions through effects on cells other than neutrophils.

Animals↗
PubMed1994

Neutrophils increase volume during migration in vivo and in vitro.

Neutrophils increase volume (approximately 15%) when stimulated in suspension, but whether a similar alteration occurs in vivo during migration is unknown. We measured neutrophil volume using serial 0.5-micron sections and three-dimensional reconstruction of rabbit neutrophils migrating into inflammatory lesions in lung and abdominal wall in vivo and of human neutrophils migrating across collagen gels in vitro. An inflammatory response was induced by local instillation of C5a in vivo or generating a gradient of FMLP in vitro. In the lung, neutrophils reconstructed within the vascular space, either in arterioles (158 microns3), capillaries (128 microns3), or venules (135 microns3), were of similar volume, while those in the airspace were markedly larger (266 microns3). Neutrophils that migrated into the abdominal wall (150 microns3) were also significantly larger than those in the abdominal wall vasculature (100 microns3). Human neutrophils induced to migrate into collagen gels by FMLP were significantly larger (290 microns3) than those that did not migrate (204 microns3). We conclude from these studies that migration of rabbit neutrophils in vivo or human neutrophils in vitro is associated with a substantial increase in volume. We speculate that these findings hold promise for elucidation of the mechanisms of neutrophil migration.

Abdominal Muscles↗
PubMed1995

5-Hydroxyeicosatetraenoic acid (HETE)-induced neutrophil transcellular migration is dependent upon enantiomeric structure.

The 5(R) and 5(S) hydroxyeicosatetraenoic acids (5[R]-HETE, 5[S]-HETE) are important inflammatory mediators in lung diseases: they increase mucus, induce airway contraction, and potentiate neutrophil chemotaxis. Neutrophils are important cells in allergic and inflammatory lung diseases. Therefore, we examined the effects of both 5(R)-HETE and 5(S)-HETE on human neutrophil migration across naked filters and human umbilical vein endothelial (HUVE) cell and human type II-like pulmonary epithelial cell (A549) monolayers cultured on these filters. Time courses for both 5(R)-HETE and 5(S)-HETE show significant neutrophil migration at 40 min and maximal migration at 60 to 90 min through all three barriers. Checkerboard analysis showed that migration was chemotactic. Dose-response curves for both isomers through cellular monolayers had the same shapes, but 5(R)-HETE was more potent than 5(S)-HETE. There was greater migration through cellular barriers than through naked filters. Actinomycin D pretreatment of the cellular monolayers slightly inhibited the neutrophil transcellular chemotactic response to both 5-HETEs equally. Enhanced transcellular migration was not due to the production of a soluble chemotactic factor. Thus, although both isomers of 5-HETE were potent chemotactic agents, 5(R)-HETE was slightly more potent. Moreover, relevant endothelial and epithelial monolayers enhance both dose- and time-dependent neutrophil migration stimulated by 5(R)-HETE and 5(S)-HETE. These data indicate that (1) both 5(R)-HETE and 5(S)-HETE are important in mediating lung inflammatory processes, and (2) 5(R)-HETE may play a more important role in neutrophil-rich lung inflammatory responses than 5(S)-HETE because it is a more potent inducer of neutrophil migration through endothelial and epithelial barriers.

Cell Movement↗
PubMed1997

Migration of guinea pig airway epithelial cells in response to bombesin analogues.

Bombesin-like peptides within neuroepithelial cells elicit proliferation of normal and malignant airway epithelial cells. It is not clear that these peptides also elicit epithelial cell migration, a necessary component of airway repair after injury. We studied the effects of the bombesin analogues, gastrin releasing peptide (GRP) and neuromedin B (NMB), on guinea pig tracheal epithelial cell (GPTEC) migration. Primary GPTEC were allowed to migrate through 8-microm-pore gelatin-coated filters for 6 h in a chemotaxis chamber, after which the number of migrated cells per 10 high power fields (10 hpf) were counted. Both neuropeptides elicited migration of GPTEC: 24.8 +/- 4.5 cells for 10(-11) M NMB (P < 0.001 versus control, n = 4) and 16.8 +/- 1.2 cells for 10(-12) M GRP (P < 0.001 versus control, n = 8). Migration was attenuated substantially by a bombesin receptor antagonist. To investigate further the relationship of migration through a filter to the repair of a damaged epithelium, we studied the repair of epithelial cells by video microscopy. A 0.3- to 0.5-microm2 wound was created in a confluent monolayer of GPTEC, and wound closure was followed over 24 h. There was no significant acceleration in the rate of repair of GRP- or NMB-stimulated monolayers compared to control. These data demonstrate that GRP and NMB elicit migration of airway epithelial cells but may not play a significant role in the early repair of the airway epithelium in culture.

Animals↗
PubMed1999

Migration of neutrophils across human pulmonary endothelial cells is not blocked by matrix metalloproteinase or serine protease inhibitors.

It has long been speculated that neutrophils deploy proteases to digest subendothelial matrix as they migrate from the bloodstream. Direct evidence for the involvement of proteases in neutrophil transendothelial migration is, however, lacking. To address this issue we used transmission electron microscopy to verify the presence of continuous basal lamina beneath pulmonary endothelial cells grown on microporous filters, and then examined the effects of protease inhibitors on neutrophil migration through the endothelial cells and their associated subcellular matrix. Inhibitors of the two major matrix-degrading protease groups present in neutrophils, the matrix metalloproteinases (MMPs) and serine proteases, were assessed for their ability to modulate neutrophil transendothelial migration in response to the chemoattractant n-formylmethionyl leucylphenylalanine (FMLP). Neither the naturally occurring MMP inhibitor, tissue inhibitor of metalloproteinase-1, nor the hydroxamic acid-based inhibitors GM-6001, BB-3103, or Ro 31-9790 had any significant effect on FMLP-stimulated neutrophil migration across endothelial cells and associated basal lamina, with >/= 80% of neutrophils migrating through the system, even in the presence of inhibitors, at concentrations that totally inhibited all the gelatinase B (MMP-9) released upon stimulation with FMLP. Similarly, with serine protease inhibitors no significant inhibition of neutrophil migration was observed with a naturally occurring inhibitor, secretory leukocyte protease inhibitor, or a low molecular-weight synthetic inhibitor, Pefabloc SC. These results indicate that neither MMP nor serine protease digestion of sub-endothelial matrix is required for successful neutrophil transendothelial migration.

Cell Movement↗
PubMed2003

HGF, MAPK, and a small physiological electric field interact during corneal epithelial cell migration.

PURPOSE: To investigate the effects of hepatocyte growth factor (HGF) and a small applied electric field (EF) on corneal epithelial cell (CEC) migration. METHODS: Primary cultures of bovine CECs were exposed to an EF (25-250 mV/mm) in the presence or absence of HGF (100 ng/mL). The rate and directionality of CEC migration were quantified. The expression of HGF receptors (HGFRs), p42/44 mitogen-activated protein kinase (MAPK) and the time-course of activation of p42/44 MAPK were investigated by confocal microscopy and Western blot analysis. RESULTS: CECs migrated significantly faster in the presence of an EF, HGF, or HGF and an EF combined. The distribution of HGFRs was intracellular and in the presence of an EF was concentrated in the cathode-facing side. This EF-induced asymmetrical accumulation of HGFRs correlated with the direction of CEC migration. The application of HGF or an EF led to the activation of the MAPK signaling pathway and in the presence of an EF, activation of MAPK was greater in the cathode-facing half of the CECs. Inhibition of the MAPK signaling pathway by PD98059 (100 micro M) reduced the ability of HGF and an EF to enhance the rate of CEC migration, but did not alter EF-induced cathodal directionality. CONCLUSIONS: These data suggest that both HGF and an EF augment the rate of CEC migration through activation of p42/44 MAPK. Moreover, EF-induced redistribution of HGFRs and asymmetry of MAPK signaling, although not instrumental in directing CEC migration cathodally, may be important for the signaling and maintenance of migration.

Animals↗
PubMed2004

TGF-beta2-induced cell surface tissue transglutaminase increases adhesion and migration of RPE cells on fibronectin through the gelatin-binding domain.

PURPOSE: Migration and adhesion of dislocated retinal pigment epithelial (RPE) cells to a fibronectin-rich extracellular matrix is an initial step in proliferative vitreoretinopathy (PVR). In the present study, the functional role of cell surface tissue transglutaminase (tTG) in adhesion and migration of RPE cells on fibronectin (Fn) and collagen type I (Col I) after stimulation with TGF-beta2 was investigated. METHODS: Cultured human RPE cells were treated with 1.0 ng/mL TGF-beta2 for 24 hours. Cell surface tTG expression was determined by cell fraction analysis. Attachment on Col I, full-length Fn, and its 45-kDa gelatin-binding and 110-kDa cell-binding fragment was measured with an MTT assay. Migration of RPE cells was measured by a Boyden chamber assay, and cell spreading was determined. Experiments were performed in the presence or absence of anti-tTG antibodies and anti-integrin alpha5 and beta1 antibodies. RESULTS: TGF-beta2 markedly induced expression of cell-surface tTG on RPE cells and increased attachment and migration on Fn and Col I. Blocking cell surface tTG inhibited attachment, migration, and spreading on Fn and its 45-kDa gelatin-binding fragment, whereas no effect was seen on Col I and the 110-kDa cell-binding Fn fragment. In contrast, blocking of integrin alpha5 and beta1 suppressed adhesion and migration on full-length Fn and the 110-kDa Fn fragment. CONCLUSIONS: These data demonstrate that TGF-beta2 increases expression of cell surface tTG, which in turn strengthens adhesion, migration, and spreading of RPE cells on Fn through the 45-kDa gelatin-binding Fn fragment. At the onset of PVR, this mechanism may help RPE cells to attach and migrate on Fn-containing matrices.

Adolescent↗
PubMed2004

Role of p38 MAP kinase in regulation of cell migration and proliferation in healing corneal epithelium.

PURPOSE: The purpose of the present study was to examine the roles of signaling pathways potentially activated by TGFbeta (i.e., Smad and p38 mitogen-activated kinase [MAPK]) in regulation of cell migration and proliferation of healing mouse corneal epithelium. METHODS: Activation of Smads or p38MAPK was evaluated by immunohistochemistry in healing mouse corneal epithelium after debridement. The role of endogenous TGFbeta or p38MAPK in epithelial healing was determined in organ-cultured mouse corneas with an epithelial defect, in the presence or absence of a TGFbeta-neutralizing antibody or p38MAPK inhibitors, respectively. Cell proliferation was evaluated by incorporation of bromodeoxyuridine. RESULTS: Migrating mouse corneal epithelium had minimal cell proliferation. Smad3 and -4 were found in nuclei of normal corneal epithelium, whereas they were absent in nuclei of migrating cells in association with Smad7 upregulation on epithelial debridement. Administration of TGFbeta-neutralizing antibody reduced the protein expression of Smad7 in vivo after a corneal injury. In contrast, phosphorylation and nuclear translocation of p38MAPK were markedly evident in migrating epithelium during healing, but not in uninjured epithelium. In organ culture, addition of p38MAPK inhibitors blocked cell migration more markedly than neutralizing TGFbeta-antibody and enhanced cell proliferation in the injured corneal epithelium, in association with phosphorylation of Erk. CONCLUSIONS: Endogenous TGFbeta enhances migration of corneal epithelium during wound healing in mice. The p38MAPK, but not the Smad, cascade plays a major role in promoting cell migration and in suppressing cell proliferation in migrating epithelium.

Animals↗
PubMed2004

Adrenomedullin affects two signal transduction pathways and the migration in retinal pigment epithelial cells.

PURPOSE: Adrenomedullin is a multifunctional regulatory peptide known to inhibit the migration of smooth muscle cells. In vitro studies were performed to identify whether adrenomedullin (ADM) also inhibits the migration of RPE cells. The aberrant behavior of these cells is an early event in proliferative vitreoretinopathy, and these studies were designed to determine how ADM acts on RPE cells at the second-messenger level. METHODS: Migration of cultured human RPE cells was determined by the Boyden chamber method, using 10% fetal calf serum (FCS) as a chemotactic factor. The attachment assay was performed on fibronectin, laminin, or poly-D-lysine-coated 96-well plates. RPE cells were incubated in PBS buffer with or without ADM for 15 minutes. Intracellular cAMP and cGMP changes were then measured by enzyme immunoassay (EIA). To determine the cytoplasmic free Ca2+ concentration ([Ca2+]i) response to ADM, fluo-3 AM-loaded RPE cells were imaged with a laser scanning confocal microscope, after stimulation with ADM (10(-12)-10(-7) M). RESULTS: ADM exhibited a concentration-dependent inhibition of FCS-stimulated RPE cell migration. The maximum inhibitory effect of ADM, observed at 10(-7) M, on basal and FCS-induced RPE cell migration was approximately 53.8% and 43.8% of the control, respectively. Exogenously added ADM (10(-9)-10(-7) M) had no significant effect on RPE cell attachment on all tested substrates. ADM increased intracellular cAMP and decreased intracellular cGMP levels dose dependently (10(-10)-10(-7) M) in RPE. The maximum effect was observed at 10(-7) M. ADM also induced a [Ca2+]i decrease in a dose-dependent manner (10(-12)-10(-7) M). The maximum effect was observed at 0.1 micro M, at which point the level declined to 42.9% of the control. CONCLUSIONS: ADM inhibits the migration of RPE cells in vitro by a mechanism that involves the reciprocal upregulation of cAMP and downregulation of cGMP, in association with reductions in [Ca2+]i. ADM-mediated fluctuations in [Ca2+]i, which are well known to be involved in cell migration, appear to be regulated in part by mechanisms involving cAMP synthase. Thus, it appears that ADM acts as a constitutive regulatory system to control aberrant RPE cell behavior and specific migration in response to inflammatory mediators.

Adrenomedullin↗
PubMed2006

Insulin-like growth factor-1 induces migration and expression of laminin-5 in cultured human corneal epithelial cells.

PURPOSE: The effects of insulin-like growth factor (IGF)-1 on laminin (Ln)-5 and the associated integrins during in vitro HCEC migration were examined. Also investigated were the effects of IGF-1 on the migration of human corneal epithelial cells (HCECs). METHODS: HCEC migration was examined by wound-healing and chemoattraction assays. For migration inhibition assays, HCECs were pretreated with inhibitors of the IGF-1 receptor (alphaIR3), the PI3-K/AKT pathway (LY294002), and the MEK-ERK pathway (PD98059). The expression levels of Ln-5 and fibronectin (Fn) were determined by Western blot analysis, and the expression levels of the beta1 and alpha3 integrins were determined by confocal microscopy and Western blot analysis. The migration inhibition with anti-integrin alpha3 and beta1 antibodies was also determined. RESULTS: HCEC migration was significantly increased in the presence of IGF-1 and Ln-5. IGF-1 enhanced the production of Ln-5 in both a dose- and time-dependent manner, and this upregulation was blocked by pretreatment with alphaIR3 or LY294002. IGF-1 treatment upregulated expression of beta1 integrin, but not alpha3 integrin. The HCEC migration facilitated by IGF-1 was inhibited with the anti-integrin antibody for beta1. However, there was no cross-talk between Ln-5 and integrin beta1 production. CONCLUSIONS: The results reveal that IGF-1 induces HCEC migration through the independent production of Ln-5 and beta1 integrin, which are directed at least in part by activation of the PI3-K/AKT pathway, but are not affected by the MEK-ERK pathway.

Blotting, Western↗
PubMed1988

The effects of partial demineralization and fibronectin on migration and growth of gingival epithelial cells on cementum in vitro.

The capacity of mineralized cementum to support epithelial cell migration and growth and the effect that fibronectin and partial demineralization of cementum have on these processes were assessed in vitro. Dog gingival explants, 1 X 2 mm, were cultured on the cementum surfaces of pig root pieces in a defined medium consisting of DMEM and F12 (1V/1V), transferrin, insulin, epidermal growth factor, cortisone, selenium, and high-density lipoprotein. Sixty root pieces were divided into four equal groups according to the treatment: (1) untreated mineralized cementum; (2) treated with 5 micrograms of fibronectin; (3) partially demineralized in 18% EDTA for 30 min; and (4) both partially demineralized and fibronectin-treated as above. Epithelial cell migration and growth on each of the four differently treated cementum surfaces were assessed histomorphometrically by means of scanning electron microscopy. The defined culture medium supported the selective migration and growth of epithelial cells from the gingival explants onto the mineralized cementum. This was confirmed by the positive immunostaining of these cells with antikeratin antibodies. Partial demineralization of cementum inhibited epithelial migration and growth by 83% and 91%, respectively. Fibronectin treatment did not affect epithelial cell migration and growth on mineralized cementum, but it decreased the degree of epithelial cell migration and growth inhibition on partially demineralized cementum to 57% and 43%, respectively. The results indicate that: (i) mineralized cementum may consist of components that are recognized by gingival epithelial cells and support their migration and growth in vitro; (ii) these components can be removed by demineralization; and (iii) fibronectin partially restores epithelial cell migration and growth on partial demineralized cementum in vitro.

Animals↗
PubMed2002

CD40 induces human multiple myeloma cell migration via phosphatidylinositol 3-kinase/AKT/NF-kappa B signaling.

Multiple myeloma (MM) is characterized by clonal expansion of malignant plasma cells in the bone marrow and their egress into peripheral blood with progression to plasma cell leukemia. Our previous study defined a functional role of CD40 activation in MM cell homing and migration. In this study, we examine signaling events mediating CD40-induced MM cell migration. We show that cross-linking CD40, using either soluble CD40L (sCD40L) or anti-CD40 monoclonal antibody (mAb), induces phosphatidylinositol 3-kinase (PI3K) activity and activates its downstream effector AKT in MM.1S cells. CD40 activation also activates the MAP kinase (MEK) pathway, evidenced by phosphorylation of extracellular signal-regulated mitogen-activated protein kinase (ERK), but not c-jun amino-terminal kinase (JNK) or p38, in a dose- and time-dependent manner. Using pharmacologic inhibitors of PI3K and MEK, as well as adenoviruses expressing dominant-negative and constitutively expressed AKT, we demonstrate that PI3K and AKT activities are required for CD40-induced MM cell migration. In contrast, inhibition of ERK/MEK phosphorylation only partially (10%-15%) prevents migration, suggesting only a minor role in regulation of CD40-mediated MM migration. We further demonstrate that CD40 induces nuclear factor (NF)-kappa B activation as a downstream target of PI3K/AKT signaling, and that inhibition of NF-kappa B signaling using specific inhibitors PS1145 and SN50 completely abrogates CD40-induced MM migration. Finally, we demonstrate that urokinase plasminogen activator (uPA), an NF-kappa B target gene, is induced by CD40; and conversely, that uPA induction via CD40 is blocked by PI3K and NF-kappa B inhibitors. Our data therefore indicate that CD40-induced MM cell migration is primarily mediated via activation of PI3K/AKT/NF-kappa B signaling, and further suggest that novel therapies targeting this pathway may inhibit MM cell migration associated with progressive MM.

CD40 Antigens↗
PubMed2003

Developing evidence-based ethical policies on the migration of health workers: conceptual and practical challenges.

It is estimated that in 2000 almost 175 million people, or 2.9% of the world's population, were living outside their country of birth, compared to 100 million, or 1.8% of the total population, in 1995. As the global labour market strengthens, it is increasingly highly skilled professionals who are migrating. Medical practitioners and nurses represent a small proportion of highly skilled workers who migrate, but the loss of health human resources for developing countries can mean that the capacity of the health system to deliver health care equitably is compromised. However, data to support claims on both the extent and the impact of migration in developing countries is patchy and often anecdotal, based on limited databases with highly inconsistent categories of education and skills.The aim of this paper is to examine some key issues related to the international migration of health workers in order to better understand its impact and to find entry points to developing policy options with which migration can be managed.The paper is divided into six sections. In the first, the different types of migration are reviewed. Some global trends are depicted in the second section. Scarcity of data on health worker migration is one major challenge and this is addressed in section three, which reviews and discusses different data sources. The consequences of health worker migration and the financial flows associated with it are presented in section four and five, respectively. To illustrate the main issues addressed in the previous sections, a case study based mainly on the United Kingdom is presented in section six. This section includes a discussion on policies and ends by addressing the policy options from a broader perspective.

Journal Article↗
PubMed2004

Impact, regulation and health policy implications of physician migration in OECD countries.

BACKGROUND: In the face of rising demand for medical services due to ageing populations, physician migration flows are increasingly affecting the supply of physicians in Organisation for Economic Co-operation and development (OECD) countries. This paper offers an integrated perspective on the impact of physician migration on home and host countries and discusses international regulation and policy approaches governing physician migration. METHODS: Information about migration flows, international regulation and policies governing physician migration were derived from two questionnaires sent to OECD countries, a secondary analysis of EUROSTAT Labour Force Surveys, a literature review and official policy documents of OECD countries. RESULTS: OECD countries increasingly perceive immigration of foreign physicians as a way of sustaining their physician workforce. As a result, countries have entered into international agreements regulating physician migration, although their success has been limited due to the imposition of licensing requirements and the protection of vested interests by domestic physicians. OECD countries have therefore adopted specific policies designed to stimulate the immigration of foreign physicians, whilst minimising its negative impact on the home country. Measures promoting immigration have included international recruitment campaigns, less strict immigration requirements and arrangements that foster shared learning between health care systems. Policies restricting the societal costs of physician emigration from developing countries such as good practice guidelines and taxes on host countries have not yet produced their expected effect or in some cases have not been established at all. CONCLUSIONS: Although OECD countries generally favour long-term policies of national self-sufficiency to sustain their physician workforce, such policies usually co-exist with short-term or medium-term policies to attract foreign physicians. As this is likely to continue, there is a need to create a global framework that enforces physician migration policies that confer benefits on home and host countries. In the long term, OECD countries need to put in place appropriate education and training policies rather than rely on physician migration to address their future needs.

Journal Article↗
PubMed2006

A cell-cycle independent role for p21 in regulating synovial fibroblast migration in rheumatoid arthritis.

Rheumatoid arthritis (RA) is characterized by synovial hyperplasia and destruction of cartilage and bone. The fibroblast-like synoviocyte (FLS) population is central to the development of pannus by migrating into cartilage and bone. We demonstrated previously that expression of the cell cycle inhibitor p21 is significantly reduced in RA synovial lining, particularly in the FLS. The aim of this study was to determine whether reduced expression of p21 in FLS could alter the migratory behavior of these cells. FLS were isolated from mice deficient in p21 (p21(-/-)) and were examined with respect to growth and migration. p21(-/-) and wild-type (WT) FLS were compared with respect to migration towards chemoattractants found in RA synovial fluid in the presence and absence of cell cycle inhibitors. Restoration of p21 expression was accomplished using adenoviral infection. As anticipated from the loss of a cell cycle inhibitor, p21(-/-) FLS grow more rapidly than WT FLS. In examining migration towards biologically relevant RA synovial fluid, p21(-/-) FLS display a marked increase (3.1-fold; p < 0.05) in migration compared to WT cells. Moreover, this effect is independent of the cell cycle since chemical inhibitors that block the cell cycle have no effect on migration. In contrast, p21 is required to repress migration as restoration of p21 expression in p21(-/-) FLS reverses this effect. Taken together, these data suggest that p21 plays a novel role in normal FLS, namely to repress migration. Loss of p21 expression that occurs in RA FLS may contribute to excessive invasion and subsequent joint destruction.

Animals↗