Circulating endothelial progenitor cells and erectile dysfunction: possibility of nutritional intervention?

To provide an overview of molecular and cellular processes involved in erectile dysfunction (ED) with emphasis on circulating endothelial progenitor cells (EPC) and discuss possible nutraceutical means of intervention. A review of literature on Pubmed related to EPC and ED was conducted. Patients with ED appear to possess a reduced number of circulating EPC, which is associated with poor endothelial function possibly as a result of underlying low-grade inflammation. Several studies support the possibility of improving erectile function by inhibition of inflammation as well as administration of various stem cell types. One particularly interesting approach is nutraceutical supplementation to increase circulating EPC, as demonstrated in the product Stem-Kine. Interventions aimed at increasing circulating EPC may have potential in treatment of vascular ED.

Rat and human aortic smooth muscle cells display differing migration and matrix metalloproteinase activities in response to dexamethasone.

OBJECTIVE: The steroid dexamethasone inhibits neointimal hyperplasia development in rats but not in humans. This study investigates the differential effects of dexamethasone on rat and human smooth muscle cell migration and matrix metalloproteinase (MMP) activity. METHODS: Rat aortic smooth muscle cells were harvested from Sprague-Dawley rats. Human aortic smooth muscle cells were obtained from Clonetics. Boyden chamber migration assays were performed with chemoattractant (platelet-derived growth factor) and varying concentrations of dexamethasone (10(-9) to 10(-5) mol/L). Zymography of culture media was used to assess MMP activity, and Western blot analysis was used for quantification of MMP-2 and tissue inhibitor of MMP-2 (TIMP-2) secretion. RESULTS: Dexamethasone inhibits rat aortic smooth muscle cell migration in a dose-dependent fashion. An increase in concentrations of dexamethasone does not effect human aortic smooth muscle cell migration. Rat aortic smooth muscle cell MMP-2 activity is inhibited with dexamethasone in a dose-dependent fashion, and human aortic smooth muscle cell MMP-2 activity is unchanged with dexamethasone. MMP-2 secretion is inhibited with dexamethasone in rat aortic smooth muscle cells but remains unaltered in human aortic smooth muscle cells. Dexamethasone increases rat aortic smooth muscle cell TIMP-2 secretion, and human aortic smooth muscle cell TIMP-2 secretion remains constant. CONCLUSION: Dexamethasone inhibits rat aortic smooth muscle cell migration, MMP-2 activity, and MMP-2 secretion and increases TIMP-2 secretion. These effects are not observed in human aortic smooth muscle cells. These findings may explain why dexamethasone inhibits neointimal hyperplasia in animal models but is ineffective in humans. Inhibition of human smooth muscle cell migration in vitro may be useful in predicting the effectiveness of future therapeutic agents for treatment of neointimal hyperplasia in humans.

Dexamethasone inhibits vascular smooth muscle cell migration via modulation of matrix metalloproteinase activity.

BACKGROUND: Dexamethasone (DEX) has been shown to inhibit development of neointimal hyperplasia in rats. We hypothesize that DEX inhibits neointimal hyperplasia by altering matrix metalloproteinase (MMP) activity, resulting in inhibition of smooth muscle cell migration. METHODS: Rat aortic smooth muscle cells (RASMC) were harvested and cultured for two to four passages. A migration assay was performed in a Boyden chamber with chemoattractant (platelet-derived growth factor) and varying concentrations of DEX (10(-9) to 10(-5) M). The number of migrated cells was counted under light microscopy. Zymography was performed on culture media to assess MMP activity, and Western blotting was performed to assay MMP and levels of tissue inhibitors of MMPs (TIMPs). RESULTS: DEX progressively inhibited RASMC migration in a dose-dependent fashion. This effect was statistically significant for concentrations of 10(-7) to 10(-5) M (P < 0.0005). Zymography showed that DEX inhibits MMP-2 activity in a dose-dependent manner. Western blots indicated that total MMP-2 secretion was inhibited and that TIMP-2 secretion was increased by DEX. CONCLUSIONS: DEX inhibits platelet-derived growth factor-induced migration of RASMCs and MMP-2 activity in vitro. Our data suggest that DEX suppresses MMP activity and secretion, resulting in the inhibition of smooth muscle cell migration. This may explain the mechanism by which DEX inhibits neointimal hyperplasia.

Safety and efficacy of early surgical decompression of the thoracic outlet for Paget-Schroetter syndrome.

The surgical treatment of Paget-Schroetter syndrome has evolved to include early thrombolytic therapy and an interval period of anticoagulation, followed by late surgical decompression of the thoracic outlet. More recently, we have developed an abbreviated course of therapy in which the thrombolytic therapy is followed by early surgical decompression during the same admission, then a period of anticoagulation. We compared early surgical decompression with the standard management protocol to determine safety and efficacy of the early treatment algorithm. Nine patients were treated with lysis and early operation. These were compared with the preceding nine consecutive patients treated with lysis and staged operation. Demographic data, risk factors, duration of thrombosis, lytic therapy, time to surgery, operative variables, and postoperative complications were analyzed. Our results showed that thrombolysis followed by early operation does not result in increased perioperative morbidity or mortality. Early surgical decompression of the thoracic outlet during the same admission as lysis is as safe and efficacious as the traditional (staged decompression) approach to Paget-Schroetter syndrome. Lysis followed by early surgical decompression should be considered a new standard of care in the management of Paget-Schroetter syndrome.

Hypertonic saline infusion: can it regulate human neutrophil function?

The down-regulation of neutrophil adhesion molecule expression after hemorrhagic shock may reduce neutrophil-mediated organ injury. Hypertonic saline (HS) blocks neutrophil activation, and HS infusion in animals reduces organ injury. In this study, we investigated whether HS infusion in healthy human volunteers can affect neutrophil function. Healthy human volunteers were administered either 4 mL/kg of a 7.5% HS (n = 6) or normal saline (NS, 0.9%; n = 5) over 15 min. Mean arterial pressure (MAP) and plasma sodium levels were measured. Blood samples were obtained before and 1 h after fluid administration. Cells were stimulated with fMLP or left untreated. Neutrophil phagocytosis and expression of CD11b and L-selectin was determined with flow cytometry. HS infusion caused a 7 +/- 2 mM rise in plasma Na+ levels that was sustained at 6 +/- 1 mM for 60 min. MAP was affected only in one subject. HS and NS infusion had little effect on neutrophil phagocytosis. After HS infusion, CD1lb expression of unstimulated neutrophils was 26 +/- 6% lower than before HS infusion, and that of fMLP-stimulated cells was 12 +/- 2% lower compared to pre-infusion values. NS infusion had no significant effects on neutrophil CD11b expression. L-selectin expression of unstimulated cells after HS infusion was 9 +/- 3% higher than in the pre-infusion samples. These data suggest that HS infusion could indeed affect human neutrophils by suppressing CD11b expression. Although modest in healthy subjects, this effect may be more pronounced in trauma patients where reduced neutrophil-endothelial cell interactions might lessen neutrophil-mediated tissue damage.

Carotid endarterectomy without pre-operative angiography.

Carotid endarterectomy is being performed with increasing frequency without the benefit of preoperative angiography, based purely on duplex scanning. The available data attest to its safety, with the caveats that the duplex scan is unimpeachable, and that the symptoms and duplex scan findings are consistent. Given the well documented risk of stoke as a consequence of cerebral angiography being at least 1%, the elimination of this risk by the omission of contrast angiography would reduce the neurological morbidity and mortality rate of the diagnosis and treatment of carotid bifurcation disease by approximately 50%. The available data make a compelling case for carotid endarterectomy based on duplex scanning, without preoperative angiography, as the preferred approach to treatment of carotid artery stenosis.

Hypertonic saline resuscitation reduces neutrophil margination by suppressing neutrophil L selectin expression.

UNLABELLED: Hypertonic saline (HS) reduces hemorrhage-induced lung injury by suppressing the neutrophil oxidative burst and reducing lung neutrophil influx. This study investigated whether this is caused by the effects of HS on endothelial adhesion molecule expression, the production of chemoattractants in the lung, or a direct effect of HS on neutrophil selectin expression. METHODS: BALB/c mice were made to hemorrhage to 40 mm Hg for 1 hour and resuscitated with shed blood and either 4 mL/kg 7.5% HS or two times the shed blood volume of lactated Ringer's solution (LRS). Neutrophil L selectin expression was determined by flow cytometry, total neutrophil counts were obtained by differential staining, and pulmonary endothelial P and E selectin expression was evaluated by immunohistochemistry. Chemoattractants in lung lavages were determined with a modified Boyden chamber migration assay. RESULTS: Chemotactic activity of lavage fluid of HS-treated animals was not significantly different from that of LRS-treated animals, and endothelial P and E selectin expression was not altered by HS resuscitation. Neutrophils of HS-treated animals, however, expressed significantly less L selectin than those of LRS-treated mice. Concomitantly, circulating neutrophil counts of LRS-treated animals were significantly decreased compared with those of HS-treated mice. CONCLUSION: HS had little effect on endothelial selectin expression and chemoattractant production in the lung. HS significantly decreased neutrophil L selectin expression, however. This suggests that HS resuscitation may reduce lung injury by preventing neutrophil L selectin expression and endothelial adhesion.

Hypertonic saline resuscitation diminishes lung injury by suppressing neutrophil activation after hemorrhagic shock.

UNLABELLED: Hypertonic saline (HS) resuscitation after hemorrhage and sepsis has been shown to markedly reduce the development of lung injury in animals, compared with traditional resuscitation with lactated Ringer's (LR). These experiments examined the effect of HS on lung injury after hemorrhage without sepsis. The effects of HS and LR resuscitation on neutrophil trafficking, neutrophil adhesion, and neutrophil oxidative burst were studied. METHODS: BALB/c mice were hemorrhaged to a mean arterial pressure of 40 torr for 1 h. Animals were resuscitated with shed blood and either 4 mL/kg of 7.5% HS or LR in twice the volume of the shed blood. Lung histology was examined 24 h after hemorrhage. Lung myeloperoxidase content and bronchoalveolar lavage fluid neutrophil counts were obtained. Peripheral blood smears were obtained to determine the neutrophil percentage. Peripheral blood neutrophil CD11b expression and neutrophil H2O2 production were assayed by flow cytometry. RESULTS: HS animals had less lung injury than LR animals. The mean myeloperoxidase activity in HS versus LR animals was 1.79+/-1.33 U/100 mg versus 3.0+/-1.33 U/100 mg, respectively. The percentage of neutrophils in the bronchoalveolar lavage fluid of HS animals (3.8%+/-.8) was significantly less than that of LR animals (10.8%+/-2.1). This corresponded to a significantly higher peripheral blood neutrophil count in HS animals compared with LR animals, 41% vs. 20%, respectively. There was no difference in neutrophil expression of the CD11b integrin between the HS and LR groups. The neutrophils of LR animals had basal H2O2 production that was 107% greater than that of controls; HS suppressed this hemorrhage-induced activation by > 60%. HS resuscitation after hemorrhagic shock protects against the development of lung injury. This protection is due, in part, to suppression of the hemorrhage-induced neutrophil oxidative burst. HS resuscitation offers immunomodulatory potential after hemorrhagic shock.

Hypertonic saline resuscitation decreases susceptibility to sepsis after hemorrhagic shock.

BACKGROUND: We hypothesized that improvements in cellular immune function after hypertonic saline (HTS) resuscitation will alter the outcome of sepsis after hemorrhage. METHODS: To test this hypothesis, a two-hit model was used. Hemorrhage was induced in BALB/c mice by catheterizing the femoral artery and bleeding until a mean arterial pressure = 35 mm Hg was reached and maintained for 1 hour. Resuscitation was performed with HTS (NaCl 7.5%, 4 mL/kg) or lactated Ringer's (LR, twice the shed blood volume), plus the shed blood. Cecal ligation and puncture (CLP) was performed 24 hours after hemorrhage. Mortality was assessed for 72 hours, comparing HTS (n = 14) and LR (n = 13) resuscitation. Another set of animals (n = 10 in each group at each time point) were killed at 2 and 24 hours after blood collection. Liver and blood were cultured for the presence of bacteria, and lung and liver samples were scored on a scale from 0 (normal) to 4 (most severe) in a blind fashion by a pathologist. RESULTS: Mortality 72 hours after CLP was 14.3% in HTS and 76.9% in LR treated animals (p < 0.002). At 24 hours after CLP, 44% of HTS, but 77% of LR treated animals had > 1,000 colony forming units/mL of blood. Positive liver cultures (> 100,000 colony forming units/g) also showed the same trend (HTS = 30%, LR = 60%). Autopsies revealed a better containment of the infection (abscess formation) in the HTS group. At 2 hours, lung scores were 1.2 +/- 0.25 and 2.6 +/- 0.31 for HTS and LR, respectively (p < 0.002). At 24 hours, HTS treated animals showed marked improvement of lung injury, while the scores in the LR group remained high. A significant difference was also observed regarding liver injury. At 2 hours, scores were 0.4 +/- 0.22 and 2.3 +/- 0.16 for HTS and LR, respectively (p < 0.002). At 24 hours, HTS treated animals showed normal hepatic architecture, although mild injury was still observed in the LR group. CONCLUSION: HTS resuscitation leads to increased survival after hemorrhage and CLP. Marked improvements were observed in lung and liver injury compared with isotonic resuscitation. The better containment of the infection observed with HTS resuscitation corresponds to a marked decreased in bacteremia. HTS resuscitation stands as an alternative resuscitation regimen with immunomodulatory potential.