Roux-en-Y Gastric Bypass Acutely Decreases Protein Carbonylation and Increases Expression of Mitochondrial Biogenesis Genes in Subcutaneous Adipose Tissue.

BACKGROUND: Mitochondrial dysfunction in adipose tissue has been implicated as a pathogenic step in the development of type 2 diabetes mellitus (T2DM). In adipose tissue, chronic nutrient overload results in mitochondria driven increased reactive oxygen species (ROS) leading to carbonylation of proteins that impair mitochondrial function and downregulation of key genes linked to mitochondrial biogenesis. In patients with T2DM, Roux-en-Y gastric bypass (RYGB) surgery leads to improvements in glycemic profile prior to significant weight loss. Consequently, we hypothesized that improved glycemia early after RYGB would be paralleled by decreased protein carbonylation and increased expression of genes related to mitochondrial biogenesis in adipose tissue. METHODS: To evaluate this hypothesis, 16 obese individuals were studied before and 7-8 days following RYGB and adjustable gastric banding (AGB). Subcutaneous adipose tissue was obtained pre- and post-bariatric surgery as well as from eight healthy, non-obese individual controls. RESULTS: Prior to surgery, adipose tissue expression of PGC1α, NRF1, Cyt C, and eNOS (but not Tfam) showed significantly lower expression in the obese bariatric surgery group when compared to lean controls (p < 0.05). Following RYGB, but not after AGB, patients showed significant decrease in HOMA-IR, reduction in adipose protein carbonylation, and increased expression of genes linked to mitochondrial biogenesis. CONCLUSIONS: These results suggest that rapid reduction in protein carbonylation and increased mitochondrial biogenesis may explain postoperative metabolic improvements following RYGB.

Effects on GLP-1, PYY, and leptin by direct stimulation of terminal ileum and cecum in humans: implications for ileal transposition.

BACKGROUND: We do not have a unified, scientifically tested theory of causation for obesity and its co-morbidities, nor do we have explanations for the mechanics of the metabolic/bariatric surgery procedures. Integral to proffered hypotheses are the actions of the hormones glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and leptin. The objective of this study was to obtain blood levels of GLP-1, PYY, and leptin after stimulation of the terminal ileum and cecum by a static infusion of a food hydrolysate in morbidly obese patients undergoing a duodenal switch procedure. SETTING: University Hospital. METHODS: Plasma levels of GLP-1, PYY, and leptin were obtained at 0, 30, 60, 90, and 120 minutes after instillation of 240 mL of a food hydrolysate into the ileum or cecum. RESULTS: The mean±SD GLP-1 values by cecal stimulation for 0, 30, 60, 90, and 120 minutes were: 41.3±23.2; 39.6±21.8; 38.9±19.1; 47.4±22.3; 51.7±27.3 pM, and by ileal stimulation: 55.0±32.8; 83.4±16.1; 78.7±23.8; 84.7±23.5; 76.4±25.6. The mean±SD PYY values by cecal stimulation were: 62.1±24.8; 91.1±32.8; 102.1±39.6; 119.6±37.5; 130.3±36.7, and by ileal stimulation: 73.8±41.6; 138.1±17.7; 149.5±23.3; 165.7±24.3; 155.5±29.1. Percent change in PYY levels increased ~150%, GLP-1 increased ~50%, and leptin decreased ~20%. CONCLUSION: Direct stimulation of the human terminal ileum and cecum by a food hydrolysate elicits significant plasma GLP-1 and PYY elevations and leptin decreases, peaking at 90-120 minutes. The ileal GLP-1 and PYY responses exceed those of the cecum, and the PYY effect is about 3-fold that of GLP-1. The results of this study question the satiety premise for ileal transposition.

Hiatal hernia repair in laparoscopic adjustable gastric banding and laparoscopic Roux-en-Y gastric bypass: a national database analysis.

Hiatal hernia (HH) repairs are commonly done concomitantly with laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic adjustable gastric banding (LAGB) to decrease gastroesophageal reflux disease (GERD). There is limited evidence about the additional surgical risk these combined procedures engender. We used the United States Nationwide Inpatient Sample 2004-2009 to compare mortality risk, prolonged length of stay (PLOS), and perioperative adverse events using propensity score-matched analysis. We repeated the analysis after removing patients diagnosed with GERD. There were 42,272 weighted patients undergoing LRYGB alone representing 206,559 discharges nationally and an additional 1,945 and 9,060, respectively, undergoing LRYGB + HH repair. For LAGB, there were 10,558 records representing 52,901 LAGB-only discharges and 1,959 representing 9,893 LAGB + HH repair discharges. Thirty-eight percent (95 % CI: 36, 41 %) of the patients in the LRYGB-only group had GERD compared to 55 % (51, 59 %) in the LRYGB + HH repair group. Among the LAGB groups, 31 % (28, 34 %) of LAGB-only patients had GERD compared to 44 % (38, 49 %) in the LAGB + HH repair group. We find that the average treatment effect on the treated (considering the concomitant procedure as treatment and the single procedure as control) for PLOS was -0.12353 (-0.15909, -0.08797) between the LRYGB groups and -0.04353 (-0.07488, -0.01217) for the LAGB groups. We find no evidence of increased risk of perioperative adverse events among patients undergoing concomitant HH repair with LRYGB or LAGB. Patients undergoing the combined procedure appear to be at lower risk of PLOS; this may be due to surgical training norms.

Does concomitant cholecystectomy at time of Roux-en-Y gastric bypass impact adverse operative outcomes?

BACKGROUND: We hypothesized that patients undergoing Roux-en-Y gastric bypass (RYGB) with concomitant cholecystectomy (RYGB + C) would be at greater risk for adverse events compared to patients undergoing RYGB alone. METHODS: Patients who underwent a RYGB were identified in the 2005-2009 American College of Surgeons National Surgical Quality Improvement Program Database. Multivariate logistic regression with adjustment for confounding variables was utilized to identify risk factors for mortality at 30 days, major adverse events, and prolonged length of stay (PLOS). RESULTS: We identified 32,946 patients who underwent RYGB; of these, 1,731 (5.2%) underwent RYGB + C. Overall, RYGB + C was a risk factor for predicting major adverse events following laparoscopic but not open procedures. Regardless of approach, PLOS was more common among RYGB + C patients following adjustment. Overall mortality at 30 days was low and did not vary with concomitant cholecystectomy following adjustment. CONCLUSIONS: The risk for major adverse events is significantly greater for RYGB + C patients following laparoscopic procedures, and the risk for PLOS is greater for RYGB + C patients following both open and laparoscopic procedures. The short-term risks identified in this study can assist in decision-making when considering concomitant cholecystectomy at the time of RYGB.

Benefits and complications of the duodenal switch/biliopancreatic diversion compared to the Roux-en-Y gastric bypass.

BACKGROUND: Despite providing superb excess weight loss and increased resolution of comorbid diseases, such as type 2 diabetes mellitus, compared to other bariatric procedures, the duodenal switch/ biliopancreatic diversion (DS/BD) has not gained widespread acceptance among patients and physicians. In this study, we investigated outcomes, symptoms and complications among postsurgical DS patients compared to RYGB patients. METHODS: We used propensity scores to retrospectively match patients who underwent DS/BD between 2005 and 2010 to comparable Roux-en-Y gastric bypass (RYGB) patients. We then reviewed patient charts, and surveyed patients using the University of Minnesota Bariatric Surgery Outcomes Survey tool to track outcomes, comorbid illnesses and complications. RESULTS: One hundred ninety consecutive patients underwent primary DS/BD between 2005 and 2010 at the University of Minnesota Medical Center. There were 178 patients available for follow-up (93.7%) who were matched to 139 RYGB patients. Type 2 diabetes, hypertension, and hyperlipidemia all significantly improved in each group. Improvements were significantly higher in the DS/BD group. Percent total weight loss was not different between groups. Loose stools and bloating symptoms were more frequently reported among DS/BD patients. With the exception of increased emergency department visits among DS/BD patients (P < .01), overall complication rates were not significantly different between DS/BD and RYGB. There was no difference in mortality rates between the groups. CONCLUSION: The DS/BD is a robust procedure that engenders both superior weight loss and improvement of major comorbidities. Complication and adverse event rates are similar to those of RYGB.

Risk for hospital readmission following bariatric surgery.

BACKGROUND AND OBJECTIVES: Complications resulting in hospital readmission are important concerns for those considering bariatric surgery, yet present understanding of the risk for these events is limited to a small number of patient factors. We sought to identify demographic characteristics, concomitant morbidities, and perioperative factors associated with hospital readmission following bariatric surgery. METHODS: We report on a prospective observational study of 24,662 patients undergoing primary RYGB and 26,002 patients undergoing primary AGB at 249 and 317 Bariatric Surgery Centers of Excellence (BSCOE), respectively, in the United States from January 2007 to August 2009. Data were collected using standardized assessments of demographic factors and comorbidities, as well as longitudinal records of hospital readmissions, complications, and mortality. RESULTS: The readmission rate was 5.8% for RYGB and 1.2% for AGB patients 30 days after discharge. The greatest predictors for readmission following RYGB were prolonged length of stay (adjusted odds ratio [OR], 2.3; 95% confidence interval [CI], 2.0-2.7), open surgery (OR, 1.8; CI, 1.4-2.2), and pseudotumor cerebri (OR, 1.6; CI, 1.1-2.4). Prolonged length of stay (OR, 2.3; CI, 1.6-3.3), history of deep venous thrombosis or pulmonary embolism (OR, 2.1; CI, 1.3-3.3), asthma (OR, 1.5; CI, 1.1-2.1), and obstructive sleep apnea (OR, 1.5; CI, 1.1-1.9) were associated with the greatest increases in readmission risk for AGB. The 30-day mortality rate was 0.14% for RYGB and 0.02% for AGB. CONCLUSION: Readmission rates are low and mortality is very rare following bariatric surgery, but risk for both is significantly higher after RYGB. Predictors of readmission were disparate for the two procedures. Results do not support excluding patients with certain comorbidities since any reductions in overall readmission rates would be very small on the absolute risk scale. Future research should evaluate the efficacy of post-surgical managed care plans for patients at higher risk for readmission and adverse events.

Routine upper gastrointestinal imaging is superior to clinical signs for detecting gastrojejunal leak after laparoscopic Roux-en-Y gastric bypass.

BACKGROUND: There are myriad symptoms and signs of gastrojejunal leak; prompt recognition is essential. Many surgeons use clinical predictors to guide selective use of upper gastrointestinal imaging (UGI). The appropriate practice remains undefined. STUDY DESIGN: A review of patients who underwent primary laparoscopic Roux-en-Y gastric bypass between January 2002 and December 2008 was conducted. All underwent routine UGI studies on postoperative day 1. Actual gastrojejunal leak within 7 days of surgery (actual leak [AL], radiologic leaks), operative reports, patient charts, and postoperative vital signs were retrospectively reviewed. RESULTS: There were 2,099 operations. Eight ALs (0.43%) occurred without associated mortality. UGI was positive in 7 AL patients and falsely positive in 6 patients. The AL patients underwent laparoscopy on postoperative days 1 and 3 (n = 5 and n = 1, respectively), laparotomy on postoperative day 3 (n = 1), and peritoneal drainage (n = 1). False-positive UGIs prompted laparoscopy (n = 3) and close observation (n = 3). Pulse was 100 to 120 beats per minute in 2 patients and fever (>38.5°C) was present in 0 AL patients. AL patients had osteogenesis imperfecta (n = 1), macronodular cirrhosis (n = 1), positive bubble test (n = 3), and concomitant splenectomy (n = 1). No jejunojejunostomy leaks were identified. CONCLUSIONS: Routine UGI after laparoscopic Roux-en-Y gastric bypass has greater sensitivity than clinical signs for detecting gastrojejunal leak. Delay in the diagnosis of leakage can impact mortality, and this suggests that indications for routine UGI might still exist. Tachycardia is not a reliable early marker of leak. There might be risk factors for leak in addition to vital signs, including patient medical history or intraoperative events, which should prompt routine UGI on postoperative day 1.

Case-matched outcomes in bariatric surgery for treatment of type 2 diabetes in the morbidly obese patient.

OBJECTIVE: To compare the relative efficacy of medical management, the duodenal switch (DS), and the laparoscopic adjustable gastric band (LAGB) to the Roux-en-Y gastric bypass (RYGB) for treatment of type 2 diabetes mellitus (T2DM). BACKGROUND: The RYGB resolves T2DM in a high proportion of patients and is considered the standard operation for T2DM resolution in morbidly obese patients. However, no data exist comparing the efficacy of medical management and other bariatric operations to the RYGB for treatment of T2DM in comparable patient populations. METHODS: We performed a retrospective case-matched study of morbidly obese patients with T2DM who had undergone medical management (nonsurgical controls [NSC]; N = 29), LAGB (N = 30), or DS (N = 27) and were compared with matched T2DM patients who had undergone RYGB. Matching was performed with respect to age, sex, body mass index, and hemoglobin A1C (HbA1C). Outcomes assessed were changes in body mass index, HbA1C, and diabetes medication scores at 1 year. RESULTS: The Roux-en-Y gastric bypass produced greater weight loss, HbA1C normalization, and medication score reduction compared to both NSC and LAGB-matched cohorts. Duodenal switch produced greater reductions in HbA1C and medication score than RYGB, despite no greater weight loss at 1 year. Surgical complications were rarely life threatening. CONCLUSIONS: This study provides an important perspective about the comparative efficacy of LAGB, DS, and NSC to the RYGB for treatment of T2DM among obese patients. After 1 year of follow-up, RYGB is superior to NSC and LAGB with respect to weight loss and improvement in diabetes whereas DS is superior to RYGB in reducing HbA1C and medication score.

Efficacy of the Roux-en-Y gastric bypass compared to medically managed controls in meeting the American Diabetes Association composite end point goals for management of type 2 diabetes mellitus.

BACKGROUND: The treatment goals recommended by the American Diabetes Association (ADA) for patients with type 2 diabetes mellitus include hemoglobin A1c (HbA1C) <7.0%, low-density lipoprotein (LDL) <100 mg/dL, and systolic blood pressure (SBP) <130 mmHg. Only 10% of conventionally treated patients reach these goals as a composite endpoint. The efficacy of the Roux-en-Y gastric bypass (RYGB) in meeting this composite endpoint has not been reported. METHODS: We compared our database of patients with type 2 diabetes undergoing RYGB to a database of patients with medically managed type 2 diabetes and at least 2 years of follow-up data. RESULTS: Ultimately, 152 RYGB patients were compared to 115 routine medical management (RMM) patients for whom data on the composite endpoint were available over 2 years. The results show significant decrease in body mass index (kilograms per square meter) in the RYGB group compared to the RMM group (P < 0.001). HbA1C, LDL cholesterol, and SBP all significantly improved in the RYGB group (all P ≤ 0.01) and did not demonstrate any significant change in the RMM group. Over 2 years, when evaluating all three endpoints, the RYGB group (10.5% to 38.2%, P < 0.001) demonstrated increased achievement of the ADA goals compared to the RMM group (13.9% to 17.4%, P = 0.47). There was a significant decrease in medication use in the RYGB cohort; however, discontinuation of medications was sometimes inappropriate. CONCLUSIONS: RYGB achieves the ADA composite endpoint more frequently than conventional therapy and with less medication.

Bariatric surgery outcomes in the elderly: an ACS NSQIP study.

INTRODUCTION: Mortality and complications following bariatric surgery occur at acceptable rates, but its safety in the elderly population is unknown. We hypothesized that short-term operative outcomes in bariatric surgery patients ≥65 years would be comparable to younger persons. METHODS: Patients with a body mass index ≥35 kg/m(2) who underwent bariatric surgery in the 2005-2009 American College of Surgeons National Surgical Quality Improvement Program were identified. Controlling for confounders, multivariate regression was used to predict the impact of age on mortality, major events and prolonged length of stay at 30 days. RESULTS: We identified 48,378 patients who underwent bariatric procedures between 2005 and 2009. Multivariate regression analysis demonstrated advancing age trended towards predicting mortality, but was not statistically significant. Additionally, patients ≥65 years did not experience higher risk of major complications for either open or laparoscopic procedures. However, patients age ≥65 years were more likely to experience prolonged length of stay for both open and laparoscopic procedures. CONCLUSION: This multi-hospital study demonstrates older age predicts short-term prolonged length of stay but not major events following bariatric surgery. Older age trends toward predicting mortality, but it is not statistically significant.

Comparative effectiveness of bariatric surgery and nonsurgical therapy in adults with type 2 diabetes mellitus and body mass index <35 kg/m2.

BACKGROUND: Outcomes of bariatric surgery in patients with a body mass index (BMI) <35 kg/m(2) have been an active area of investigation. We examined the comparative effectiveness of Roux-en-Y gastric bypass (RYGB) to routine medical management (nonsurgical controls; NSCs) in achieving appropriate targets defined by the American Diabetes Association for type 2 diabetes mellitus (T2DM) in patients with class I obesity (BMI 30.0-34.9 kg/m(2)) T2DM at 1 year. METHODS: We identified patients undergoing RYGB (N = 17) with both class I obesity and T2DM and compared them to similar NSC (N = 17) treated in the Primary Care Center. Data were collected at baseline and 1 year for systolic blood pressure (SBP), as well as blood levels for low-density lipoprotein (LDL) cholesterol and hemoglobin A1c (HbA1c). RESULTS: After RYGB, BMI decreased from 34.6 ± 0.8 kg/m(2) to 25.8 ± 2.5 kg/m(2) (P < .001) and HbA1c decreased from 8.2 ± 2.0% to 6.1 ± 2.7% (P < .001). The NSC cohort had no significant change in either BMI or HbA1c. SBP and LDL did not significantly change in either group. The RYGB group had a decrease in medication use compared to the NSC group (P < .001). The RYGB group ceased the use of antihypertensive and antihyperlipidemia medications by 1 year despite abnormal values. CONCLUSION: RYGB can be performed in patients with both a BMI <35 kg/m(2) and T2DM with better weight loss, glycemic control, and fewer antihyperglycemic medications than NSC. Inappropriate cessation of medications may partially explain the persistent increase in both SBP and LDL after RYGB.

Management of the metabolic/bariatric surgery patient.

There is currently a global pandemic of obesity and obesity-engendered comorbidities; in particular, certain major chronic metabolic diseases (eg, type 2 diabetes) which markedly reduce life expectancy and quality of life. This review is predicated on the fact that management of the obese patient is a primary concern of all physicians and health care providers, and that metabolic/bariatric surgery is a highly successful therapeutic option for this disease.

Transdiaphragmatic adrenalectomy for metastatic cervical adenocarcinoma: a technical case report.

We present a 60-year old woman with recurrent cervical adenocarcinoma who presented with metastasis to both lungs and to her right adrenal gland. A thoracotomy was performed for resection of her pulmonary metastasis and then the right adrenal gland was excised through a trans-diaphragmatic approach. The adrenal gland resection was more complex due to involvement of the tumor with the inferior vena cava (IVC) which was repaired with a PTFE patch graft. This case demonstrates both an interesting approach to surgical resection of multiple metastases as well as a safe, although more challenging, alternative to partially resect and repair the IVC.

Obesity, insulin resistance and hepatic perfusion.

Insulin resistance brings together the collection of hyperglycemia, hyperinsulinemia, and dyslipidemia associated with pathologies such as obesity and type 2 diabetes. As such, it is an important target for the prevention of complications linked with these pathologies. To the extent that insulin resistance involves hyperglycemia and dyslipidemia, there are obvious associations between impaired insulin signaling and microvascular dysfunction. In fact, there is evidence that insulin resistance significantly participates in the microvascular damage that occurs with obesity and type 2 diabetes. Since the liver plays a critical role in glucose homeostasis and lipid metabolism, and the state of the microcirculation reflects its function, the impact of insulin resistance on hepatic microvascular perfusion deficits is important. However, as of yet, no single body of work has addressed the relationships that exist between insulin resistance and the derangements in hepatic microvascular perfusion. Although there is distinct hepatic microvascular dysfunction associated with insulin resistance, a controversy still arises as to whether this dysfunction occurs as a result of reductions to the sinusoidal lumen. Nonetheless, the literature appears to agree that the general effects of obesity and insulin resistance on the hepatic microcirculation are linked to the selective impairment of phosphatidylinositol 3'-kinase signaling, as well as the presence of swollen fatty hepatocytes and sinusoidal "capillarization." This manuscript sets out to review the main aspects of hepatic glucose homeostasis and lipid metabolism, as well as the cellular and molecular mediators regulating hepatic microvascular perfusion deficits during obesity and insulin resistance.

NAD(P)H oxidase contributes to the progression of remote hepatic parenchymal injury and endothelial dysfunction, but not microvascular perfusion deficits.

Oxidative stress occurs in remote liver injury, but the origin of the oxidant generation has yet to be thoroughly delineated. Some reports suggest that the source of the distant oxidative stress originates from the site of initial insult [i.e., xanthine oxidase (XO)]; however, it could also be derived from sources such as phagocytic and/or vascular NAD(P)H oxidase (Nox) enzymes. With a murine model of bilateral hindlimb ischemia-reperfusion, we describe here a mechanism for Nox-dependent oxidant production that contributes, at least in part, to remote hepatic parenchymal injury and sinusoidal endothelial cell (SEC) dysfunction. To determine whether Nox enzymes were the source of oxidants, mice were treated immediately after the onset of hindlimb ischemia with specific inhibitors to XO (50 mg/kg ip allopurinol) or Nox (10 mg/kg ip gp91ds-tat and 3 mg/kg ip apocynin). After 1 h of ischemia, hindlimbs were reperfused for either 3 or 6 h. Inhibition of XO failed to provide any improvement in parenchymal injury, SEC dysfunction, neutrophil accumulation, or microvascular dysfunction. In contrast, the inhibition of Nox enzymes prevented the progression (6 h) of parenchymal injury, significantly protected against SEC dysfunction, and completely prevented signs of neutrophil-derived oxidant stress. At the same time, however, inhibition of Nox failed to protect against the early parenchymal injury and microvascular dysfunction at 3 h of reperfusion. These data confirm that microvascular perfusion deficits are not essential for the pathogenesis of remote hepatic parenchymal injury. The data also suggest that Nox enzymes, not XO, are involved in the progression of compromised hepatic parenchymal and endothelial integrity during a systemic inflammatory response.

Cobalt protoporphyrin protects against hepatic parenchymal injury and microvascular dysfunction during experimental rhabdomyolysis.

Although heme is necessary in many life-sustaining functions, its overwhelming systemic release with rhabdomyolysis (RM) is believed to be the cause of subsequent organ injury and dysfunction. We investigated the acute effects of experimental RM on hepatic parenchymal viability and microvascular function in vivo, while also determining the impact of cobalt protoporphyrin (CoPP) on its outcome. With a murine model of RM induced by hind limb glycerol administration (11.5 microL/g, i.m.), we show that plasma heme is elevated as early as 30 min after hind limb glycerol. However, significant hepatic heme accumulation did not occur until 3 h later, with a return to basal levels by 6 h. Using in vivo digital microscopy, hepatic parenchymal viability and microvascular function were found to be significantly compromised by 3 h of RM. Moreover, this response included the upregulation of hepatic heme oxygenase protein expression and activity. The administration of CoPP (5 mg/kg, i.p.) protected hepatic parenchymal and microvascular integrity in the face of the RM insult. This hepatoprotection appears to involve the rapid degradation of heme by heme oxygenase, with subsequent alterations in hepatic microvascular resistance and heme accumulation. The evidence from this investigation suggests that RM mediates a detrimental response in the hepatic parenchyma and microcirculation, and that these responses can be mediated by the rapid degradation of hepatic heme via CoPP-induced heme oxygenase activity.

Generation and functional significance of CXC chemokines for neutrophil-induced liver injury during endotoxemia.

The hypothesis that the neutrophil chemoattractant CXC chemokines KC and macrophage inflammatory protein-2 (MIP-2) are involved in neutrophil transmigration and liver injury was tested in C3Heb/FeJ mice treated with galactosamine (Gal, 700 mg/kg), endotoxin (ET, 100 microg/kg), or Gal + ET (Gal/ET). Hepatic KC and MIP-2 mRNA levels and plasma CXC chemokine concentrations were dramatically increased 1.5 h after Gal/ET or ET alone and gradually declined up to 7 h. Murine recombinant cytokines (TNF-alpha, IL-1 alpha, and IL-1 beta), but not Gal/ET, induced CXC chemokine formation in the ET-resistant C3H/HeJ strain. To assess the functional importance of KC and MIP-2, C3Heb/FeJ mice were treated with Gal/ET and control IgG or a combination of anti-KC and anti-MIP-2 antibodies. Anti-CXC chemokine antibodies did not attenuate hepatocellular apoptosis, sinusoidal neutrophil sequestration and extravasation, or liver injury at 7 h. Furthermore, there was no difference in liver injury between BALB/cJ wild-type and CXC receptor-2 gene knockout (CXCR2-/-) mice treated with Gal/ET. The higher neutrophil count in livers of CXCR2-/- than in wild-type mice after Gal/ET was caused by the elevated number of neutrophils located in sinusoids of untreated CXCR2-/- animals. The pancaspase inhibitor Z-Val-Ala-Asp-fluoromethylketone eliminated Gal/ET-induced apoptosis and neutrophil extravasation and injury but not CXC chemokine formation. Thus Gal/ET induced massive, cytokine-dependent CXC chemokine formation in the liver. However, neutrophil extravasation and injury occurred in response to apoptotic cell injury at 6-7 h and was independent of CXC chemokine formation.

Heme oxygenase-1 induction in hepatocytes and non-parenchymal cells protects against liver injury during endotoxemia.

INTRODUCTION: Heme oxygenase-1 (HO-1) is a stress response enzyme, which catalyses the breakdown of heme into biliverdin-IX alpha, carbon monoxide and ferrous iron. Under situations of oxidative stress, heat stress, ischemia/reperfusion injury or endotoxemia, HO-1 has been shown to be induced and to elicit a protective effect. The mechanism of how this protective effect is executed is unknown. RESULTS: HO-1 induction with cobalt protoporphorin (Co-PP) dose-dependently protected against apoptotic cell death as well as neutrophil-mediated oncosis in the galactosamine/endotoxin (Gal/ET) shock model. Induction of HO-1 with Co-PP dose-dependently protected against neutrophil-mediated oncosis as indicated by attenuated ALT release and TNF-mediated apoptotic cell death as indicated by reduced caspase-3 activation. HO-1 induction did not attenuate Gal/ET-induced TNF-alpha formation. Furthermore, a similar protective effect with the high dose of Co-PP was observed when animals were treated with Gal/TNF-alpha. CONCLUSIONS: HO-1 induction attenuates apoptosis and neutrophil-mediated oncosis in the Gal/ET shock model. However, the protective effect is not due to the reduction of TNF-alpha release or the attenuation of neutrophil accumulation in the liver sinusoids.