Sung W. Cho

The mobilization and extracellular release of nuclear high mobility group box-1 (HMGB1) by ischemic cells activates inflammatory pathways following liver ischemia/reperfusion (I/R) injury. In immune cells such as macrophages, post-translational modification by acetylation appears to be critical for active HMGB1 release. Hyperacetylation shifts its equilibrium from a predominant nuclear location toward cytosolic accumulation and subsequent release. However, mechanisms governing its release by parenchymal cells such as hepatocytes are unknown. In this study, we found that serum HMGB1 released following liver I/R in vivo is acetylated, and that hepatocytes exposed to oxidative stress in vitro also released acetylated HMGB1. Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups and control the acetylation status of histones and various intracellular proteins. Levels of acetylated HMGB1 increased with a concomitant decrease in total nuclear HDAC activity, suggesting that suppression in HDAC activity contributes to the increase in acetylated HMGB1 release after oxidative stress in hepatocytes. We identified the isoforms HDAC1 and HDAC4 as critical in regulating acetylated HMGB1 release. Activation of HDAC1 was decreased in the nucleus of hepatocytes undergoing oxidative stress. In addition, HDAC1 knockdown with siRNA promoted HMGB1 translocation and release. Furthermore, we demonstrate that HDAC4 is shuttled from the nucleus to cytoplasm in response to oxidative stress, resulting in decreased HDAC activity in the nucleus. Together, these findings suggest that decreased nuclear HDAC1 and HDAC4 activities in hepatocytes following liver I/R is a mechanism that promotes the hyperacetylation and subsequent release of HMGB1. The mobilization and extracellular release of nuclear high mobility group box-1 (HMGB1) by ischemic cells activates inflammatory pathways following liver ischemia/reperfusion (I/R) injury. In immune cells such as macrophages, post-translational modification by acetylation appears to be critical for active HMGB1 release. Hyperacetylation shifts its equilibrium from a predominant nuclear location toward cytosolic accumulation and subsequent release. However, mechanisms governing its release by parenchymal cells such as hepatocytes are unknown. In this study, we found that serum HMGB1 released following liver I/R in vivo is acetylated, and that hepatocytes exposed to oxidative stress in vitro also released acetylated HMGB1. Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups and control the acetylation status of histones and various intracellular proteins. Levels of acetylated HMGB1 increased with a concomitant decrease in total nuclear HDAC activity, suggesting that suppression in HDAC activity contributes to the increase in acetylated HMGB1 release after oxidative stress in hepatocytes. We identified the isoforms HDAC1 and HDAC4 as critical in regulating acetylated HMGB1 release. Activation of HDAC1 was decreased in the nucleus of hepatocytes undergoing oxidative stress. In addition, HDAC1 knockdown with siRNA promoted HMGB1 translocation and release. Furthermore, we demonstrate that HDAC4 is shuttled from the nucleus to cytoplasm in response to oxidative stress, resulting in decreased HDAC activity in the nucleus. Together, these findings suggest that decreased nuclear HDAC1 and HDAC4 activities in hepatocytes following liver I/R is a mechanism that promotes the hyperacetylation and subsequent release of HMGB1.

OBJECTIVES: To compare the outcomes of umbilical hernia repair in patients with and without signs of portal hypertension, such as esophageal varices or ascites; to assess the effect of emergency surgery on complication rates; and to identify predictors of postoperative mortality. DESIGN: Database search from January 1, 2005, through December 31, 2009. SETTING: North American hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program initiative. PATIENTS: We studied patients who underwent umbilical hernia repair. Those with congestive heart failure, disseminated malignant tumor, or chronic renal failure while undergoing dialysis were excluded. MAIN OUTCOME MEASURES: Preoperative variables and perioperative course were analyzed. Main outcome measures were morbidity and mortality after umbilical hernia repair. RESULTS: A total of 390 patients with ascites and/or esophageal varices formed the study group, and the remaining 22 952 patients formed the control group. The overall morbidity and mortality rates for the study group were 13.1% and 5.1%, whereas these rates were 3.9% and 0.1% for the control group, respectively (P < .001). For the study group, the mortality after elective repair among patients with a model for end-stage liver disease (MELD) score greater than 15 was 11.1% compared with 1.3% in patients with a MELD score of 15 or less. The patients with ascites and/or esophageal varices underwent emergency surgery more frequently than the control group (37.7% vs 4.9%; P < .001). Emergency surgery for the study group was associated with a higher morbidity than elective surgery (20.8% vs 8.3%; P < .001) but not a significantly higher mortality (7.4% vs 3.7%; P = .11). However, logistic regression analysis showed that age older than 65 years, MELD score higher than 15, albumin level less than 3.0 g/dL (to convert to grams per liter, multiply by 10), and sepsis at presentation were more predictive of postoperative mortality. CONCLUSIONS: Umbilical hernia repair in the presence of ascites and/or esophageal varices is associated with significant postoperative complication rates. Emergency surgery is associated with higher morbidity rates but not significantly higher mortality rates. Elective repair of umbilical hernia should be avoided for those with adverse predictors, such as age older than 65 years, MELD score higher than 15, and albumin level less than 3.0 g/dL.