Inhaled carbon monoxide inhibits intimal hyperplasia and provides added benefit with nitric oxide (original) (raw)
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Inhaled Carbon Monoxide Prevents Graft-Induced Intimal Hyperplasia in Swine
The Journal of Surgical Research, 2007
Background. Arteriovenous grafts often fail due to stenosis caused by venous anastomotic intimal hyperplasia (IH) and vascular smooth muscle cell (VSMC) proliferation. We examined the effects of inhaled carbon monoxide (CO), a product of heme-oxygenase-1 degradation of heme, on IH in a porcine arteriovenous graft model. Materials and methods. Eighteen Yorkshire pigs were divided into three groups (N ؍ 6/group): (1) CO 100 ppm preoperatively for 1 h; (2) CO 250 ppm preoperatively for 1 h and intraoperatively; and (3) airtreated controls. Animals underwent end-to-side placement of polytetrafluoroethylene grafts connecting the common femoral artery and vein in both groins. Intimal thickness of the venous anastomosis at 30 days was measured blinded. The effect of CO on pig VSMC proliferation was studied in cell culture using [ 3 H]thymidine incorporation. Results. Pigs in the group receiving CO 250 ppm showed significantly less IH compared to animals in the group receiving 100 ppm and the air-treated group (267.5 ؎ 21.4, 824 ؎ 145.8, and 914.8 ؎ 133.7 pixels, respectively, P < 0.0001). This effect was not observed when comparing the 100 ppm group to the air-treated group. COHb levels were significantly elevated in the 100 ppm and 250 ppm compared to air-treated pigs (5.8 ؎ 0.47, 13.2 ؎ 1.0 versus 2.3 ؎ 0.11%, respectively, P < 0.001). Oxygen saturation, respiratory rate, and hemodynamics were not significantly different between the groups. CO induced VSMC growth arrest compared to air in vitro (11.9 ؎ 4 versus 20.3 ؎ 5 10 3 counts/min/well, P < 0.01). Conclusion. A single exposure to a low concentration of inhaled CO (250 ppm) confers protection against intimal proliferation of VSMCs when given perioperatively in a clinically relevant model of arteriovenous grafts. These data are the first to suggest, in a clinically relevant model, the potential role for CO in clinical applications.
Cellular and Molecular Biology, 2005
Recent studies indicate that systemic induction of heme oxygenase-1 (HO-1), which oxidatively degrades heme into iron, biliverdin, and carbon monoxide (CO), or adenoviral-mediated gene transfer of HO-1 inhibits neointima formation after experimental vascular injury. In the present study, we investigated whether the acute, local administration of the HO-1 product, CO, regulates the arterial remodeling response following injury. Immediately after balloon injury of rat carotid arteries, a saturated solution of CO or nitrogen (N 2), or phosphate buffered saline (PBS) was incubated luminally within the injured vessels for 30 min. Two weeks after injury, arteries exposed to CO exhibited significantly reduced neointimal area, neointimal area/medial wall area ratio, neointimal thickness, and medial wall area compared to arteries exposed to N 2 or PBS. Arteries exposed to CO also demonstrated significantly reduced DNA synthesis in the medial wall two days after injury as suggested by proliferating cell nuclear antigen immunostaining, and this was associated with a decrease in the protein expression of the G 1 cyclins, cyclin E and A, and transforming growth factor-beta1. These results indicate that the acute, local delivery of CO blocks the pathophysiological remodeling response to vascular injury, and identifies CO as a potentially important therapeutic agent in the treatment of vasculoproliferative disease.
Delayed inhaled carbon monoxide mediates the regression of established neointimal lesions
Journal of vascular surgery, 2015
Intimal hyperplasia (IH) contributes to the failure of vascular interventions. While many investigational therapies inhibit the development of IH in animal models, few of these potential therapies can reverse established lesions. Inhaled carbon monoxide (CO) dramatically inhibits IH in both rats and pigs when given perioperatively. It also prevented the development of pulmonary arterial hypertension in rodents. Interestingly, CO could reverse pulmonary artery structural changes and right heart hemodynamic changes when administered after the establishment of pulmonary hypertension. Thus, we hypothesize that inhaled CO may mediate the regression of established neointimal lesions. Rats underwent carotid artery balloon angioplasty injury. Carotid arteries were collected at 2 and 4 weeks after injury for morphometric analysis of the neointima. Another group was treated with inhaled CO (250 parts per million) for 1 hour daily from week 2 until week 4. Additional rats were sacrificed 3 day...
Brazilian Journal of Cardiovascular Surgery, 2006
Objective: The purpose of this study was to assess the effect of CO 2 on the wall of the Left Internal Thoracic Artery (LITA) and Anterior Interventricular Artery (AIVA) in an experimental model using goats, comparing the immediate effects of the use of CO 2 at flow rates of 5 L/min and 10 L/min during 20 minutes, with intermittent flow (every 30 seconds) with and without humidification, simultaneously to the LITA and AIVA.
The role of short-term oxygen administration in the prevention of intimal hyperplasia
Journal of Vascular Surgery, 2013
Objective: Intimal hyperplasia (IH) is the cause of most failed arteriovenous fistulas (AVFs), resulting in repeat procedures and leading to increased utilization of scarce health care resources. Our laboratory has previously demonstrated the role of supplemental oxygen in preventing IH and smooth muscle cell proliferation (SMCp) at an artery-to-graft anastomosis and at the deployment site of an intra-arterial stent. This study examines the effect of supplemental oxygen in preventing IH and SMCp in an AVF in a rabbit model. Methods: Ninety-six rabbits were randomized into four groups: group 1, control; group 2, no surgery with supplemental oxygen; group 3, AVF without supplemental oxygen; and group 4, AVF with supplemental oxygen. Rabbits receiving supplemental oxygen received 30% oxygen for up to 42 days. Specimens were collected in all groups at days 1, 3, 7, 21, 42, and 90. IH and SMCp were measured at the AVF site as well as in the artery and vein proximal and distal to the AVF. Results: IH was first noted at day 7 and significantly increased through day 90 at all locations in the nonoxygen-supplemented groups. No significant IH was noted in the oxygen-supplemented group at any location or any time point. SMCp was noted at day 3 through day 21 in the nonoxygen-supplemented group, whereas almost no SMCp was noted in the oxygen-supplemented group at any location or time point. Conclusions: Without oxygen supplementation, SMCp begins at day 3 and is no longer noted at day 21 after creation of an AVF, whereas IH begins by day 7 and increases at least through day 90 after creation of an AVF. Forty-two days of 30% supplemental oxygen inhibits IH and SCMp after creation of an AVF. These data suggest a role for the short-term administration of low-dose O 2 to prevent both IH and SMCp after creation of an AVF that may prolong patency and function.
The FASEB Journal, 2004
Carbon monoxide (CO) has recently emerged as having potent cytoprotective properties; the mechanisms underlying these effects, however, are just beginning to be elucidated. In a rat model of lipopolysaccharide (LPS)-induced multiorgan failure, we demonstrate that exposure to a low concentration of CO for only 1 h imparts a potent defense against lethal endotoxemia and effectively abrogates the inflammatory response. Exposure to CO leads to long-term survival of >80% of animals vs. 20% in controls. In the lung, CO suppressed LPS-induced lung alveolitis and associated edema formation, while in the liver, it reduced expression of serum alanine aminotransferase, a marker of liver injury. This protection appears to be based in part on different mechanisms in the lung and liver in that CO had reciprocal effects on LPS-induced expression of iNOS and NO production, important mediators in the response to LPS. CO prevented the up-regulation of iNOS and NO in the lung while augmenting expression of iNOS and NO in the liver. Studies of primary lung macrophages and hepatocytes in vitro revealed a similar effect; CO inhibited LPS-induced cytokine production in lung macrophages while reducing LPS-induced iNOS expression and nitrite accumulation and protected hepatocytes from apoptosis while augmenting iNOS expression. Although it is unclear to which extent these changes in iNOS contribute to the cytoprotection conferred by CO, it is fascinating that in each organ CO influences iNOS in a manner known to be protective in that organ: NO is therapeutic in the liver while it is damaging in the lung. Key words: nitric oxide • iNOS/NOS2 • heme oxygenase • oxidative stress • inflammation dministration of lipopolysaccharide (LPS), a constituent of the gram-negative bacterial cell wall, induces inflammatory responses when administered to cells or animals similar to those seen in septic shock, a major cause of death worldwide (1-3). Heme oxygenase A (HO), the rate-limiting enzyme in the oxidative degradation of heme, has been demonstrated by numerous laboratories to provide potent protection against oxidative stress (4-6), including models of endotoxic shock and acute lung and liver failure in rodents (7-10). Carbon monoxide (CO), a product of HO action on heme, induces an anti-inflammatory phenotype in vivo at low concentrations (<250 ppm). CO effectively inhibits the proinflammatory LPS-induced cytokine TNF-α, while simultaneously augmenting expression of the anti-inflammatory cytokine IL-10 (11). CO also protects via antiapoptotic mechanisms in many cells (12-14). Until recently, CO has been studied primarily in the vascular and neuronal systems and has been shown to be an important signaling molecule, similar to nitric oxide (NO) (15-18). Recent data suggest a role for CO as a biological effector molecule based on its antiinflammatory properties and its ability to modulate apoptosis and proliferation of a variety of cells (12, 19-22).