Biomedical subjects

Lee J Goldstein

Publications and source records attributed to Lee J Goldstein.

6 recordsLinked to original sources

PubMed2006

Endothelial progenitor cell release into circulation is triggered by hyperoxia-induced increases in bone marrow nitric oxide.

Endothelial progenitor cells (EPC) are known to contribute to wound healing, but the physiologic triggers for their mobilization are often insufficient to induce complete wound healing in the presence of severe ischemia. EPC trafficking is known to be regulated by hypoxic gradients and induced by vascular endothelial growth factor-mediated increases in bone marrow nitric oxide (NO). Hyperbaric oxygen (HBO) enhances wound healing, although the mechanisms for its therapeutic effects are incompletely understood. It is known that HBO increases nitric oxide levels in perivascular tissues via stimulation of nitric oxide synthase (NOS). Here we show that HBO increases bone marrow NO in vivo thereby increasing release of EPC into circulation. These effects are inhibited by pretreatment with the NOS inhibitor l-nitroarginine methyl ester (l-NAME). HBO-mediated mobilization of EPC is associated with increased lower limb spontaneous circulatory recovery after femoral ligation and enhanced closure of ischemic wounds, and these effects on limb perfusion and wound healing are also inhibited by l-NAME pretreatment. These data show that EPC mobilization into circulation is triggered by hyperoxia through induction of bone marrow NO with resulting enhancement in ischemic limb perfusion and wound healing.

Animals↗

PubMed2006

The bone marrow-derived endothelial progenitor cell response is impaired in delayed wound healing from ischemia.

OBJECTIVE: Vasculogenesis relies on the recruitment of bone marrow-derived endothelial progenitor cells (BMD EPCs) and is stimulated by tissue-level ischemia. We hypothesized that the BMD EPC response is impaired in ischemic wounds and studied the relationship between BMD EPCs and wound healing. METHODS: We used transgenic Tie-2/LacZ mice, which carry the beta-galactosidase (beta-gal) reporter gene under Tie-2 promoter control. Wild-type mice were lethally irradiated and reconstituted with Tie-2/LacZ bone marrow. Four weeks later, the mice underwent unilateral femoral artery ligation/excision and bilateral wounding of the hindlimbs. Ischemia was confirmed and monitored with laser Doppler imaging. A subset of mice received incisional vs excisional nonischemic bilateral hindlimb wounds, without femoral ligation. Excisional wound closure was measured by using daily digital imaging and software-assisted calculation of surface area. RESULTS: Ischemia resulted in significantly delayed wound healing and differentially affected the number of BMD EPCs recruited to wound granulation tissue and muscle underlying the wounds. At 3 days postwounding, the granulation tissue of the wound base contained significantly fewer numbers of BMD EPCs in ischemic wounds compared with the nonischemic wounds (P < .05). In contrast, significantly more BMD EPCs were present in the muscle underlying the ischemic wounds at this same time point compared with the muscle under the nonischemic wounds (P < .05). In ischemic wounds, eventual wound closure significantly correlated with a delayed rise in BMD EPCs within the wound granulation tissue (Kendall's correlation, -.811, P = .0005) and was significantly associated with a gradual recovery of hindlimb perfusion (P < .0001). By 7 days postwounding, BMD EPCs were incorporated into the neovessels in the granulation tissue. At 14 days and 75 days, BMD EPCs were rarely observed within the wounds. CONCLUSIONS: Granulation tissue of excisional ischemic wounds showed significantly less BMD EPCs 3 days postwounding, in association with significantly delayed wound closure. However, the number of BMD EPCs were increased in ischemic hindlimb skeletal muscle, consistent with the notion that ischemia is a powerful signal for vasculogenesis. To our knowledge, this is the first report identifying a deficit in BMD EPCs in the granulation tissue of ischemic skin wounds and reporting the key role for these cells in both ischemic and nonischemic wound healing.

Animals↗

PubMed2005

Stem cell mobilization by hyperbaric oxygen.

We hypothesized that exposure to hyperbaric oxygen (HBO(2)) would mobilize stem/progenitor cells from the bone marrow by a nitric oxide (*NO) -dependent mechanism. The population of CD34(+) cells in the peripheral circulation of humans doubled in response to a single exposure to 2.0 atmospheres absolute (ATA) O(2) for 2 h. Over a course of 20 treatments, circulating CD34(+) cells increased eightfold, although the overall circulating white cell count was not significantly increased. The number of colony-forming cells (CFCs) increased from 16 +/- 2 to 26 +/- 3 CFCs/100,000 monocytes plated. Elevations in CFCs were entirely due to the CD34(+) subpopulation, but increased cell growth only occurred in samples obtained immediately posttreatment. A high proportion of progeny cells express receptors for vascular endothelial growth factor-2 and for stromal-derived growth factor. In mice, HBO(2) increased circulating stem cell factor by 50%, increased the number of circulating cells expressing stem cell antigen-1 and CD34 by 3.4-fold, and doubled the number of CFCs. Bone marrow *NO concentration increased by 1,008 +/- 255 nM in association with HBO(2). Stem cell mobilization did not occur in knockout mice lacking genes for endothelial *NO synthase. Moreover, pretreatment of wild-type mice with a *NO synthase inhibitor prevented the HBO(2)-induced elevation in stem cell factor and circulating stem cells. We conclude that HBO(2) mobilizes stem/progenitor cells by stimulating *NO synthesis.

Animals↗

PubMed2005

Normal human fibroblasts enable melanoma cells to induce angiogenesis in type I collagen.

BACKGROUND: We previously reported that fibroblasts induce human microvascular endothelial cells (HMVECs) to differentiate from monolayer to capillarylike morphology. We now test the hypothesis that fibroblasts modulate angiogenesis in melanoma cells. METHODS: We tested 12 human melanoma lines (2 radial growth phase (RGP), 3 vertical growth phase (VGP), and 7 metastatic (MM)) for ability to induce HMVECs to invade/migrate into collagen and form capillarylike networks. HMVEC monolayers were overlaid with 3-dimensional collagen gels embedded with melanoma cells alone (M), fibroblasts alone (F), or a 1:1 mixture of the 2 cells (M+F). After 5 days, gels were removed, fixed, and HMVEC networks were quantified by von Willebrand's factor (vWF) immunofluorescence. The influence of soluble factors on HMVEC invasion/migration into collagen was assessed with the use of acellular 3-D collagen gels overlaid on HMVEC monolayers, cultured with conditioned media (CM) derived from monolayers of M, F, or M+F. Angiogenic growth factors involved in the observed invasion/migration were identified with the use of a RayBio Cytokine Antibody Array (RayBiotech, Norcross, Ga). RESULTS: Cell line-specific variability in melanoma-supported angiogenesis was observed only when in combination with fibroblasts (analysis of variance [ANOVA], P < .01). Melanoma plus fibroblasts uniformly resulted in a significantly higher angiogenic response than melanoma alone (P < .05). One vertical growth phase and one metastatic melanoma line, while weakly angiogenic alone, induced significantly higher angiogenesis than either fibroblast or melanoma alone (P < .05) when combined with fibroblasts. CM from M or M+F induced significantly less HMVEC invasion/migration into collagen than CM from fibroblasts alone. Interleukin 8, monocyte chemotactic protein-1, and tissue inhibitor of metalloproteinase-2 were identified as significantly elevated in the media derived from M+F cultures, compared with either cell type alone. CONCLUSION: To our knowledge, this is the first report demonstrating that melanoma-supported angiogenesis in collagen is more significantly influenced by normal skin-derived fibroblasts than by the intrinsic biology of the melanoma cell type. Interleukin 8, monocyte chemotactic protein-1, and tissue inhibitor of metalloproteinase-2 are implicated as potential paracrine factors regulating this observed effect.

Angiogenic Proteins↗

PubMed2002

Yearly rupture or dissection rates for thoracic aortic aneurysms: simple prediction based on size.

BACKGROUND: Prior work has clarified the cumulative, lifetime risk of rupture or dissection based on the size of thoracic aneurysms. Ability to estimate simply the yearly rate of rupture or dissection would greatly enhance clinical decision making for specific patients. Calculation of such a rate requires robust data. METHODS: Data on 721 patients (446 male, 275 female; median age, 65.8 years; range, 8 to 95 years) with thoracic aortic disease was prospectively entered into a computerized database over 9 years. Three thousand one hundred fifteen imaging studies were available on these patients. Five hundred seventy met inclusion criteria in terms of length of follow-up and form the basis for the survival analysis. Three hundred four patients were dissection-free at presentation; their natural history was followed for rupture, dissection, and death. Patients were excluded from analysis once operation occurred. RESULTS: Five-year survival in patients not operated on was 54% at 5 years. Ninety-two hard end points were realized in serial follow-up, including 55 deaths, 13 ruptures, and 24 dissections. Aortic size was a very strong predictor of rupture, dissection, and mortality. For aneurysms greater than 6 cm in diameter, rupture occurred at 3.7% per year, rupture or dissection at 6.9% per year, death at 11.8%, and death, rupture, or dissection at 15.6% per year. At size greater than 6.0 cm, the odds ratio for rupture was increased 27-fold (p = 0.0023). The aorta grew at a mean of 0.10 cm per year. Elective, preemptive surgical repair restored life expectancy to normal. CONCLUSIONS: This study indicates that (1) thoracic aneurysm is a lethal disease; (2) aneurysm size has a profound impact on rupture, dissection, and death; (3) for counseling purposes, the patient with an aneurysm exceeding 6 cm can expect a yearly rate of rupture or dissection of at least 6.9% and a death rate of 11.8%; and (4) elective surgical repair restores survival to near normal. This analysis strongly supports careful radiologic follow-up and elective, preemptive surgical intervention for the otherwise lethal condition of large thoracic aortic aneurysm.

Adolescent↗

PubMedDate not supplied

Hyperbaric oxygen and bone marrow-derived endothelial progenitor cells in diabetic wound healing.

Endothelial progenitor cells (EPCs) are the key cellular effectors of postnatal vasculogenesis and play a central role in wound healing. In diabetes, there is a significant impairment in the number and function of circulating and wound-tissue EPC. Recent evidence indicates, that tissue-level hyperoxia achieved by therapeutic hyperbaric oxygen protocols (HBO2) can increase the mobilization of EPC from the bone marrow into peripheral blood. In this paper we review the recent reports on hyperoxia-mediated mobilization of bone marrow-derived EPC and postulate avenues of future research in this area as it applies to improving healing in chronic wounds affected by diabetes and peripheral arterial disease (PAD).

Animals↗