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Biomedical subjects

Keith T Oldham

Publications and source records attributed to Keith T Oldham.

At least 19 recordsLinked to original sources
PubMed2007

Pediatric vascular injuries: patterns of injury, morbidity, and mortality.

PURPOSE: The purpose of this study was to identify the patterns of injury and associated morbidity/mortality related to pediatric vascular trauma. METHODS: A retrospective review of children and adolescents treated between 1993 and 2005 was performed. Patients were identified by International Classification of Diseases, Ninth Revision codes within an institutional pediatric trauma registry. RESULTS: One hundred seventy-six patients with vascular injury were identified. Those with injuries isolated to the digits and unspecified vessels were excluded (n = 73). The remaining 103 patients were evaluable and are the basis for subsequent comparisons. Seventy-four percent of injuries occurred in male patients. The average age of the male patients was 11.3 years and that of the female patients was 9.1 years (range, 1-18 years; overall, 10.7 years). Penetrating wounds caused 68% of the injuries, followed by blunt trauma (31%) and burns (0.97%). Anatomical locations of injury included the head/neck (19.4%), torso (13.5%), and extremities (67%). Amputation was required in 11 (10.7%) patients. The average hospital length of stay of the patients was 12.1 days (range, 1-155 days). The overall mortality was 9.7%. Nonoperative management was given to 9.7% of the patients; one death caused by carotid injury occurred. Overall, 24 patients underwent arteriography, with 1 patient receiving definitive treatment in interventional radiology. Of the 103 patients, 29.1% were managed by pediatric surgeons, 38.8% were managed by extremity specialists, 17% were managed by vascular surgeons, 5.8% were managed by neurosurgeons, and 9.3% were managed by others. CONCLUSIONS: Despite the available multidisciplinary diagnostic and treatment modalities at tertiary care pediatric trauma centers, traumatic vascular injuries in children and adolescents are associated with significant morbidity and mortality in contemporary surgical practice.

Adolescent↗
PubMed2006

An in vivo murine model of rosiglitazone use in pregnancy.

OBJECTIVE: To identify the effects of rosiglitazone use during murine pregnancy. DESIGN: The effect of rosiglitazone on blastocyst development was determined by culturing two-cell mouse embryos with rosiglitazone for 72 hours. From January to June 2005, five independent groups of ICR/CD1 female mice were treated with rosiglitazone during pregnancy, from the time of identification of seminal plugs until delivery of pups. SETTING: Controlled animal facility. ANIMAL(S): Two-cell mouse embryos and an outbred line of mice, ICR/CD1. INTERVENTION(S): Two-cell embryos were cocultured with rosiglitazone (10 microM) for 72 hours and scored. Ten-week-old female ICR mice were mated. Females with seminal plugs then were randomized to rosiglitazone (10 or 0.1 mg/kg per day) or to carrier alone, by gavage, until delivery. Weekly weights were obtained, and pregnancy outcomes were documented. MAIN OUTCOME MEASURE(S): Blastocyst development, number of pups and pup weights, and morphological changes. RESULT(S): Embryos exposed to rosiglitazone progressed to the blastocyst stage within 72 hours. Pregnant animals demonstrated normal weight gain throughout pregnancy. Postnatal growth and litter size were not statistically different between groups. No changes in normal mouse neonate development were observed. CONCLUSION(S): Rosiglitazone did not impair murine blastocyst development in vitro or cause phenotypic harm to the mouse fetus when administered during pregnancy, suggesting potential safety for rosiglitazone use in pregnancy.

Animals↗
PubMed2006

Outcomes and delivery of care in pediatric injury.

PURPOSE: To design effective pediatric trauma care delivery systems, it is important to correlate site of care with corresponding outcomes. Using a multistate administrative database, we describe recent patient allocation and outcomes in pediatric injury. METHODS: The 2000 Kids' Inpatient Database, containing 2,516,833 inpatient discharge records from 27 states, was filtered by E-code to yield pediatric injury cases. Injury Severity Scores (ISSs) were derived for each discharge using ICDMAP-90 (Tri-Analytics, Inc, Forest Hill, MD). After weighting to estimate national trends, cases were grouped by age (0-10, >10-20 years), ISS (< or =15, >15), and National Association of Children's Hospitals and Related Institutions-designated site of care. Measured outcomes included mortality, length of stay, and total charges. Analysis was completed using Student's t test and chi2. RESULTS: Among 79,673 injury cases, mean age was 12.2 +/- 6.2 years and ISS was 7.4 +/- 7.6. Eighty-nine percent of injured children received care outside of children's hospitals. In the subgroup of patients aged 0 to 10 years with ISS of greater than 15, the mean ISS for adult hospitals and children's hospitals was not significantly different (18.9 +/- 9.1 vs. 19.4 +/- 9.3, P = .08). However, in-hospital mortality, length of stay, and charges were all significantly higher in adult hospitals (P < .0001). CONCLUSIONS: Younger and more seriously injured children have improved outcomes in children's hospitals. Appropriate triage may improve outcomes in pediatric trauma.

Adolescent↗
PubMed2006

Endothelium-derived microparticles inhibit human cardiac valve endothelial cell function.

Elevated numbers of endothelium-derived microparticles (EMPs) in the circulation are found in a variety of critical illnesses. EMPs have been associated with vascular dysfunction, including thrombotic complications and loss of normal vascular reactivity, common responses associated with cardiac valve injury. However, the exact mechanisms of this dysfunction and the potential impact on cardiac endothelium are unknown. We hypothesize that pathologic levels of circulating EMPs negatively regulate proliferation and migration of valvular endothelial cells (ECs), leading to downstream endothelial dysfunction. EMPs were generated from plasminogen activation inhibitor 1-stimulated human umbilical vein endothelial cells (HUVECs). Human mitral valve endothelial cells (HMVECs) were isolated and characterized by platelet endothelial cell-derived adhesion molecule-1 (PECAM-1, or CD31) and von Willebrand factor immunocytochemistry. HMVECs were treated with increasing EMP doses, and then, the effects of EMPs on growth factor-induced proliferation and migration were tested. Proliferation was assessed by H-thymidine incorporation. EC migration was assayed by photographing microtubules of HMVECs and HUVECs in fibrin gel incubated with EMPs +/- growth factors for 48 h. The EMP effects on non-valve HUVECs were tested in parallel. EMPs inhibited HMVEC proliferation at high doses but stimulated HUVEC proliferation at all doses. In HMVECs, EMPs inhibited basic fibroblast growth factor- and vascular endothelial growth factor-induced proliferation and migration. Taken together, these data suggest EMPs regulate valvular EC proliferation in a dose-dependent manner and, furthermore, modulate growth factor signaling in ECs. These results implicate EMPs as a possible source of downstream EC dysfunction in disease states. EMPs may play a role in valvular leaflet injury in human disease by inhibiting normal growth and repair of endothelium.

Cell Movement↗
PubMed2006

Endothelium-derived microparticles induce endothelial dysfunction and acute lung injury.

Acute lung injury (ALI) carries a high mortality in critically ill patients. Recent reports correlate elevated concentrations of endothelium-derived microparticles (EMPs) with diseases of endothelial dysfunction. Many of these diseases have ALI sequelae. We hypothesize that EMPs contribute to endothelial cell (EC) dysfunction and development of ALI. To test this hypothesis, we treated isolated vessels with EMPs and examined changes in vasodilation. Endothelial cell cultures were incubated with EMPs and examined for changes in stimulated nitric oxide (*NO) production and nitric oxide synthase (eNOS) activation. Finally, EMPs were injected into rats and mice and lungs examined for ALI. In both mouse and human ex vivo vessel preparations, we found a marked attenuation of endothelium-mediated vasodilation after EMP treatment (4 x 10(6)/mL). This dysfunction was not corrected by pretreatment of EMPs with free radical scavengers. Coincubation of EMPs with EC cultures yielded a three-fold reduction in A23187-stimulated *NO release. Western analysis of these cells showed a corresponding decrease in eNOS phosphorylation at Ser1179 and a decrease in hsp90 association. Measurements of lung permeability, myeloperoxidase activity, and histology of EMPs-treated Brown Norway rats demonstrated pulmonary edema, neutrophil recruitment, and compromise of the endothelial-alveolar barrier as a second hit phenomenon. In C57BL/6 mice, exogenous EMPs caused a significant rise in pulmonary capillary permeability both as a primary and secondary injury. These findings demonstrate EMPs are capable of inducing significant lung injury at pathophysiologically relevant concentrations. Endothelium-derived microparticles inhibit endothelium-mediated vasodilation and *NO generation from eNOS. Once elucidated, EMP mechanisms of inducing ALI and endothelial dysfunction may present new therapeutic targets.

Animals↗
PubMed2005

Variation in treatment of pediatric spleen injury at trauma centers versus nontrauma centers: a call for dissemination of American Pediatric Surgical Association benchmarks and guidelines.

BACKGROUND: American Pediatric Surgical Association consensus guidelines for children with blunt spleen injuries have been defined and validated in children's hospitals, but large administrative data sets indicate that only 10% to 15% of children with blunt spleen injuries are treated at children's hospitals. We sought to identify the frequency and compare the treatment of children with spleen injury in hospitals with and without recognized trauma expertise, with the aim of identifying a meaningful target for dissemination of benchmarks and consensus guidelines. STUDY DESIGN: State health departments' administrative data sets from California, Florida, New Jersey, and New York were analyzed for 2000, 2001, and 2002. All children with head injury or other nonspleen abdominal injuries requiring surgery were excluded. Injury Severity Scores were determined by ICDMAP-90. RESULTS: There were 3,232 patients with blunt spleen injury. Trauma centers had a significantly lower rate of operation for both multiply injured patients (15.3% versus 19.3%, p < 0.001) and those with isolated injury (9.2% versus 18.5%, p < 0.0001) when compared with nontrauma centers. The operative rates at both trauma centers and nontrauma centers exceed published American Pediatric Surgical Association benchmarks for all children with spleen injury (5% to 11%) and the subset with isolated spleen injury (0% to 3%). Independent risk factors for splenectomy included ages 15 to 19 years (p < 0.002), spleen injury severity (p < 0.0001), and presence of multiple injuries (p < 0.04). Adjusted odds ratio for risk of splenic operation in all patients with spleen injury was 2.122 (95% CI:1.455- 3.096) when treated at a nontrauma center (p < 0.0001). CONCLUSIONS: These multistate discharge data indicate that treatment of children with blunt spleen injury differs significantly when comparing trauma centers and nontrauma centers. Because nearly two-thirds of these children were treated at trauma centers, dissemination of American Pediatric Surgical Association guidelines and benchmarks through state or regional trauma systems may reduce the number of children having operations for splenic injury.

Adolescent↗
PubMed2005

Effects of D-4F on vasodilation and vessel wall thickness in hypercholesterolemic LDL receptor-null and LDL receptor/apolipoprotein A-I double-knockout mice on Western diet.

Previously we showed L-4F, a novel apolipoprotein A-I (apoA-I) mimetic, improved vasodilation in 2 dissimilar models of vascular disease: hypercholesterolemic LDL receptor-null (Ldlr(-/-)) mice and transgenic sickle cell disease mice. Here we determine the mechanisms by which D-4F improves vasodilation and arterial wall thickness in hypercholesterolemic Ldlr(-/-) mice and Ldlr(-/-)/apoA-I null (apoA-I(-/-)), double-knockout mice. Ldlr(-/-) and Ldlr(-/-)/apoA-I(-/-) mice were fed Western diet (WD) with and without D-4F. Oral D-4F restored endothelium- and endothelial NO synthase (eNOS)-dependent vasodilation in direct relationship to duration of treatments and reduced wall thickness in as little as 2 weeks in vessels with preexisting disease in Ldlr(-/-) mice. D-4F had no effect on total or HDL cholesterol concentrations but reduced proinflammatory HDL levels. D-4F had no effect on plasma myeloperoxidase concentrations but reduced myeloperoxidase association with apoA-I as well as 3-nitrotyrosine in apoA-I. D-4F increased endothelium- and eNOS-dependent vasodilation in Ldlr(-/-)/apoA-I(-/-) mice but did not reduce wall thickness as it had in Ldlr(-/-) mice. Vascular endothelial cells were treated with 22(R)-hydroxycholesterol with and without L-4F. 22(R)-Hydroxycholesterol decreased NO (*NO) and increased superoxide anion (O2*-) production and increased ATP-binding cassette transporter-1 and collagen expression. L-4F restored *NO and O2*- balance, had little effect on ATP-binding cassette transporter-1 expression, but reduced collagen expression. These data demonstrate that although D-4F restores vascular endothelial cell and eNOS function to increase vasodilation, HDL containing apoA-I, or at least some critical concentration of the antiatherogenic lipoprotein, is required for D-4F to decrease vessel wall thickness.

ATP Binding Cassette Transporter 1↗
PubMed2005

Use of vacuum-assisted closure system in the management of complex wounds in the neonate.

The vacuum-assisted closure (VAC) system has become an accepted treatment modality for acute and chronic wounds in adults. The use of negative-pressure dressing has been documented in adults and, to some extent, in children. However, its use in premature infants has not been reported in the literature. The results of using the VAC system were examined in two premature infants with complex wounds. The VAC system was found to be effective in facilitating the closure of large and complex wounds in these patients. Complete epithelialization of the wounds was achieved in both patients without skin grafting. In conclusion, in two premature neonates with extraordinary soft tissue defects, the VAC system was a safe and effective choice to assist in closing these wounds.

Bandages↗
PubMed2005

Pediatric pelvic injury: functional outcome at 6-month follow-up.

BACKGROUND/PURPOSE: Data on functional outcomes after pediatric pelvic fractures are limited to those obtained at hospital discharge. This study assesses functional status at both hospital discharge and at 6 months after injury. METHODS: A national multicenter prospective study began in February 2002 and is ongoing. Patients completed WeeFIM functional assessments at hospital discharge and at 6-month follow-up as part of this study. This report summarizes preliminary functional assessment results from 20 patients. RESULTS: Patient data were accrued into 3 domains (self-care, mobility, and cognition), which constitute a total raw rating. Significant improvement at 6 months after injury was evident in self-care, mobility, and total raw ratings. This significance remained when total raw ratings were converted to age-adjusted functional quotients. CONCLUSIONS: This preliminary assessment shows that after pelvic fractures, children improve their functional status at 6 months, returning to near-normal status.

Accidental Falls↗
PubMed2004

Abdominal drain placement versus laparotomy for necrotizing enterocolitis with perforation.

Perforated NEC in the fragile, premature infant remains a complex neonatal and surgical problem. Future investigation into the basic mechanisms of the intestinal inflammatory response in the premature neonate may allow for preventive strategies in the management of NEC. Until then, surgical management for perforated NEC will remain a necessary intervention to treat the complications of this disease. The two most commonly used surgical strategies for perforated NEC are laparotomy, bowel resection, and enterostomy versus primary peritoneal drainage. There are no compelling, prospective, controlled data supporting one procedure over the other. Although there are several surgical options for treating perforated NEC, definitive evidence-based guidelines for the best surgical treatment in terms of survival outcome remain to be determined.

Anastomosis, Surgical↗
PubMed2004

Thymic transplantation for complete DiGeorge syndrome: medical and surgical considerations.

BACKGROUND/PURPOSE: Complete DiGeorge syndrome results in the absence of functional T cells. Our program supports the transplantation of allogeneic thymic tissue in infants with DiGeorge syndrome to reconstitute immune function. This study reviews the multidisciplinary care of these complex infants. METHODS: From 1991 to 2001, the authors evaluated 16 infants with complete DiGeorge syndrome. All infants received multidisciplinary medical and surgical support. Clinical records for the group were reviewed. RESULTS: Four infants died without receiving a thymic transplantation, and 12 children survived to transplantation. The mean age at time of transplantation was 2.7 months (range, 1.1 to 4.4 months). All 16 infants had significant comorbidity including congenital heart disease (16 of 16), hypocalcemia (14 of 16), gastroesophageal reflux disease or aspiration (13 of 16), CHARGE complex (4 of 16), and other organ involvement (14 of 16). Nontransplant surgical procedures included central line placement (15 of 16), fundoplication or gastrostomy (10 of 16), cardiac repair (10 of 16), bronchoscopy or tracheostomy (6 of 16), and other procedures (12 of 16). Complications were substantial, and 5 of the 12 transplanted infants died of nontransplant-related conditions. All surviving infants have immune reconstitution, with follow-up from 2 to 10 years. CONCLUSIONS: Although the transplantation of thymic tissue can restore immune function in infants with complete DiGeorge syndrome, these children have substantial comorbidity. Care of these children requires coordinated multidisciplinary support.

DiGeorge Syndrome↗
PubMed2004

Bariatric surgery for severely overweight adolescents: concerns and recommendations.

As the prevalence of obesity and obesity-related disease among adolescents in the United States continues to increase, physicians are increasingly faced with the dilemma of determining the best treatment strategies for affected patients. This report offers an approach for the evaluation of adolescent patients' candidacy for bariatric surgery. In addition to anthropometric measurements and comorbidity assessments, a number of unique factors must be critically assessed among overweight youths. In an effort to reduce the risk of adverse medical and psychosocial outcomes and increase compliance and follow-up monitoring after bariatric surgery, principles of adolescent growth and development, the decisional capacity of the patient, family structure, and barriers to adherence must be considered. Consideration for bariatric surgery is generally warranted only when adolescents have experienced failure of 6 months of organized weight loss attempts and have met certain anthropometric, medical, and psychologic criteria. Adolescent candidates for bariatric surgery should be very severely obese (defined by the World Health Organization as a body mass index of > or =40), have attained a majority of skeletal maturity (generally > or =13 years of age for girls and > or =15 years of age for boys), and have comorbidities related to obesity that might be remedied with durable weight loss. Potential candidates for bariatric surgery should be referred to centers with multidisciplinary weight management teams that have expertise in meeting the unique needs of overweight adolescents. Surgery should be performed in institutions that are equipped to meet the tertiary care needs of severely obese patients and to collect long-term data on the clinical outcomes of these patients.

Adolescent↗
PubMed2003

Heat shock protein 90 and tyrosine kinase regulate eNOS NO* generation but not NO* bioactivity.

An increase in the association of heat shock protein 90 (HSP90) with endothelial nitric oxide (NO) synthase (eNOS) is well recognized for increasing NO (NO*) production. Despite the progress in this field, the mechanisms by which HSP90 modulates eNOS remain unclear due, in part, to the fact that geldanamycin (GA) redox cycles to generate superoxide anion (O(2)(-*) and the fact that inhibiting HSP90 with GA or radicicol (RAD) destabilizes tyrosine kinases that rely on the chaperone for maturation. In this report, we determine the extent to which these side effects alter vascular and endothelial cell function in physiologically relevant systems and in cultured endothelial cells. Vascular endothelial growth factor (VEGF)-stimulated vascular permeability, as measured by Evans blue leakage in the ears of male Swiss mice in vivo, and acetylcholine-induced vasodilation of isolated, pressurized mandibular arterioles from male C57BL6 mice ex vivo were attenuated by N(omega)-nitro-L-arginine methyl ester (L-NAME), GA, and RAD. Z-1[N-(2-aminoethyl)-N-(2-ammonoethyl)amino]diazen-1-ium-1,2-dioate (DETA-NONOate), a slow releasing NO. donor, increased vasodilation of arterioles pretreated with GA, RAD, and L-NAME equally well except at 10(-5) M, the highest concentration used, where vasodilation was greater in pressurized arterioles treated with L-NAME than in arterioles pretreated with GA or RAD alone. Both GA and RAD reduced NO* release from stimulated endothelial cell cultures and increased O(2)(-*) production in the endothelium of isolated aortas by an L-NAME-inhibitable mechanism. Pretreatment with RAD increased stimulated O(2)(-*) production from eNOS, whereas pretreatment with genistein (GE), a broad-spectrum tyrosine kinase inhibitor, did not; however, pretreatment with GE + RAD resulted in a super-induced state of uncoupled eNOS activity upon stimulation. These data suggest that the tyrosine kinases, either directly or indirectly, and HSP90-dependent signaling pathways act in concert to suppress uncoupled eNOS activity.

Acetylcholine↗
PubMed2003

Hypoxia-induced acute lung injury in murine models of sickle cell disease.

Vaso-occlusive events are the major source of morbidity and mortality in sickle cell disease (SCD); however, the pathogenic mechanisms driving these events remain unclear. Using hypoxia to induce pulmonary injury, we investigated mechanisms by which sickle hemoglobin increases susceptibility to lung injury in a murine model of SCD, where mice either exclusively express the human alpha/sickle beta-globin (halphabetaS) transgene (SCD mice) or are heterozygous for the normal murine beta-globin gene and express the halphabetaS transgene (mbeta+/-, halphabetaS+/-; heterozygote SCD mice). Under normoxia, lungs from the SCD mice contained higher levels of xanthine oxidase (XO), nitrotyrosine, and cGMP than controls (C57BL/6 mice). Hypoxia increased XO and nitrotyrosine and decreased cGMP content in the lungs of all mice. After hypoxia, vascular congestion was increased in lungs with a greater content of XO and nitrotyrosine. Under normoxia, the association of heat shock protein 90 (HSP90) with endothelial nitric oxide synthase (eNOS) in lungs of SCD and heterozygote SCD mice was decreased compared with the levels of association in lungs of controls. Hypoxia further decreased association of HSP90 with eNOS in lungs of SCD and heterozygote SCD mice, but not in the control lungs. Pretreatment of rat pulmonary microvascular endothelial cells in vitro with xanthine/XO decreased A-23187-stimulated nitrite + nitrate production and HSP90 interactions with eNOS. These data support the hypotheses that hypoxia increases XO release from ischemic tissues and that the local increase in XO-induced oxidative stress can then inhibit HSP90 interactions with eNOS, decreasing *NO generation and predisposing the lung to vaso-occlusion.

Acute Disease↗
PubMed2003

AP-4F, antennapedia peptide linked to an amphipathic alpha helical peptide, increases the efficiency of Lipofectamine-mediated gene transfection in endothelial cells.

Typically, endothelial cells are difficult to transfect. In this study, we report that antennapedia peptide (AP) linked to L-4F, a water-soluble, amphipathic alpha helical peptide that avidly binds lipids (AP-4F) increases Lipofectamine 2000-mediated transfection of bovine coronary endothelial cell cultures. Transfection efficiency was monitored by flow cytometry and fluorescent microscopy. Lipofectamine 2000 transfection of endothelial cell cultures with green fluorescence protein (GFP)-DNA typically yields transfection efficiencies of 35.4+/-3.3% with low levels of cell death (8.1+/-1.0%). Pre-treatment of the Lipofectamine 2000-GFP-DNA complexes with AP-4F for 5 min increased transfection to 58.2+/-2.8% without increasing cell death. AP-4F increases Lipofectamine 2000-mediated transfection in a time-dependent fashion (within 10-20 min). Systematic studies reveal that the individual components of AP-4F, i.e., AP and L-4F alone, are ineffective in increasing Lipofectamine 2000-mediated transfection and that AP-4F must be directly associated with DNA liposomes prior to transfection for optimal uptake by endothelial cells. These observations demonstrate that AP-4F may be useful for increasing the transfection efficiency of endothelial cell cultures with standard commercially available reagents.

Amino Acid Sequence↗
PubMed2003

L-4F, an apolipoprotein A-1 mimetic, dramatically improves vasodilation in hypercholesterolemia and sickle cell disease.

BACKGROUND: Hypercholesterolemia and sickle cell disease (SCD) impair endothelium-dependent vasodilation by dissimilar mechanisms. Hypercholesterolemia impairs vasodilation by a low-density lipoprotein (LDL)-dependent mechanism. SCD has been characterized as a chronic state of inflammation in which xanthine oxidase (XO) from ischemic tissues increases vascular superoxide anion (O2*-) generation. Recent reports indicate that apolipoprotein (apo) A-1 mimetics inhibit atherosclerosis in LDL receptor-null (Ldlr-/-) mice fed Western diets. Here we hypothesize that L-4F, an apoA-1 mimetic, preserves vasodilation in hypercholesterolemia and SCD by decreasing mechanisms that increase O2*- generation. METHODS AND RESULTS: Arterioles were isolated from hypercholesterolemic Ldlr-/- mice and from SCD mice that were treated with either saline or L-4F (1 mg/kg per day). Vasodilation in response to acetylcholine was determined by videomicroscopy. Effects of L-4F on LDL-induced increases in endothelium-dependent O2*- generation were determined on arterial segments via the hydroethidine assay and on stimulated endothelial cell cultures via superoxide dismutase-inhibitable ferricytochrome c reduction. Effects of L-4F on XO bound to pulmonary arterioles and content in livers of SCD mice were determined by immunofluorescence. Hypercholesterolemia impaired vasodilation in Ldlr-/- mice, which L-4F dramatically improved. L-4F inhibited LDL-induced increases in O2*- in arterial segments and in stimulated cultures. SCD impaired vasodilation, increased XO bound to pulmonary endothelium, and decreased liver XO content. L-4F dramatically improved vasodilation, decreased XO bound to pulmonary endothelium, and increased liver XO content compared with levels in untreated SCD mice. CONCLUSIONS: These data show that L-4F protects endothelium-dependent vasodilation in hypercholesterolemia and SCD. Our findings suggest that L-4F restores vascular endothelial function in diverse models of disease and may be applicable to treating a variety of vascular diseases.

Anemia, Sickle Cell↗
PubMed2003

Trichloroethylene decreases heat shock protein 90 interactions with endothelial nitric oxide synthase: implications for endothelial cell proliferation.

Trichloroetheylene (TRI) is an environmental pollutant that has been linked to congenital heart defects (CHD). Endothelial nitric oxide synthase (eNOS) generation of nitric oxide (NO) plays an important role in endothelial cell proliferation, which is considered essential for normal blood vessel growth and development. We hypothesized that TRI alters the balance of NO and superoxide anion (O2-) to impair endothelial cell proliferation. Proliferating endothelial cells were pretreated with TRI (5 microM) and then stimulated with the calcium ionophore, A23187 (5 microM), to determine changes in endothelial cell and eNOS function with respect to NO and O2- generation. Immunoblots of eNOS, phospho-eNOS at serine 1179 (S1179), and the levels of associated heat shock protein 90 (hsp90) were used to define the activation state of eNOS. The effects of TRI (0.05-100 microM) on vascular endothelial growth factor (VEGF, 0.58 nM) induced endothelial cell proliferation were determined from cell counts. TRI decreased A23187-stimulated nitrite + nitrate production from 1.99 +/- 0.90 to 0.89 +/- 0.51 pmol/mg protein (p < 0.05; n = 6). In controls, Lomega-nitroargininemethylester (L-NAME) increased A23187-stimulated O2- production from 0.130 +/- 0.089 to 0.214 +/- 0.071 nmol/min/mg protein (p < 0.05; n = 5). In TRI-treated cultures, however, L-NAME decreased A23187-stimulated O2- production from 0.399 +/- 0.121 to 0.199 +/- 0.055 nmol/min/mg protein (p < 0.05; n = 5). TRI decreased hsp90 associated with eNOS by 46.7% and inhibited VEGF-stimulated endothelial cell proliferation by 12 to 35%. These data show that TRI alters hsp90 interactions with eNOS and induces eNOS to shift from NO to O2- generation. Our findings provide new insight into how TRI alters endothelial and eNOS function to impair VEGF-stimulated endothelial proliferation. Such changes in endothelial function may play an important role in the development of congenital heart defects.

Animals↗