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ABSTRACT: HTS significantly enhances neutrophil-mediated intracellular killing of bacteria. This provides further evidence of the beneficial
effects of hypertonic resuscitation in the critically ill patient.
Irish Journal of Medical Science 04/2012; 171:10-10. · 0.58 Impact Factor
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ABSTRACT: These findings demonstrate for the first time that taurolidine can inhibit angiogenesis in a dose-dependent manner. Taurolidine
may prevent VEGF-mediated angiogenesis and thus it may potentially inhibit the growth of dormant micrometastases following
surgical removal of a primary tumour.
Irish Journal of Medical Science 04/2012; 171:10-11. · 0.58 Impact Factor
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Irish Journal of Medical Science 04/2012; 171:11-11. · 0.58 Impact Factor
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Irish Journal of Medical Science 04/2012; 171:49-50. · 0.58 Impact Factor
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ABSTRACT: These findings identify a novel pathway through which open surgery and laparoscopy differentially modulate perioperative tumour
angiogenesis and growth.
Irish Journal of Medical Science 04/2012; 171:50-51. · 0.58 Impact Factor
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ABSTRACT: Antiviral therapy is a potentially successful approach for the treatment of patients with Hepatitis B virus (HBV) infection. One antiviral agent is the nucleoside analogue adefovir dipivoxil (ADV). Its efficiency is compromised by the emergence of drug-resistant HBV mutants. Although three major ADV-resistant mutations of HBV are known, rtA181T/V and rtN236T, HBV mutations associated with ADV resistance have not been fully identified. We analyzed DNA sequences that covered a 244 base pair region of the HBV polymerase gene from patients with clinical manifestations of ADV resistance. A novel pattern of amino acid substitutions in HBV polymerase was detected in 26 out of 86 patients. This mutant exhibited a substitution of glycine for glutamic acid at residue 218 (rtE218G). Transient transfection of the HBV replication-competent construct including the rtE218G mutation was performed in HepG2 cells in order to determine the relevance of this mutation to ADV resistance. Phenotypic analyses demonstrated that the rtE218G mutation could independently confer resistance to ADV in vitro, with a 50% inhibitory concentration (IC50) 5.5-fold higher than wild-type HBV. RtE218G-mutated HBV also showed a decreased replication capacity in vitro, equal to 87% of wild-type HBV. The present study showed that the rtE218G mutation may be a novel ADV-resistant mutation. Further work will focus on resistance surveillance and cross-resistance analyses, and the molecular mechanisms involved.
Journal of Viral Hepatitis 02/2010; 17:66 - 72. · 4.09 Impact Factor
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ABSTRACT: Chronic hepatitis B (CHB) virus hepatitis B virus (HBV) infection is the key cause of hepatocellular carcinoma (HCC) in Asians. Recent studies have shown that levels of CD4+CD25+ regulatory T cells (Tregs) were increased and were linked to an impaired immune response in patients with CHB. Evaluating whether Tregs are involved in the progression of CHB to HCC will provide insight into the immunopathogenesis of HCC. In the present study, we showed that circulating and liver-residing Tregs increased in CHB (n = 15) and HCC (n = 49) patients, particularly in the peripheral blood of HCC patients with HBV infection (n = 29). The increased Tregs in CHB patients suppressed the specific immune response induced by not only HBV antigen, but also by HCC tumour antigen. When peripheral blood mononuclear cells (PBMC) were co-cultured with human hepatoma cell lines that are stably transfected with HBV (HepG2.2.15), CD4+CD25+ Treg populations increased and upregulated the expression of forkhead box P3 transcriptional regulator (FoxP3), cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and glucocorticoid-induced tumour necrosis factor (TNF) receptor family gene (GITR). In contrast, PBMCs co-cultured with HepG2 cells (the parental cell line of HepG2.2.15) did not. CD4+CD25+ Tregs isolated from PBMCs that were co-cultured with HepG2.2.15 cells also had a greater suppressive ability with respect to the tumour antigen-specific immune response induced by NY-ESO-1 or MAGE-A3 compared with CD4+CD25+ Tregs isolated from PBMCs co-cultured with HepG2 cells. The results offer evidence that the expansion of CD4+CD25+ Tregs and the enhancement of the suppressor function of CD4+CD25+ Tregs induced by HBV infection-related factors could suppress the anti-tumour immune response to HCC tumour antigen and inhibit tumour immuno-surveillance against HCC, which may be involved in the immunopathogenesis from CHB to HCC.
Journal of Viral Hepatitis 02/2010; 17:34 - 43. · 4.09 Impact Factor
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M J Smith,
A C Culhane,
M Donovan,
J C Coffey,
B D Barry,
M A Kelly,
D G Higgins, J H Wang,
W O Kirwan,
T G Cotter,
H P Redmond
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ABSTRACT: Tumour stroma gene expression in biopsy specimens may obscure the expression of tumour parenchyma, hampering the predictive power of microarrays. We aimed to assess the utility of fluorescence-activated cell sorting (FACS) for generating cell populations for gene expression analysis and to compare the gene expression of FACS-purified tumour parenchyma to that of whole tumour biopsies. Single cell suspensions were generated from colorectal tumour biopsies and tumour parenchyma was separated using FACS. Fluorescence-activated cell sorting allowed reliable estimation and purification of cell populations, generating parenchymal purity above 90%. RNA from FACS-purified and corresponding whole tumour biopsies was hybridised to Affymetrix oligonucleotide microarrays. Whole tumour and parenchymal samples demonstrated differential gene expression, with 289 genes significantly overexpressed in the whole tumour, many of which were consistent with stromal gene expression (e.g., COL6A3, COL1A2, POSTN, TIMP2). Genes characteristic of colorectal carcinoma were overexpressed in the FACS-purified cells (e.g., HOX2D and RHOB). We found FACS to be a robust method for generating samples for gene expression analysis, allowing simultaneous assessment of parenchymal and stromal compartments. Gross stromal contamination may affect the interpretation of cancer gene expression microarray experiments, with implications for hypotheses generation and the stability of expression signatures used for predicting clinical outcomes.
British Journal of Cancer 06/2009; 100(9):1452-64. · 5.04 Impact Factor
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ABSTRACT: Perioperative exposure to lipopolysaccharide (LPS) is associated with accelerated metastatic colorectal tumour growth. LPS directly affects cells through Toll-like receptor 4 (TLR-4) and the transcription factor NF-kappaB. The urokinase plasminogen activator (u-PA) system is intimately implicated in tumour cell extracellular matrix (ECM) interactions fundamental to tumour progression. Thus we sought to determine if LPS directly induces accelerated tumour cell ECM adhesion and invasion through activation of the u-PA system and to elucidate the cellular pathways involved. Human colorectal tumour cell lines were stimulated with LPS. u-PA concentration, u-PA activity, active u-PA, surface urokinase plasminogen activator receptor (u-PAR) and TLR-4 expression were assessed by ELISA, colorimetric assay, western blot analysis and flow cytometry respectively. In vitro tumour cell vitronectin adhesion and ECM invasion were analysed by vitronectin adhesion assay and ECM invasion chambers. u-PA and u-PAR function was inhibited with anti u-PA antibodies or the selective u-PA inhibitors amiloride or WXC-340, TLR-4 by TLR-4-blocking antibodies and NF-kappaB by the selective NF-kappaB inhibitor SN-50. LPS upregulates u-PA and u-PAR in a dose-dependent manner, enhancing in vitro tumour cell vitronectin adhesion and ECM invasion by >40% (P<0.01). These effects were ameliorated by u-PA and u-PAR inhibition. LPS activates NF-kappaB through TLR-4. TLR-4 and NF-kappaB inhibition ameliorated LPS-enhanced u-PA and u-PAR expression, tumour cell vitronectin adhesion and ECM invasion. LPS promotes tumour cell ECM adhesion and invasion through activation of the u-PA system in a TLR-4- and NF-kappaB-dependent manner.
British Journal of Cancer 05/2009; 100(10):1589-602. · 5.04 Impact Factor
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ABSTRACT: Background: Surgical trauma potentiates tumour growth. Endothelial progenitor cells (EPC), derived from bone-marrow, enhance tumour angiogenesis and growth. We hypothesized that laparotomy and laparoscopy differentially affect the mobilization of EPCs and hence tumour angiogenesis.Methods: C57BL/6 mice, bearing Lewis lung (3LL) flank tumours, were randomized to laparotomy, laparoscopy (CO2 pneumoperitoneum), and anaesthetic-only treatment groups (n = 12 per group). Bone marrow EPC were detected by flow cytometry using stem cell antigen (SCA-1) at 6, 24 and 48 h after treatment. Differentiated EPC were identified, at the same time points, in splenic homogenates by dual staining for lectin/UEA-1 and acetylated low density lipoprotein uptake. These findings were correlated with changes in tumour volume and microvessel density for each group. In addition, EPC uptake in tumours was evaluated using CM-Dil-labelling. This was further correlated with tumour growth and angiogenesis.Results: Laparotomy induced an 11-fold (P = <0.001) increase in bone marrow EPC, compared with anaesthetic-only control (table) at 24 h. Laparoscopy significantly (P = <0.001) attenuated EPC mobilization compared with laparotomy. This correlated with reduced tumour growth and angiogenesis. Following laparotomy, increased EPC were demonstrated lining tumour microvessels. This phenomenon was significantly (P = <0.001) attenuated in the laparoscopy group.Conclusions: Laparotomy is associated with significant mobilization of EPC for perioperative tumour angiogenesis and growth. Laparoscopy attenuates this effect. These findings identify a novel pathway by which open surgery promotes tumour angiogenesis.
British Journal of Surgery 01/2009; 89(S1):31 - 32. · 4.61 Impact Factor
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ABSTRACT: Postnatal vasculogenesis, the process by which vascular committed bone marrow stem cells or endothelial precursor cells (EPC) migrate, differentiate, and incorporate into the nacent endothelium contributing to physiological and pathological neovascularization, has stimulated much interest. Its contribution to tumor nonvascularization, wound healing, and revascularization associated with skeletal and cardiac muscles ischaemia is established. We evaluated the mobilization of EPCs in response to musculoskeletal trauma. Blood from patients (n = 15) following AO type 42a1 closed diaphyseal tibial fractures was analyzed for CD34 and AC133 cell surface marker expression. Immunomagnetically enriched CD34+ mononuclear cell (MNC(CD34+)) populations were cultured and examined for phenotypic and functional vascular endothelial differentiation. Circulating MNC(CD34+) levels increased sevenfold by day 3 postinjury. Circulating MNC(AC133+) increased 2.5-fold. Enriched MNC(CD34+) populations from day 3 samples in culture exhibited cell cluster formation with sprouting spindles. These cells bound UEA-1 and incorporated fluorescent DiI-Ac-LDL intracellularily. Our findings suggest a systemic provascular response is initiated in response to musculoskeletal trauma. Its therapeutic manipulation may have implications for the potential enhancement of fracture healing.
Journal of Orthopaedic Research 02/2007; 25(1):44-50. · 2.81 Impact Factor
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ABSTRACT: The urokinase plasminogen activator (u-PA) is intimately associated with tumour invasion and metastases. Surgery facilitates accelerated metastatic tumour growth in murine models, a phenomenon related to elevated perioperative bacterial lipopolysaccaride (LPS) and inflammatory cytokine levels. The objectives of the study were to examine the role of u-PA in cytokine-enhanced tumour cell invasion in vitro and surgery-induced accelerated metastatic tumour growth in vivo and to assess the potential benefit of a novel selective u-PA inhibitor WXC-340 in this setting. CT-26 murine colorectal carcinoma cells were stimulated with LPS, tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). Cell supernatant u-PA expression and activity were determined using a colorimetric assay and Western blot analysis, respectively. Baseline and cytokine-stimulated in vitro invasion were assessed using ECmatrix invasion chambers. Two established murine models of accelerated metastatic tumour growth were used to investigate the consequences of u-PA inhibition on postoperative metastatic tumour burden. The effect of u-PA inhibition in vitro and in vivo was examined using the novel selective u-PA inhibitor, WXC-340. Proinflammatory cytokine stimulation significantly enhanced in vitro u-PA expression, activity and extracellular matrix invasion by approximately 50% compared to controls (P<0.05). This was abrogated by WXC-340. In vivo WXC-340 almost completely ameliorated both LPS- and surgery-induced, metastatic tumour growth compared to controls (P>0.05). In conclusion, u-PA cascade is actively involved in cytokine-mediated enhanced tumour cell invasion and LPS and surgery-induced metastatic tumour growth. Perioperative u-PA inhibition with WXC-340 may represent a novel therapeutic paradigm.
British Journal of Cancer 02/2007; 96(2):262-8. · 5.04 Impact Factor
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ABSTRACT: Post-natal vasculogenesis, the process by which vascular committed bone marrow stem cells or endothelial precursor cells migrate, differentiate and incorporate into the nacent endothelium and thereby contribute to physiological and pathological neurovascularisation, has stimulated much interest. Its contribution to neovascularisation of tumours, wound healing and revascularisation associated with ischaemia of skeletal and cardiac muscles is well established. We evaluated the responses of endothelial precursor cells in bone marrow to musculoskeletal trauma in mice. Bone marrow from six C57 Black 6 mice subjected to a standardised, closed fracture of the femur, was analysed for the combined expression of cell-surface markers stem cell antigen 1 (sca-1(+)) and stem cell factor receptor, CD117 (c-kit(+)) in order to identify the endothelial precursor cell population. Immunomagnetically-enriched sca-1(+) mononuclear cell (MNC(sca-1+)) populations were then cultured and examined for functional vascular endothelial differentiation. Bone marrow MNC(sca-1+,c-kit+) counts increased almost twofold within 48 hours of the event, compared with baseline levels, before decreasing by 72 hours. Sca-1(+) mononuclear cell populations in culture from samples of bone marrow at 48 hours bound together Ulex Europus-1, and incorporated fluorescent 1,1'-dioctadecyl- 3,3,3,'3'-tetramethylindocarbocyanine perchlorate-labelled acetylated low-density lipoprotein intracellularily, both characteristics of mature endothelium. Our findings suggest that a systemic provascular response of bone marrow is initiated by musculoskeletal trauma. Its therapeutic manipulation may have implications for the potential enhancement of neovascularisation and the healing of fractures.
Journal of Bone and Joint Surgery - British Volume 02/2007; 89(1):116-20. · 2.83 Impact Factor
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ABSTRACT: Endothelial progenitor cells (EPCs) derived from bone marrow incorporate into foci of neovascularization to propagate tumor growth. These cells are mobilized in response to surgical injury. Laparoscopic surgery may protect against the oncologic adverse effects of open surgical tumor excision, and this may be related to attenuated mobilization of EPCs.
For this study, 132 C57BL/6 mice were randomized to standardized laparotomy, laparoscopy, or control groups. The animals were killed at 6, 24, 48, and 72 h. Femur bone marrow and peripheral blood were harvested. Bone marrow EPCs were detected by flow cytometric dual staining for the stem cell antigen-1/cKit phenotype. Circulating EPCs were characterized in blood by vascular endothelial growth factor receptor 2 positive/macrophage activating complement-1 negative staining. Separately, 12 C57/bl6 mice bearing 3LL Lewis lung tumors 12 days after laparotomy or laparoscopy had their tumors excised and examined for endothelial cell expression (marker P1H12).
Laparoscopy decreased circulating EPCs and bone-marrow EPC levels, as compared with laparotomy, at all time points. Bone marrow EPC levels were 2.95% +/- 0.32% after laparotomy, as compared with 0.65 +/- 0.21 in the laparoscopy group (p < 0.05). The circulating EPC level in the laparotomy group was 35.2% +/- 6% of cells, as compared with 3.1% +/- 0.2% in the laparoscopy group (p < 0.05). In homogenized tumors, the percentage of P1H12 expression among laparoscopy-treated animals was 22.1% +/- 4.2%, as compared with 39% +/- 8% in the laparotomy group (p < 0.05).
Laparoscopy decreased EPC levels in both bone marrow and circulation, resulting in decreased tumor endothelial cell burden. This may represent a novel mechanism by which laparoscopy protects against the oncologic adverse effects of open surgical tumor excision.
Surgical Endoscopy 01/2007; 21(1):87-90. · 4.01 Impact Factor
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ABSTRACT: Postnatal vasculogenesis, the process by which vascular committed bone marrow stem cells or endothelial precursor cells (EPC) migrate, differentiate, and incorporate into the nacent endothelium contributing to physiological and pathological neovascularization, has stimulated much interest. Its contribution to tumor nonvascularization, wound healing, and revascularization associated with skeletal and cardiac muscles ischaemia is established. We evaluated the mobilization of EPCs in response to musculoskeletal trauma. Blood from patients (n = 15) following AO type 42a1 closed diaphyseal tibial fractures was analyzed for CD34 and AC133 cell surface marker expression. Immunomagnetically enriched CD34+ mononuclear cell (MNCCD34+) populations were cultured and examined for phenotypic and functional vascular endothelial differentiation. Circulating MNCCD34+ levels increased sevenfold by day 3 postinjury. Circulating MNCAC133+ increased 2.5-fold. Enriched MNCCD34+ populations from day 3 samples in culture exhibited cell cluster formation with sprouting spindles. These cells bound UEA-1 and incorporated fluorescent DiI-Ac-LDL intracellularily. Our findings suggest a systemic provascular response is initiated in response to musculoskeletal trauma. Its therapeutic manipulation may have implications for the potential enhancement of fracture healing. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:44–50, 2007
Journal of Orthopaedic Research 12/2006; 25(1):44 - 50. · 2.81 Impact Factor
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ABSTRACT: The toll-like receptor (TLR) system constitutes a pylogenetically ancient, evolutionary conserved, archetypal pattern recognition system, which underpins pathogen recognition by and activation of the immune system. Toll-like receptor agonists have long been used as immunoadjuvants in anti cancer immunotherapy. However, TLRs are increasingly implicated in human disease pathogenesis and an expanding body of both clinical and experimental evidence suggests that the neoplastic process may subvert TLR signalling pathways to advance cancer progression. Recent discoveries in the TLR system open a multitude of potential therapeutic avenues. Extrapolation of such TLR system manipulations to a clinical oncological setting demands care to prevent potentially deleterious activation of TLR-mediated survival pathways. Thus, the TLR system is a double-edge sword, which needs to be carefully wielded in the setting of neoplastic disease.
British Journal of Cancer 09/2006; 95(3):247-52. · 5.04 Impact Factor
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ABSTRACT: In the recent past, several papers have pointed to the possibility that tumour removal generates a permissive environment in which tumour growth is potentiated. This phenomenon has been coined "perioperative tumour growth" and whilst it represents a departure in terms of our attitude to the surgical process, this concept was first hinted at by Paget(1) himself. Despite this, the time interval immediately before and after cancer surgery (i.e. the perioperative period) remains an underutilised interval during which chemotherapeutic regimens are rarely implemented. Herein, we present a summarised review of the literature that supports the concept that tumour removal may potentiate the growth of residual neoplastic disease. We also outline current knowledge regarding underlying mechanisms and in this manner highlight potential therapeutic entry points. Finally, we emphasise the urgent need for trials of agents that could protect patients against the harmful host-tumour interactions that may occur during the perioperative period.
BioEssays 05/2006; 28(4):433-7. · 4.95 Impact Factor
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ABSTRACT: In the recent past, several papers have pointed to the possibility that tumour removal generates a permissive environment in which tumour growth is potentiated. This phenomenon has been coined “perioperative tumour growth” and whilst it represents a departure in terms of our attitude to the surgical process, this concept was first hinted at by Paget† himself. Despite this, the time interval immediately before and after cancer surgery (i.e. the perioperative period) remains an underutilised interval during which chemotherapeutic regimens are rarely implemented. Herein, we present a summarised review of the literature that supports the concept that tumour removal may potentiate the growth of residual neoplastic disease. We also outline current knowledge regarding underlying mechanisms and in this manner highlight potential therapeutic entry points. Finally, we emphasise the urgent need for trials of agents that could protect patients against the harmful host–tumour interactions that may occur during the perioperative period. BioEssays 28: 433–437, 2006. © 2006 Wiley Periodicals, Inc.
BioEssays 03/2006; 28(4):433 - 437. · 4.95 Impact Factor
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ABSTRACT: Activated protein C (APC) is an endogenous anti-coagulant with anti-inflammatory properties. The purpose of the present study was to evaluate the effects of activated protein C in the setting of skeletal muscle ischaemia reperfusion injury (IRI). IRI was induced in rats by applying rubber bands above the levels of the greater trochanters bilaterally for a period of 2h followed by 12h reperfusion. Treatment groups received either equal volumes of normal saline or activated protein C prior to tourniquet release. Following 12h reperfusion, muscle function was assessed electrophysiologically by electrical field stimulation. The animals were then sacrificed and skeletal muscle harvested for evaluation. Activated protein C significantly attenuated skeletal muscle reperfusion injury as shown by reduced myeloperoxidase content, wet to dry ratio and electrical properties of skeletal muscle. Further in vitro work was carried out on neutrophils isolated from healthy volunteers to determine the direct effect of APC on neutrophil function. The effects of APC on TNF-alpha stimulated neutrophils were examined by measuring CD18 expression as well as reactive oxygen species generation. The in vitro work demonstrated a reduction in CD18 expression and reactive oxygen species generation. We conclude that activated protein C may have a protective role in the setting of skeletal muscle ischaemia reperfusion injury and that this is in part mediated by a direct inhibitory effect on neutrophil activation.
Journal of Orthopaedic Research 12/2005; 23(6):1454-9. · 2.81 Impact Factor
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ABSTRACT: Osteoblasts and endothelial cells are intimately located within the skeleton, and their interaction is an integral component of bone repair, a complex process which continues for weeks under conditions of low oxygen tension. This study investigated the paracrine factors that couple angiogenesis and osteogenesis and demonstrates that hypoxia is an integral mediator of this complex phenomenon. Hypoxia stimulates vascular endothelial growth factor (VEGF) and not basic fibroblast growth factor (bFGF) release from primary human osteoblasts and is directly angiogenic, enhancing human microvascular endothelial cell proliferation and vessel tube formation in vitro. Hypoxic endothelial cells release potent osteogenic mitogens, endothelin-1 (Et-1) and insulin-like growth factor-1 (IGF-1). The conditioned medium of hypoxic osteoblasts significantly enhance blood vessel formation (indirect angiogenesis), far in excess of hypoxia alone, via a primarily VEGF-dependent mechanism. Et-1 and IGF-1 from hypoxic endothelial cells cause osteoblasts to proliferate and differentiate and further enhance their angiogenic potential. In summary, this study describes a reciprocal regulatory and autoregulatory process that couples the mutually dependent processes of angiogenesis and osteogenesis and demonstrates that the hypoxia characteristic of healing bone is an integral mediator of this complex phenomenon.Ostoblastes et cellules endothliales sont localiss de faon intime dans le squelette et leur interaction est un composant intgral de la rparation osseuse, un processus complexe qui continue pendant des semaines dans des conditions de basse pression doxygne. Dans cette tude ont t analyss les facteurs paracrines qui couplent langiogense et lostogense, et dmontre que lhypoxie est un mdiateur intgral de ce phnomne complexe. Lhypoxie stimule le facteur VEGF et pas le facteur bFGF des ostoblastes humains primaires et est directement lie laugmentation angiognique microvasculaire des cellules endothliales humaines et la formation des axes vasculaires in vitro. Les cellules endothliales hypoxiques librent les mitognes ostogniques efficaces, endothelin-1 (Et-1) et insuline-like, growth factor-1 (IGF-1). Le milieu ainsi conditionn des ostoblastes hypoxiques a augment de manire significative la formation de vaisseaux sanguins, (angiogense indirecte) bien plus que la seule hypoxie, par lintermdiaire principalement dun mcanisme base de VEGF. Et-1 et Igf-1 partir des cellules endothliales hypoxiques font prolifrer des ostoblastes, diffrencient et augmentent plus loin leur potentiel angiogniques. En rsum cette tude dcrit un processus de normalisation et autorgulatrice rciproque qui couple les processus mutuellement dpendants de langiogense et de lostogense, et dmontre que lhypoxie caractristique de los en rparation, est un mdiateur intgral de ce phnomne complexe.
European Journal of Orthopaedic Surgery & Traumatology 07/2005; 15(3):214-225. · 0.10 Impact Factor
