Showing papers by "Geoffrey C. Gurtner published in 2005"

Hyperglycemia-Induced Reactive Oxygen Species and Impaired Endothelial Progenitor Cell Function

Abstract: Vascular complications in diabetes are a significant source of human morbidity and mortality, affecting multiple organ systems and persisting despite tight glucose control. Many of these complications can be linked to impairments in vasculogenesis, the process by which circulating and bone marrow-derived endothelial progenitor cells (EPCs) contribute to new vessel formation. Recent evidence suggests that hyperglycemia alone, through the mitochondrial overproduction of reactive oxygen species (ROS), can induce changes in gene expression and cellular behavior in diabetes. In this review, we examine how hyperglycemia-induced overproduction of ROS could explain EPC impairments observed in diabetes. Experimentally, impairments in EPC function prevent new blood vessel growth and are potentially reversible by manipulations to decrease ROS. Novel strategies aimed at reducing hyperglycemia-induced ROS may be a useful adjuvant to antihyperglycemic therapies in the restoration of vasculogenesis and the prevention of diabetic complications.

Effect of carbon dioxide pneumoperitoneum on bacteraemia and endotoxaemia in an animal model of peritonitis.

Abstract: Laparoscopy is increasingly used in conditions complicated by peritonitis A theoretical concern is that carbon dioxide pneumoperitoneum may increase bacteraemia This study examines the effect of carbon dioxide pneumoperitoneum on bacteraemia, endotoxaemia and physiological correlates of sepsis in an animal model of peritonitis New Zealand white rabbits were assigned to three groups of six animals Group 1 received an intraperitoneal inoculation of 10(9) colony-forming units of Escherichia coli followed by a 10-cm midline laparotomy Group 2 received an identical bacterial inoculum followed by a 12-mmHg carbon dioxide pneumoperitoneum for 1 h Group 3 received no bacteria but had a 12-mmHg carbon dioxide pneumoperitoneum for 1 h Groups 1 and 2 had significantly higher levels of bacteraemia (P < 001) and endotoxaemia (P < 001) accompanied by significantly lower mean arterial pressures (P < 005) and higher heart rates (P < 005) compared with group 3 After 6 h groups 1 and 2 were significantly hypocarbic (P < 001), leucopenic (P < 001) and thrombocytopenic (P < 001) There was no difference between group 1 and group 2 A carbon dioxide pneumoperitoneum of 12 mmHg does not increase bacteraemia or endotoxaemia, nor does it adversely affect physiological or laboratory correlates of sepsis compared with laparotomy in this animal model of peritonitis

Topical vascular endothelial growth factor reverses delayed wound healing secondary to angiogenesis inhibitor administration.

Abstract: The prevention of new blood vessel growth is an increasingly attractive strategy to limit tumor growth. However, it remains unclear whether anti-angiogenesis approaches will impair wound healing, a process thought to be angiogenesis dependent. Results of previous studies differ as to whether angiogenesis inhibitors delay wound healing. We evaluated whether endostatin at tumor-inhibiting doses delayed excisional wound closure. C57/BL6J mice were treated with endostatin or phosphate-buffered solution 3 days prior to the creation of two full-thickness wounds on the dorsum. Endostatin was administered daily until wound closure was complete. A third group received endostatin, but also had daily topical vascular endothelial growth factor applied locally to the wound. Wound area was measured daily and the wounds were analyzed for granulation tissue formation, epithelial gap, and wound vascularity. Endostatin-treated mice showed a significant delay in wound healing. Granulation tissue formation and wound vascularity were significantly decreased, but reepithelialization was not effected. Topical vascular endothelial growth factor application to wounds in endostatin-treated mice resulted in increased granulation tissue formation, increased wound vascularity, and wound closure approaching that of control mice. This study shows that the angiogenesis inhibitor endostatin delays wound healing and that topical vascular endothelial growth factor is effective in counteracting this effect.

Mechanical strain alters gene expression in an in vitro model of hypertrophic scarring.

Abstract: Fibroblasts represent a highly mechanoresponsive cell type known to play key roles in normal and pathologic processes such as wound healing, joint contracture, and hypertrophic scarring. In this study, we used a novel fibroblast-populated collagen lattice (FPCL) isometric tension model, allowing us to apply graded biaxial loads to dermal fibroblasts in a 3-dimensional matrix. Cell morphology demonstrated dose-dependent transition from round cells lacking stress fibers in nonloaded lattices to a broad, elongated morphology with prominent actin stress fibers in 800-mg-loaded lattices. Using quantitative real-time RT-PCR, a dose dependent induction of both collagen-1 and collagen-3 mRNA up to 2.8- and 3-fold, respectively, as well as a 2.5-fold induction of MMP-1 (collagenase) over unloaded FPCLs was observed. Quantitative expression of the proapoptotic gene Bax was down-regulated over 4-fold in mechanically strained FPCLs. These results suggest that mechanical strain up-regulates matrix remodeling genes and down-regulates normal cellular apoptosis, resulting in more cells, each of which produces more matrix. This "double burden" may underlie the pathophysiology of hypertrophic scars and other fibrotic processes in vivo.

Stem cells and distraction osteogenesis: endothelial progenitor cells home to the ischemic generate in activation and consolidation.

Abstract: BACKGROUND Ischemia is a limiting factor during distraction osteogenesis. The authors sought to determine the extent of ischemia in the distraction zone and whether endothelial progenitor cells home to the distraction zone and participate in local vasculogenesis. METHODS Laser Doppler imaging was used to assess the extent of blood flow in the distraction zone in gradually distracted, immediately distracted, and osteotomized rat mandibles during activation and consolidation. Animals (n = 50; 25 rats with unilateral gradual distraction and contralateral osteotomy as an internal control, and 25 rats with unilateral immediate distraction) were examined on postoperative days 4, 6, and 8 of activation, and after 1 and 2 weeks of consolidation. Endothelial progenitor cells isolated from human peripheral blood were labeled with fluorescent DiI dye, and 0.5 x 10 cells were injected intra-arterially under direct vision into each carotid artery at the start of activation in nude rats (n = 18) that then underwent the distraction protocol outlined above. RESULTS Doppler flow analysis demonstrated relative ischemia during the activation period in the distraction osteogenesis group and increased blood flow in the osteotomized control group as compared with flow in a normal hemimandible [normal, 1 (standardized); distraction osteogenesis, 0.58 +/- 0.05; control, 2.58 +/- 0.21; p < 0.05 for both results]. We observed a significantly increased endothelial progenitor cell population at the generate site versus controls at midactivation and at 1 and 2 weeks of consolidation [25 +/- 1.9 versus 1 +/- 0.3 DiI-positive cells per high-power field (p < 0.05), 124 +/- 21 versus 8 +/- 4 DiI-positive cells per high-power field (p < 0.05), and 106 +/- 18 versus 9 +/- 3 DiI-positive cells per high-power field (p < 0.05), respectively]. CONCLUSIONS These data suggest that the distraction zone becomes relatively ischemic during activation and that endothelial progenitor cells home to the ischemic generate site during the activation phase and remain during the consolidation phase. Selective expansion of these stem cells may be useful in overcoming ischemic limitations of distraction osteogenesis. Moreover, their homing capability may be used to effect site-specific transgene delivery to the generate.

Sonographically guided percutaneous carpal tunnel release: an anatomic and cadaveric study.

Abstract: Minimally invasive techniques have become the standard of care for multiple procedures. This paper demonstrates both the surgeons' capacity to perform an accurate anatomic evaluation of the hand and forearm (n = 10) and the use of this anatomic information to accurately perform sonographically guided, percutaneous carpal tunnel release using a single-portal endoscope without direct or indirect visualization in a cadaver model (n = 6). Open dissection was then performed to confirm complete ligament transection and to evaluate the surrounding structures for injury. In all 6 cadavers, the transverse carpal ligament was transected completely without injury to any surrounding structures. With further investigation, this novel technique may offer a less invasive, office-based method for the surgical treatment of carpal tunnel syndrome that may offer patients an expedited recovery.

Two‐team synchronous oesophagectomy

Abstract: Between 1984 and 1992, 131 patients underwent two-team synchronous oesophagectomy for carcinoma. Some 95 per cent of tumours were successfully resected by this technique. In 5 per cent of patients the tumour was found to be irresectable at operation and gastric bypass was performed. The overall operative mortality rate was 8 per cent and the pulmonary complication rate 10 per cent. The actuarial survival rate was 55 per cent at 1 year, 22 per cent at 3 years and 16 per cent at 5 years. When compared with the traditional two-stage Lewis approach, two-team synchronous oesophagectomy was significantly faster (mean 222 versus 282 min), but was not significantly different with respect to blood loss, transfusion requirement, pulmonary complications or operative mortality rate. Patients undergoing two-team oesophagectomy had a significantly shorter hospital stay than those receiving the two-stage procedure (mean 16 versus 24 days).

Method of treating or preventing pathologic effects of acute increases in hyperglycemia and/or acute increases of free fatty acid flux

Abstract: One aspect of the present invention relates to a method of treating or preventing pathologic sequelae of acute hyperglycemia and/or increased fatty acid flux in a subject. This method involves administering an ROS inhibitor to the subject. In addition, methods of promoting neovascularization, inhibiting oxidation or excessive release of free fatty acids, and identifying compounds suitable for treatment or prevention of ROS-mediated injury are also disclosed.

Circulating endothelial progenitor cells and vascular anomalies.

Abstract: Recent findings regarding pathways of stem/progenitor cell involvement in adult blood vessel growth (postnatal vasculogenesis) suggest new theories for the pathogenesis of vascular anomalies. The somatic growth of vascular malformations and the mysterious pattern of proliferation and involution in infantile hemangioma can no longer be purely understood through the paradigm of angiogenesis. Molecular signals for postnatal vasculogenesis are being discovered in numerous animal models of cancer and ischemia, yet little research has addressed the importance of vasculogenesis in the growth of vascular anomalies. In this review, we discuss early studies that have investigated stem/progenitor cell involvement in the pathophysiology of infantile hemangioma and other congenital vascular anomalies.

Method for producing hypertrophic scarring animal model for identification of agents for prevention and treatment of human hypertrophic scarring

Abstract: The present invention relates to a method of producing a non-human animal model of hypertrophic scarring. This involves producing an incision in a non-human animal and applying mechanical strain over the incision under conditions effective to produce hypertrophic scarring, thereby producing a non-human animal model of hypertrophic scarring. The present invention also relates to a method of determining the efficacy of an agent for prevention or treatment of a disease condition. This method involves providing a non-human animal having an incision over which mechanical strain is applied under conditions effective to produce hypertrophic scarring, administering an agent to the incision, and determining whether the agent is efficacious for prevention or treatment of a disease condition. Also provided is a non-human animal model of hypertrophic scarring. This involves a non-human animal having an incision over which mechanical strain has been applied under conditions effective to produce hypertrophic scarring.

Manipulating stem-progenitor cell trafficking to injured tissue and/or tumors by altering HIF-1 and/or SDF-1 activity

Abstract: The present invention relates to a method for modulating recruitment of stem cells or progenitor cells to a selected tissue site. Methods for treating damaged tissue and for treating cancerous tumor tissue are also disclosed. These methods involve regulating HIF-1 and/or SDF-1 activity in the tissue.

Mechanical strain causes hypertrophic scarring in vivo by blocking fibroblast apoptosis in the proliferative phase of wound healing

Abstract: INTRODUCTION: Pathophysiology of hypertrophic scarring remains unclear. Possible etiology includes mechanical strain, burns, or infection. We selectively examined mechanical strain, and developed a novel murine model whereby hypertrophic scars are created by mechanical strain alone. Since apoptosis is important in transitioning from proliferative to remodeling phases of wound healing, we specifically examined apoptosis in hypertrophic scarring.

Methode de traitement ou de prevention d'effets pathologiques d'augmentations aigues de l'hyperglycemie et/ou d'augmentations aigues de flux d'acides gras libres

Abstract: Un mode de realisation de l'invention concerne une methode de traitement ou de prevention des sequelles pathologiques de l'hyperglycemie aigue et/ou des flux accrus d'acides gras chez un sujet. Cette methode consiste a administrer un inhibiteur de ROS au sujet. De plus, l'invention concerne des procedes permettant de favoriser la neovascularisation, d'inhiber l'oxydation ou une liberation excessive d'acides gras libres et d'identifier des composes concus pour le traitement ou la prevention de blessures induites par ROS.