Changes in inflammatory endometrial cancer risk biomarkers in individuals undergoing surgical weight loss.

OBJECTIVE: Obesity has been strongly linked to endometrial cancer (EC) risk. A number of potential EC risk biomarkers have been proposed, including heightened pro-inflammatory cytokines and adipokines. To evaluate if bariatric surgery can serve as a means for altering levels of such EC risk biomarkers, we investigated changes in these biomarkers after weight loss. METHODS: Blood samples were collected pre-operatively and 6months post-operatively in 107 female bariatric surgery patients aged 18-72years. Wilcoxon signed-rank tests were used to compare biomarker levels (measured using xMAP immunoassays) pre- and post-surgery. Normative comparisons were implemented to contrast 6-month post-surgery biomarker levels to levels in a sample of 74 age-matched non-obese women. Linear regression was used to evaluate the relationship between biomarker expression at baseline and 6months post-surgery and the relationship between race and biomarker levels. RESULTS: On average, participants lost 30.15kg (SD: 12.26) after the bariatric intervention. Levels of C-peptide, insulin, CRP, leptin, IL-1Rα, and IL-6 significantly decreased, while levels of SHBG, IGFBP1, and adiponectin significantly increased with weight loss. Normative comparisons showed the levels of SHBG, C-peptide, insulin, IGFBP1, adiponectin, CRP, and TNFα after bariatric intervention approached the level of markers in comparison group. Multiple regression analyses revealed significant relationships between changes in BMI and changes in biomarker levels. The changes in IL-1Rα were significantly associated with race. CONCLUSIONS: Our findings demonstrate that normalization of EC risk biomarkers can be achieved with bariatric surgery. Improved understanding of biological mechanisms associated with weight loss may inform preventive strategies for EC.

Endometrial cancer associated biomarkers in bariatric surgery candidates: exploration of racial differences.

BACKGROUND: Obesity is the main risk factor for endometrial cancer (EC), the most common gynecologic malignancy in the United States. A number of potential risk biomarkers have been associated with EC development, including altered proinflammatory cytokines, chemokines, and adipokines. OBJECTIVES: The overarching aim of this research is to investigate racial differences in the expression of EC-associated biomarkers among bariatric surgery candidates. SETTING: Tertiary academic medical center METHODS: Blood samples were collected from 175 women aged 18 to 72 (mean age: 42.93; standard deviation 11.66), before bariatric surgery. Levels of biomarkers associated with obesity and EC risk were measured using xMAP immunoassays. Wilcoxon rank sum and Fisher's exact tests were utilized to compare biomarker and demographic variables between African American and European American women. Linear regression models, adjusted for menopause status and diabetes, were utilized to identify factors associated with biomarker levels. RESULTS: When the biomarker levels were compared by race, insulin-like growth factor-binding protein 1 and adiponectin were significantly lower in African American women (P<.05), whereas estradiol was significantly higher in African American women (P<.05). Linear regression models found that race significantly predicted insulin-like growth factor binding protein 1, adiponectin, resistin, and interleukin-1 receptor alpha expression levels, menopause status and diabetes status were significantly associated with adiponectin and leptin levels, whereas body mass index was significantly associated with leptin, adiponectin, interleukin-1 receptor alpha, and interleukin-6 levels. CONCLUSION: As one of the first efforts to explore racial differences in EC-associated biomarkers in a cohort of women with severe obesity, this study found several significant differences that should be further explored in large-scale studies.

Type 2 Diabetes Remission Rates After Laparoscopic Gastric Bypass and Gastric Banding: Results of the Longitudinal Assessment of Bariatric Surgery Study.

OBJECTIVE: The goals of this study were to determine baseline and postbariatric surgical characteristics associated with type 2 diabetes remission and if, after controlling for differences in weight loss, diabetes remission was greater after Roux-en-Y gastric bypass (RYGBP) than laparoscopic gastric banding (LAGB). RESEARCH DESIGN AND METHODS: An observational cohort of obese participants was studied using generalized linear mixed models to examine the associations of bariatric surgery type and diabetes remission rates for up to 3 years. Of 2,458 obese participants enrolled, 1,868 (76%) had complete data to assess diabetes status at both baseline and at least one follow-up visit. Of these, 627 participants (34%) were classified with diabetes: 466 underwent RYGBP and 140 underwent LAGB. RESULTS: After 3 years, 68.7% of RYGBP and 30.2% of LAGB participants were in diabetes remission. Baseline factors associated with diabetes remission included a lower weight for LAGB, greater fasting C-peptide, lower leptin-to-fat mass ratio for RYGBP, and a lower hemoglobin A1c without need for insulin for both procedures. After both procedures, greater postsurgical weight loss was associated with remission. However, even after controlling for differences in amount of weight lost, relative diabetes remission rates remained nearly twofold higher after RYGBP than LAGB. CONCLUSIONS: Diabetes remission up to 3 years after RYGBP and LAGB was proportionally higher with increasing postsurgical weight loss. However, the nearly twofold greater weight loss-adjusted likelihood of diabetes remission in subjects undergoing RYGBP than LAGB suggests unique mechanisms contributing to improved glucose metabolism beyond weight loss after RYGBP.

Endometrial histology in severely obese bariatric surgery candidates: an exploratory analysis.

BACKGROUND: Endometrial pathology risk has been linked to obesity; however, little is known of its prevalence in severely obese women not seeking care for endometrial pathology associated symptoms. This pilot study was designed to explore the frequency and risk factors associated with endometrial pathology in cancer-free, severely obese, bariatric surgery candidates using the Pipelle endometrial sampling technique (SureFlex Preferred Curette, Bioteque America, Inc, New Taipei City, Taiwan). METHODS: Twenty-nine severely obese bariatric surgery candidates with intact uteruses and no history of endometrial cancer or endometrial ablation were included in this subanalysis from a larger cohort of 47. Endometrial samples were obtained using a Pipelle endometrial suction curette at a single time point before surgery. Logistic regression was used to assess the relationship between body mass index and endometrial pathology when adjusting for age and race. RESULTS: Of the 29 successful biopsies, 8 (27.6%) were classified as abnormal endometrium: 1 was classified as complex atypical hyperplasia, 1 was classified as hyperplasia without atypia, 4 samples were identified with endometrial polyps, and 2 samples were identified with metaplasia. None presented with cancer. Increasing body mass index was significantly associated with higher risk of abnormal endometrium (OR = 1.19, 95% CI [1.03-1.36], P = .01). CONCLUSIONS: The findings in this sample suggest that obesity may be associated with increased risk of having undiagnosed endometrial pathology. More thorough examination of relationships between levels of obesity and endometrial pathology are needed to better characterize high cancer risk groups who may benefit from introducing new screening measures.

Technical factors associated with anastomotic leak after Roux-en-Y gastric bypass.

BACKGROUND: Anastomotic leak is one of the most serious complications after Roux-en-Y gastric bypass (RYGB). Our objective was to examine the relationship between technical factors and incidence of clinically relevant anastomotic leak after RYGB in longitudinal assessment of bariatric surgery (LABS). The setting of the study was 11 bariatric centers in the United States, university, and private practice. METHODS: Patient characteristics, technical factors of surgery, and postoperative outcomes were assessed by trained researchers using standardized protocols. Correlation of surgical factors of patients undergoing RYGB (n = 4444) with the incidence of postoperative anastomotic leak was assessed by univariate χ(2) analysis. RESULTS: Forty-four participants (1.0%, 95% CI .7%-1.3%) experienced a clinically relevant anastomotic leak. Of these, 39 (89%) underwent abdominal reoperation and 3 (7%) died. Technical factors associated with anastomotic leak were open surgery (P<.0001), revision surgery (P<.0001), and use of an abdominal drain (P = .02). Provocative leak testing, method of gastrojejunostomy, and use of fibrin sealant were not associated with anastomotic leak. CONCLUSIONS: Anastomotic leak after RYGB was rare (1.0%). Most cases required reintervention; however, the majority (93%) recovered from this event. Open surgery, revision surgery, and routine drain placement were associated with increased leak rate. Some of these findings may be due to differences in preoperative patient risk.

Changes in hormones and biomarkers in polycystic ovarian syndrome treated with gastric bypass.

BACKGROUND: Small retrospective studies have demonstrated reduction in weight and co-morbid hirsutism and diabetes in women with polycystic ovary syndrome (PCOS) treated with Roux-en-Y gastric bypass. The objective of this study was to prospectively determine clinical improvements in obese women with PCOS treated with gastric bypass and identify postoperative biomarker changes. METHODS: Data were collected on obese women with PCOS undergoing Roux-en-Y gastric bypass over 1 year. Testosterone, follicle stimulating hormone, lutenizing hormone, insulin, fasting glucose, and lipid levels were obtained preoperatively at baseline, and 6 and 12 months after surgery. Testosterone was used as the primary hormonal biomarker. A physical examination for body mass index (BMI) and hirsutism, and information on menstrual pattern were collected at baseline and 3, 6, and 12 months after surgery. RESULTS: Data were available for 14 women. Mean BMI decreased from 44.8±5.9 kg/m(2) at baseline to 29.2±5.9 kg/m(2) at 12 months postoperatively. Significant improvements were seen in testosterone, fasting glucose, insulin, cholesterol, and triglyceride at 12 months (P<.05). At baseline, irregular menses were reported in 10 patients; all patients were experiencing regular menses 6 and 12 months after surgery. Hirsutism was present in 11 patients at baseline and only 7 patients at 12 months. Improvements in biomarkers, menstrual cycling, and hirsutism was not correlated with degree of weight change. CONCLUSION: Gastric bypass achieved significant reductions in BMI, testosterone, and markers of glucose and lipid metabolism. These data confirm reports of previous retrospective studies showing weight reduction and health improvement in women with PCOS treated with gastric bypass.

StomaphyX vs a sham procedure for revisional surgery to reduce regained weight in Roux-en-Y gastric bypass patients : a randomized clinical trial.

IMPORTANCE: Revisional laparoscopic surgery after Roux-en-Y gastric bypass (RYGB) has been linked to substantial complications and morbidity. OBJECTIVE: To investigate the safety and effectiveness of endoscopic gastric plication with the StomaphyX device vs a sham procedure for revisional surgery in RYGB patients to reduce regained weight. DESIGN, SETTING, AND PARTICIPANTS: A prospective, single-center, randomized, single-blinded study from July 2009 through February 2011, evaluating revisional surgery using StomaphyX was conducted in patients with initial weight loss after RYGB performed at least 2 years earlier. We planned for 120 patients to be randomized 2:1 to multiple full-thickness plications within the gastric pouch and stoma using the StomaphyX device with SerosFuse fasteners or a sham endoscopic procedure and followed up for 1 year. The primary efficacy end point was reduction in pre-RYGB excess weight by 15% or more excess body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) loss and BMI less than 35 at 12 months after the procedure. Adverse events were recorded. RESULTS: Enrollment was closed prematurely because preliminary results indicated failure to achieve the primary efficacy end point in at least 50% of StomaphyX-treated patients. One-year follow-up was completed by 45 patients treated with StomaphyX and 29 patients in the sham treatment group. Primary efficacy outcome was achieved by 22.2% (10) with StomaphyX vs 3.4% (1) with the sham procedure (P < .01). Patients undergoing StomaphyX treatment experienced significantly greater reduction in weight and BMI at 3, 6, and 12 months (P ≤ .05). There was one causally related adverse event with StomaphyX, that required laparoscopic exploration and repair. CONCLUSIONS AND RELEVANCE: StomaphyX treatment failed to achieve the primary efficacy target and resulted in early termination of the study. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00939055.

Bariatric surgery: a safe and effective conduit to cardiac transplantation.

BACKGROUND: Obesity and obesity-related co-morbidities, including advanced heart failure, are epidemic. Some of these patients will progress to require cardiac allografts as the only means of long-term survival. Unfortunately, without adequate weight loss, they may never be deemed acceptable transplant candidates. Often surgical weight loss may be the only effective and durable option for these complex patients. The objective of this study was to assess whether bariatric surgery is feasible and safe in patients with severe heart failure, which in turn, after adequate weight loss, would allow these patients to be listed for a heart transplant. METHODS: Four patients who underwent bariatric procedures, such as laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (SG), for the purpose of attaining adequate weight loss with the goal to improve their eligibility for orthotopic heart transplants are presented. RESULTS: All patients did well around the time of surgery, and 3 of the 4 progressed to receiving a heart transplant. The fourth patient will be listed pending attaining adequate weight loss. CONCLUSION: Bariatric surgery may be an important bridge to transplantation for morbidly obese patients with severe heart failure. With the appropriate infrastructure, bariatric surgery is a feasible and effective weight loss method in this population.

The effect of gastric bypass on the pharmacokinetics of serotonin reuptake inhibitors.

OBJECTIVE: Morbidly obese patients frequently present with mood and anxiety disorders, which are often treated with serotonin reuptake inhibitors (SRIs). Having observed that patients treated with SRIs frequently relapse after Roux-en-Y gastric bypass surgery, the authors sought to assess whether SRI bioavailability is reduced postoperatively. METHOD: Twelve gastric bypass candidates treated with an SRI for primary mood or anxiety disorders were studied prospectively. Timed blood samples for SRI plasma levels were drawn for pharmacokinetic studies before surgery and 1, 6, and 12 months afterward. Maximum concentration, time to maximum concentration, and area under the concentration/time curve (AUC) were determined. RESULTS: In eight of the 12 patients, AUC values 1 month after surgery dropped to an average of 54% (SD=18) of preoperative levels (range=36%-80%); in six of these patients, AUC values returned to baseline levels (or greater) by 6 months. Four patients had an exacerbation of depressive symptoms, which resolved by 12 months in three of them. Three of the four patients had a reduced AUC level at 1 month and either gained weight or failed to lose weight between 6 and 12 months. Normalization of the AUC was associated with improvement in symptom scores. CONCLUSIONS: Patients taking SRIs in this study were at risk for reduced drug bioavailability 1 month after Roux-en-Y gastric bypass. The authors recommend close psychiatric monitoring after surgery.

Preoperative weight loss in high-risk superobese bariatric patients: a computed tomography-based analysis.

BACKGROUND: Superobesity, through organomegaly, excessive adiposity, and associated severe co-morbidities, is a recognized risk factor for bariatric surgery. Our study examined the utility of preoperative weight loss with a liquid low-calorie diet (LCD) as a method of risk reduction. METHODS: All patients with a body mass index (BMI) >50 kg/m(2) were instructed to consume a LCD (800 kcal/d) with the goal of losing ≥10% of their body weight. The co-morbidities were monitored. The abdominal wall depth and cross-sectional areas of subcutaneous adipose tissue (SAT) at 12 and 20 cm below the costal margin, visceral adipose tissue (VAT), and liver volume were measured, using computed tomography, at baseline and after completion of the LCD. Laparoscopic gastric bypass was performed in all patients. RESULTS: The study included 30 patients (27 men and 3 women) with a mean age of 53 years (range 34-53). The mean BMI was reduced from 56 kg/m(2) (range 50-69) at baseline to 49 kg/m(2) (range 43-60) after an average of 9 weeks of the LCD. The VAT decreased from a mean of 388 cm(2) to 342 cm(2). The abdominal wall depth decreased from 3.6 to 3.2 cm at 12 cm below the costal margin and from 3.7 to 3.4 cm at 20 cm. The mean SAT at both 12 and 20 cm below the costal margin had decreased from 577 cm(2) and 687 cm(2) to 509 cm(2) and 614 cm(2), respectively. The liver volume was reduced by 18%. All co-morbidities were well controlled at LCD completion. No patient died, and 2 minor complications occurred postoperatively. CONCLUSION: The results of our study have shown that preoperative LCD is a safe and effective tool leading to a significant decrease in liver volume and abdominal wall depth, as well as a reduction in both VAT and SAT. Its use might contribute to improved short-term surgical outcomes in high-risk superobese patients.

Perioperative safety in the longitudinal assessment of bariatric surgery.

BACKGROUND: To improve decision making in the treatment of extreme obesity, the risks of bariatric surgical procedures require further characterization. METHODS: We performed a prospective, multicenter, observational study of 30-day outcomes in consecutive patients undergoing bariatric surgical procedures at 10 clinical sites in the United States from 2005 through 2007. A composite end point of 30-day major adverse outcomes (including death; venous thromboembolism; percutaneous, endoscopic, or operative reintervention; and failure to be discharged from the hospital) was evaluated among patients undergoing first-time bariatric surgery. RESULTS: There were 4776 patients who had a first-time bariatric procedure (mean age, 44.5 years; 21.1% men; 10.9% nonwhite; median body-mass index [the weight in kilograms divided by the square of the height in meters], 46.5). More than half had at least two coexisting conditions. A Roux-en-Y gastric bypass was performed in 3412 patients (with 87.2% of the procedures performed laparoscopically), and laparoscopic adjustable gastric banding was performed in 1198 patients; 166 patients underwent other procedures and were not included in the analysis. The 30-day rate of death among patients who underwent a Roux-en-Y gastric bypass or laparoscopic adjustable gastric banding was 0.3%; a total of 4.3% of patients had at least one major adverse outcome. A history of deep-vein thrombosis or pulmonary embolus, a diagnosis of obstructive sleep apnea, and impaired functional status were each independently associated with an increased risk of the composite end point. Extreme values of body-mass index were significantly associated with an increased risk of the composite end point, whereas age, sex, race, ethnic group, and other coexisting conditions were not. CONCLUSIONS: The overall risk of death and other adverse outcomes after bariatric surgery was low and varied considerably according to patient characteristics. In helping patients make appropriate choices, short-term safety should be considered in conjunction with both the long-term effects of bariatric surgery and the risks associated with being extremely obese. (ClinicalTrials.gov number, NCT00433810.)

Safety and efficacy of bariatric surgery in morbidly obese patients with severe systolic heart failure.

BACKGROUND: Morbid obesity (MO) is a risk factor for congestive heart failure (CHF). The presence of MO impairs functional status and disqualifies patients for cardiac transplantation. Bariatric surgery (BAS) is a frontline, durable treatment for MO; however, the safety and efficacy of BAS in advanced CHF is unknown. HYPOTHESIS: We hypothesized that by utilizing a coordinated approach between an experienced surgical team and heart failure specialists, BAS is safe in patients with advanced systolic CHF and results in favorable outcomes. METHODS: We performed a retrospective chart review of 12 patients with MO (body mass index [BMI] 53 +/- 7 kg/m2) and systolic CHF (left ventricular ejection fraction [LVEF] 22 +/- 7%, New York Heart Association [NYHA] class 2.9 +/- 0.7) who underwent BAS, and then compared outcomes with 10 matched controls (BMI 47.2 +/- 3.6 kg/m2, LVEF 24 +/- 7%, and NYHA class 2.4 +/- 0.7) who were given diet and exercise counseling. RESULTS: At 1 y, hospital readmission in BAS patients was significantly lower than controls (0.4 +/- 0.8 versus 2.5 +/- 2.6, p = 0.04); LVEF improved significantly in BAS patients (35 +/- 15%, p = 0.005), but not in controls (29 +/- 14%, p = not significant [NS]). The NYHA class improved in BAS patients (2.3 +/- 0.5, p = 0.02), but deteriorated in controls (3.3 +/- 0.9, p = 0.02). One BAS patient was successfully transplanted, and another listed for transplantation. CONCLUSIONS: Bariatric surgery is safe and effective in patients with MO and severe systolic CHF, and should be considered in patients who have failed conventional therapy to improve clinical status.

Laparoscopic colorectal surgery is safe in the high-risk patient: a NSQIP risk-adjusted analysis.

BACKGROUND: Laparoscopic colectomy was considered initially to be contraindicated in patients at high risk for operative morbidity and mortality. We hypothesized that this procedure is safe to perform in high-risk patients, stratifying this risk using National VA Surgical Quality Improvement Program (NSQIP) algorithms. METHODS: A case-matched, comparative study was performed for high-risk veteran patients who underwent colectomy during the period October 2002-September 2004. Consecutive patients undergoing laparoscopic colectomy were matched to patients who underwent open colectomy during the same period for age, body mass index (BMI), procedure, and NSQIP-predicted risk. The groups were compared for risk-stratified, 30-day morbidity/mortality, length of stay (LOS), and operating time. RESULTS: Forty-five patients (23 laparoscopic and 22 open cases) were defined as at high risk for complications (predicted complication >0.15). The rate of major complications was significantly less in the laparoscopic group. There were 4 (18%) cases of postoperative respiratory failure in the open group and none in the laparoscopic group. There was no surgically related mortality in the laparoscopic group, compared with 2 deaths in the open group (P = .5). Median LOS was less in the laparoscopic group (5 days) compared with open (8 days) (P = .001). There were no significant differences in operating time or the number of minor complications. CONCLUSIONS: Our results suggest that the laparoscopic approach to colorectal diseases is safe in the population of patients at high risk for operative morbidity and mortality. Rather, this approach may represent a safer alternative to open access.

Hypoxia activates c-Jun N-terminal kinase via Rac1-dependent reactive oxygen species production in hepatocytes.

The earliest events after the induction of hemorrhagic shock (HS) are complex and poorly understood. We have recently demonstrated that decreased tissue perfusion and hypoxia during HS lead to an increased phosphorylation of c-Jun N-terminal kinase (JNK) in vivo. The purpose of these investigations was to test the hypothesis that hypoxia activates JNK via Rac1-dependent reactive oxygen species (ROS) signaling. Mice subjected to HS and resuscitated with Ringer's ethyl pyruvate solution (REPS) or N-acetylcysteine (NAC), two scavengers of ROS, demonstrated decreased levels of phosphorylated JNK. Exposure of primary mouse hepatocytes in culture to 1% oxygen led to increased production of ROS and phosphorylation of JNK. The duration of hypoxia correlated with the level of generation of ROS and JNK activation. The phosphorylation of JNK was attenuated in the presence of ROS scavengers or the nicotinamide adenosine dinucleotide phosphate [NDA(P)H] oxidase inhibitor, diphenyleneiodonium (DPI). In addition, hypoxia increased activation of Rac1. Inhibition of Rac1 activation by adenoviral gene transfer of dominant-negative Rac1 (AdRac1) attenuated both ROS formation and JNK activation. Together, these data suggest that ROS generation during hypoxia in the liver directly leads to JNK activation in a Rac1-dependent process.

The role of hepatic type 1 plasminogen activator inhibitor (PAI-1) during murine hemorrhagic shock.

Hemorrhagic shock (HS) followed by resuscitation (HS-R) is characterized by profound physiological changes. Even if the patient survives the initial blood loss, these poorly understood changes can lead to morbidity. One of the tissues most often affected is liver. We sought to recognize specific hepatic changes induced by this stressor to identify targets for therapeutic intervention. Gene array analyses using mouse liver mRNAs were used to identify candidate genes that contribute to hepatic damage. To verify the role of one of the genes identified using the arrays, mice were subjected to HS-R, and multiple parameters were analyzed. A profound increase in plasminogen activator inhibitor type 1 (PAI-1) mRNA was observed using hepatic mRNAs from C57Bl/6 mice after HS, both with and without resuscitation. Constitutive loss of PAI-1 resulted in notable tissue preservation and lower (P < .05) alanine aminotransferase (ALT) levels. Fibrin degradation products (FDPs) and interleukins 6 and 10 (IL-6 and IL-10) were unaffected by loss of PAI-1; however, enhanced urokinase activity, an elevation of active hepatocyte growth factor (HGF), an increase in unprocessed transforming growth factor-beta1 (TGF-beta1), and retention of ERK phosphorylation after HS-R were associated with improved hepatic function. In conclusion, PAI-1 protein is a negative effector of hepatic damage after HS-R through its influence on classic regulators of hepatic growth, as opposed to its role in fibrinolysis.

Carbon monoxide prevents multiple organ injury in a model of hemorrhagic shock and resuscitation.

The insult from severe hemorrhage is a multifactorial injury involving ischemia/reperfusion with inflammatory dysfunction. Our laboratories and others have demonstrated that the administration of exogenous carbon monoxide (CO) at low concentrations provides cytoprotection in vivo and in vitro. The purpose of these investigations was to test the hypothesis that CO protects against hemorrhagic shock- and resuscitation-induced systemic inflammation and end-organ damage. C57BL/6 mice underwent anesthesia and arterial cannulation. Mice were bled to reach a mean arterial pressure (MAP) of 25 mmHg and were maintained at this pressure for 2.5 h. Mice were then resuscitated with shed blood plus two times the volume of shed blood with Ringer's lactate. Sham animals were not bled. Additionally, mice were maintained in room air or in an environment of CO (250 parts per million). Primary mouse hepatocytes were harvested and used for in vitro cell viability and ATP measurement. These data demonstrate that delivery of a low concentration of inhaled CO protects against the development of end-organ injury decreases serum levels of inflammatory cytokines and increases serum levels of the anti-inflammatory cytokine IL-10. Additionally, CO paradoxically abrogates hemorrhage-induced hepatic cellular hypoxia. Furthermore, CO protected mouse hepatocytes from hypoxia-induced death while maintaining normal ATP levels. CO protects against systemic effects of hemorrhagic shock and resuscitation. The precise cellular mechanisms involved require further elucidation. CO may prove to be an adjunctive therapy that could be instituted rapidly and with ease as an out-of-hospital therapeutic modality for severe blood loss after trauma.

Overexpression of mutated IkappaBalpha inhibits vascular smooth muscle cell proliferation and intimal hyperplasia formation.

PURPOSE: Vascular injury and inflammation are associated with elaboration of a number of cytokines that signal through multiple pathways to act as smooth muscle cell (SMC) mitogens. Activation of the nuclear factor-kappa B (NF-kappaB) transcription factor is essential for SMC proliferation in vitro and is activated by vascular injury in vivo. Activation of NF-kappaB is controlled by several upstream regulators, including the inhibitors of kappa B (IkappaB). These proteins bind to and keep NF-kappaB inactivated. The purpose of this study was to determine whether adenoviral gene transfer of a mutated IkappaBalpha super-repressor (AdIkappaBalphaSR) could inhibit development of intimal hyperplasia in vivo and to investigate how over-expression of this construct influences in vitro SMC proliferation and cell cycle regulatory proteins. METHODS: A rat carotid injury model was used to study prevention of intimal hyperplasia. Arteries were assayed 14 days after injury and infection with AdIkappaBalphaSR or adenoviral beta-galactosidase (AdLacZ). Untreated SMC or SMC infected with AdLacZ or AdIkappaBalphaSR were stimulated with 10% fetal bovine serum, interleukin-1beta, or tumor necrosis factor-alpha. Electrophoretic mobility shift assays were used to assay for NF-kappaB activation. Protein levels of IkappaBalpha and cyclin-dependent kinase inhibitors p21(Cip1/Waf1) and p27(Kip1) were determined with Western blot analysis. Proliferation was measured with (3)H-thymidine incorporation assays. RESULTS: AdIkappaBalphaSR inhibited the development of intimal hyperplasia by 49% (P <.05). Infection with AdIkappaBalphaSR significantly suppressed in vitro SMC proliferation when stimulated with serum, interleukin 1, or tumor necrosis factor alpha, and did not result in cell death. Inhibition of proliferation was associated with increased p21(Cip1/Waf1) and p27(Kip1) protein levels. CONCLUSIONS: Gene transfer of IkappaBalpha super-repressor inhibited development of intimal hyperplasia in vivo and SMC proliferation in vitro. The antiproliferative activity may be related to cell cycle arrest through upregulation of the cyclin-dependent kinase inhibitors p21 and p27. Overexpression of IkappaBalpha may be a future therapeutic option in treatment of vascular diseases.