Factors Associated With Long-Term Weight Loss Following Bariatric Surgery Using 2 Methods for Repeated Measures Analysis.

We used electronic health record data from 162 patients enrolled in the NUgene Project (2002-2013) to determine demographic factors associated with long-term (from 1 to up to 9.5 (mean = 5.6) years) weight loss following Roux-en-Y gastric bypass surgery. Ninety-nine (61.1%) patients self-reported white, and 63 (38.9%) self-reported black, mixed, or missing race. The average percent weight loss was -33.4% (standard deviation, 9.3) at 1 year after surgery and -30.7% (standard deviation, 12.5) at the last follow-up point. We used linear mixed and semiparametric trajectory models to test the association of surgical and demographic factors (height, surgery age, surgery weight, surgery body mass index, marital status, sex, educational level, site, International Classification of Diseases code, Current Procedural Terminology code, Hispanic ethnicity, and self-reported race) with long-term percent weight loss and pattern of weight loss. We found that black, mixed, and missing races (combined) in comparison with white race were associated with a decreased percent weight loss of -4.31% (95% confidence interval: -7.30, -1.32) and were less likely to have higher and sustained percent weight loss (P = 0.04). We also found that less obese patients were less likely to have higher and sustained percent weight loss (P = 0.01). These findings may be helpful to patients in setting expectations after weight loss surgery.

Six month outcomes in patients experiencing weight gain after gastric bypass who underwent gastrojejunal revision using an endoluminal suturing device.

BACKGROUND: Weight gain after Roux-en-Y gastric bypass occurs in approximately 25 % of cases, and this may contribute to recurrence of comorbid conditions. Currently, adequate treatment strategies for this group of patients are limited. Endoscopic narrowing of the gastrojejunal anastomosis may result in a low-risk, minimally invasive treatment alternative compared to standard surgical revision. We assessed short-term outcomes in patients undergoing endoscopic gastrojejunal revisions (EGJR) using an endoluminal suturing device. METHODS: We performed an institutional review board-approved retrospective analysis of 25 consecutive patients who underwent EGJR. Patients preoperatively presented with a dilated gastrojejunal anastomosis of greater than 15 mm and weight gain. An endoluminal suturing device (Overstitch(TM), Apollo Endosurgery, Austin TX) was used to reduce the diameter of the anastomosis. Follow-up occurred at 2 and 6 weeks, 3 and 6 months, and 1 year RESULTS: Prior to EGJR, patients regained an average of 23.4 ± 13.2 kg from their weight loss nadir and had a mean body mass index of 42.2 ± 6.6 kg/m(2). At 6 weeks, 100 % of patients experienced weight loss (average 5.8 ± 4.4 kg; p < .001). At 3 months, 94 % had weight loss (average 7.0 ± 6.2 kg; p < .001). At 6 months, 91 % maintained weight loss (average 5.6 ± 6.2 kg; p = 0.013). Lastly, at 1 year following EGJR, 100 % of available cases maintained weight loss (average 7.5 ± 6.4 kg; p = 0.057). The average percent excess weight loss was 12.5, 15.4, 12.4, and 17.1 % at 6 weeks, 3 and 6 months, and 1 year, respectively. There was a negative time effect in the mixed effect model using both on-treatment and intent-to-treat analyses, illustrating a significant weight reduction over time. The average follow-up per patient was 146 days. There were no complications reported during the follow-up period. CONCLUSIONS: Six month follow-up for EGJR patients demonstrated a low-risk, minimally invasive treatment option to reverse weight gain subsequent to a failed gastric bypass. Procedures presented no complications and may provide an attractive alternative to standard surgical revision.

Severity and mortality of experimental pancreatitis are dependent on interleukin-1 converting enzyme (ICE).

Interleukin-1 beta (IL-1 beta) is produced in large amounts during acute pancreatitis and is believed to play a role in disease progression. Because secretion of IL-1 beta is dependent on intracellular processing of pro-IL-1 beta by IL-1 converting enzyme (ICE), we aimed to determine the efficacy of a novel ICE inactivator (VE-13045) in inhibiting secretion of active IL-1 beta in vivo and if the loss of ICE activity would affect the severity and mortality of experimental pancreatitis. Severe hemorrhagic pancreatitis was induced in adult rats by infusion of bile acid into the pancreatic duct. Animals were randomized to receive VE-13045 or vehicle before induction of pancreatitis. To confirm our findings and to ensure that the results were not model dependent, a second series of experiments was conducted using mice possessing a homozygous knockout of the ICE gene in which lethal pancreatitis was induced by feeding a choline-deficient, ethionine-supplemented diet. The severity of pancreatitis was assessed for both experiments by standard surrogate markers, blind histologic grading, and serum IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) levels. Pancreatic IL-1 beta mRNA induction was assessed by differential RT-PCR. Acute pancreatitis was associated with a 120-fold increase in IL-1 beta mRNA, which was not affected by ICE inhibition or gene deletion. Cytokine processing and secretion were affected, as evidenced by decreased serum levels of IL-1 beta and TNF-alpha (p < 0.001) in all animals with an inactive ICE enzyme. This lack of cytokine production increased survival from 32% to 78% following bile salt pancreatitis (p < 0.01) and from 24% to 80% following diet-induced pancreatitis (p < 0.005). Both ICE-defective groups demonstrated decreased pancreatic necrosis, edema, inflammation, wet weight (all p < 0.05), and amylase and lipase (p < 0.01). In vivo blockade or genetic deletion of ICE inhibits pancreatitis-induced secretion of proinflammatory cytokines without altering IL-1 mRNA production and is associated with decreased pancreatitis severity and dramatic survival benefits.

The physiologic consequences of macrophage pacification during severe acute pancreatitis.

Macrophage overproduction of inflammatory mediators is detrimental in the progression of acute pancreatitis. Although inhibition of inflammatory mediators has been shown to decrease the severity of experimental pancreatitis and improve overall survival, less is known about the mechanism by which blockade produces these benefits. Prior to the induction of lethal acute pancreatitis, rats were randomized to receive a single dose (.01, .1, 1.0, or 10 mg/kg) of a macrophage-pacifying compound (CNI-1493) or vehicle. Escalating doses provided incremental increases in survival from 10% (vehicle) to a maximum of 70% (CNI-1493, 1.0 mg/kg). To evaluate the physiologic mechanism responsible for the improved survival, continuous arterial blood pressure, serial hematocrit, ascites volume, pancreatic edema, bronchoalveolar leukocytes and protein, and pancreatic histology were determined in additional rats receiving CNI-1493 (1.0 mg/kg). Serum tumor necrosis factor-alpha and nitrites were also determined to assess the mechanism of action of CNI-1493. Macrophage pacification decreased pancreatitis severity as determined by enzyme release and pancreatic histology score. Ascites volume and bronchoalveolar protein levels were also decreased, indicating that CNI-1493 prevents the loss of circulating blood volume and maintains hematocrit and mean arterial pressure, thus improving survival. CNI-1493 prevented the increase of serum tumor necrosis factor-alpha but not serum nitrites, implicating macrophage-derived cytokines and not nitric oxide in the pathogenesis of physiologic decompensation and death in this model of pancreatitis.

Evidence for an unknown component of pancreatic ascites that induces adult respiratory distress syndrome through an interleukin-1 and tumor necrosis factor-dependent mechanism.

BACKGROUND: The development of acute respiratory distress syndrome (ARDS) during acute pancreatitis is associated with interleukin (IL)-1 and tumor necrosis factor (TNF) gene expression within the pulmonary parenchyma. Although activated pancreatic enzymes have been thought to mediate pancreatitis-induced ARDS, they are not capable of inducing cytokine production in vitro. We hypothesized that IL-1 and TNF production in the lungs is essential to the development of ARDS and is induced by a mediator released from the inflamed pancreas. METHODS: Pancreatic ascites was obtained from rats after induction of bile-salt pancreatitis, cultured, and assayed for IL-1, TNF, IL-6, IL-8, IL-10, interferon-gamma, and endotoxin. Sterile, cytokine-free ascites or saline (control) was subsequently administered intravenously (20 ml/kg) to healthy rats and to IL-1 R1 or TNF R1 knockout mice. RESULTS: Animals administered intravenous ascites had a 30-fold rise in pulmonary IL-1 and TNF mRNA, as well as increased alveolar leukocytes and protein. Knockout animals devoid of active IL-1 or TNF receptors failed to develop increased alveolar protein or leukocytes. CONCLUSIONS: A component of pancreatic ascites other than activated enzymes, bacteria, or inflammatory cytokines is capable of inducing ARDS in healthy animals. The mechanism appears to be directly attributable to the activity of pulmonary IL-1 and TNF.

Evidence of a central role for p38 map kinase induction of tumor necrosis factor alpha in pancreatitis-associated pulmonary injury.

BACKGROUND: Tumor necrosis factor alpha (TNF alpha) has been implicated as an important mediator in acute pancreatitis-associated adult respiratory distress syndrome, but the precise pathogenesis remains unclear. The purpose of this work was to clarify the role of TNF alpha that is produced within the lung parenchyma in the inducement of pancreatitis-related pulmonary injury and to examine 1 of the potential pathways leading to the production of pulmonary TNF alpha. METHODS: Bile salt pancreatitis was induced in rats (n = 40) that were randomized to receive a p38 mitogen-activated protein (MAP) kinase inhibitor or vehicle. A separate group (n = 16) underwent sham operation. Pulmonary capillary permeability was determined with fluorescein isothiocyanate-labeled albumin and Evans blue dye, and lung histologic analysis was performed. TNF alpha protein was measured in bronchoalveolar lavage fluid, and p38 MAP kinase was activity determined by Western blot analysis. RESULTS: The induction of pancreatitis resulted in increased pulmonary capillary leakage and worsened histologic condition (P < .01 vs sham). Effective inhibition of p38 MAP kinase-induced TNF alpha production completely prevented pancreatitis-associated pulmonary injury (P < .01 vs vehicle). CONCLUSIONS: p38 MAP kinase-induced TNF alpha production plays a central role in the development of pulmonary dysfunction, which accompanies severe acute pancreatitis in this rodent model.

Directed antisense therapy confirms the role of protein kinase C-alpha in the tumorigenicity of pancreatic cancer.

BACKGROUND: The level of expression of the alpha isoform of protein kinase C (PKC-alpha) has been shown to correlate inversely with the pathologic differentiation of human pancreatic cancers. METHODS: We stably transfected a moderately differentiated pancreatic cell line (HPAC) to overexpress PKC-alpha and examined the survival rates compared with parent HPAC according to an orthotopic model. Next we used a PKC-alpha antisense oligonucleotide specifically to down-regulate this isoform in vitro and examine the effect of treatment in vivo again according to the orthotopic model. RESULTS: Animals implanted with the overexpressing cell line had a mortality rate almost twice that of those implanted with the parent cell line (P < .01). Treatment with antisense oligonucleotide in increasing concentrations down-regulated PKC-alpha mRNA by Northern blot analysis and reverse transcriptase-polymerase chain reaction. Animals treated with antisense oligonucleotide after orthotopic implantation of pancreatic cancer cells survived statistically longer than those treated with vehicle alone (P = .005). Treatment with a scrambled oligonucleotide also conferred a survival benefit compared with vehicle alone (P < .01). CONCLUSIONS: Tumorigenicity of pancreatic cancer is related directly to PKC-alpha expression in vivo as demonstrated by decreased survival when overexpressed. PKC-alpha expression can be down-regulated directly (antisense) and indirectly (scrambled) in vitro, which subsequently confers a dramatic survival benefit in vivo.

Pancreatic ascites as a powerful inducer of inflammatory cytokines. The role of known vs unknown factors.

OBJECTIVES: To determine if pancreatic ascites will induce interleukin 1 beta (IL-1 beta) or tumor necrosis factor alpha (TNF-alpha) production outside the pancreas and examine the possible components responsible. DESIGN: Severe pancreatitis was induced in rats (n = 30) by pancreatic duct infusion with 4% glycodeoxycholic acid; pancreatic ascites was collected 18 hours later. In vitro studies used quiescent murine splenic or pulmonary macrophages (10(5)/mL) which were exposed to media alone (control), trypsin, chymotrypsin, cathepsin-B, 20% ascites (vol/vol), 50% ascites, or endotoxin (lipopolysaccharide, 10 micrograms/mL, positive control) for 4 hours. Subsequently, pancreatic ascites was cultured for bacteria and assayed for endotoxin and cytokines (interleukin 1, interleukin 6, interleukin 8, TNF-alpha, or interferon gamma). The experiments were then repeated using 20% and 50% ascites that was sterile and cytokine-free (SCF ascites). In vivo studies used 100% (n = 8) or 50% (n = 12) SCF ascites or normal rat serum (control, n = 12) for a 10-second pulmonary lavage (100 microL) in adult mice, with lungs collected at 6 hours for cytokine gene analysis. SETTING: Surgical basic science research laboratory. MAIN OUTCOME MEASURES: Interleukin 1 beta and TNF-alpha gene induction was assessed by quantitative competitive reverse-transcription polymerase chain reaction and cytokine protein production was determined by enzyme-linked immunosorbent assay. RESULTS: Macrophages responded to untested and SCF ascites in a dose-dependent fashion, with a multifold increase in both IL-1 beta and TNF-alpha messenger RNA (mRNA) and protein, which was often more potent than lipopolysaccharide. Expression of IL-1 beta and TNF-alpha mRNA could not be induced by trypsin, chymotrypsin, or cathepsin-B. All animals undergoing lavage with 100% SCF ascites died within 2 hours, while those undergoing lavage with 50% SCF ascites showed a multifold increase in pulmonary IL-1 beta and TNF-alpha mRNA. CONCLUSIONS: Pancreatic ascites contains factors that are capable of inducing IL-1 beta and TNF-alpha production in vitro and in vivo. This effect cannot be reproduced by activated digestive enzymes and is propagated despite the absence of known inducers of cytokines such as bacteria, endotoxin, or other inflammatory cytokines.

Clostridium difficile toxins influence hepatocyte protein synthesis through the interleukin 1 receptor.

HYPOTHESIS: Clostridium difficile toxins require interleukin 1 (IL-1) production or a functioning IL-1 receptor to elicit acute-phase protein production by murine hepatocytes. DESIGN: Experimental study. SETTING: Research laboratory at the DVA Medical Center, St Louis, Mo. CELLS STUDIED: Hepatocytes prepared from normal mice, from knockout mice deficient in IL-1 production due to loss of IL-1 converting enzyme, or from knockout mice deficient in the IL-1 p80 receptor. INTERVENTIONS: Cells were treated with lipopolysaccharide, a crude C difficile toxin extract, or purified C difficile toxins A or B for 24 hours in vitro, then radiolabeled with (35)S methionine. Newly synthesized acute-phase proteins were identified by electrophoresis and autoradiography. MAIN OUTCOME MEASURES: Synthesis of a 23-kd acute-phase protein in response to the various stimuli. RESULTS: Lipopolysaccharide, C difficile culture extract, and purified toxins A and B stimulated the synthesis of the 23-kd acute-phase protein by hepatocytes from normal mice and by hepatocytes from knockout mice deficient in the IL-1 converting enzyme. However, hepatocytes from knockout mice deficient in the IL-1 p80 receptor failed to produce this acute-phase protein when treated with the C difficile toxins, although they responded fully to lipopolysaccharide. CONCLUSIONS: Stimulation of acute-phase protein synthesis by C difficile toxins does not require IL-1 production, but does require a functioning IL-1 p80 receptor. This suggests that some of the actions of these toxins are mediated by this receptor.

Specific pancreatic enzymes activate macrophages to produce tumor necrosis factor-alpha: role of nuclear factor kappa B and inhibitory kappa B proteins.

The triggering events by which mononuclear cells throughout the body are induced to produce large amounts of cytokines during acute pancreatitis are unclear. However, recent work in our laboratory demonstrated that three specific pancreatic enzymes (elastase, carboxypeptidase A, and lipase) induced dramatic tumor necrosis factor-alpha (TNF-alpha) protein production from macrophages, whereas all others could not. This series of experiments was designed to examine the second messenger system by which this occurs. The rat macrophage cell line NR8383 was incubated for 3 hours with elastase, carboxypeptidase A, lipase, trypsin, or lipopolysaccharide (positive control). Activation of nuclear factor kappa B (NF-kappa B) was demonstrated by electrophoretic mobility shift assay, presence of inhibitory kappa B alpha and beta (I kappa B-alpha and I kappa B-beta) by Western blot analysis, and TNF-alpha protein production by enzyme-linked immunosorbent assay. Elastase, carboxypeptidase A, and lipase induced degradation of I kappa B-beta (but not I kappa B-alpha), activation of NF-kappa B, and production of TNF-alpha protein, whereas inhibition of I kappa B with pyrrolidine dithiocarbamate attenuated this response. Trypsin was unable to elicit any of these responses. Macrophages can be induced by specific activated pancreatic enzymes-elastase, carboxypeptidase A, and lipase-to produce TNF-alpha. This process is dependent on I kappa B-beta degradation and NF- kappa B activation, suggesting that these enzymes trigger this second messenger system through specific membrane-bound receptors.

Cationic liposome-mediated gene transfer during acute pancreatitis: tissue specificity, duration, and effects of acute inflammation.

Production of inflammatory cytokines in the pancreas, lung, and liver is believed to play a major role in the development of severe pancreatitis. This tissue-specific production could lend itself to directed anti-cytokine gene therapy if an appropriate delivery system could be developed. This study was undertaken to examine a novel approach for the delivery of protein-based therapies to the tissues involved during acute pancreatitis. Healthy mice received an intraperitoneal injection of cationic liposomes and a DNA plasmid containing the chloramphenicol acetyltransferase (CAT) reporter gene. Animals were killed at 12 hours and 1, 2, 3, 7, and 14 days with serum, pancreas, lung, and liver harvested. Acute pancreatitis was induced (cerulein, 50 micrograms/kg/hr intraperitoneally x4) in additional mice before or after CAT transfection. The presence of pancreatitis was established in all animals by histologic scoring of pancreata and by serum amylase and lipase levels. CAT transfection efficiency was determined by quantitative CAT enzyme activity within tissue homogenates. Animals that received the liposome were successfully transfected with the CAT gene into the pancreas, lungs, and liver. Maximal transfection in each tissue occurred at 12 hours with decreasing CAT activity over the ensuing 14 days. No healthy animals receiving the CAT gene developed elevations in amylase, lipase, or any histologic parameter of pancreatitis. Transfection efficiency in the pancreas was markedly increased by preexisting or delayed induction of pancreatitis, whereas transfection of the lung and liver was increased to a lesser extent. Gene transfection into the pancreas, liver, and lungs is possible using a cationic liposome delivery system that does not induce pancreatitis or pancreatic inflammation. Pancreatic expression of the gene product is equal to or greater than that of the organs of the reticuloendothelial system and continues at very high efficiency rates during acute pancreatitis.

The potential role of therapeutic cytokine manipulation in acute pancreatitis.

The central, detrimental role of the inflammatory cytokines IL-1 and TNF and the biologically active phospholipid PAF in the pathogenesis of AP has been established over the past 8 years. A number of antagonists to these mediators have been used successfully in the laboratory setting and are currently being examined in prospective randomized trials. The effectiveness of any antagonist depends not only on its ability to block the effects of the inflammatory mediators but also on its administration early enough in the course of the pancreatitis before pancreatic necrosis or organ dysfunction.

Small molecule inhibition of tumor necrosis factor gene processing during acute pancreatitis prevents cytokine cascade progression and attenuates pancreatitis severity.

The morbidity and mortality associated with acute pancreatitis are primarily a result of pancreatic parenchymal necrosis and the development of marked pulmonary dysfunction. Recent evidence suggests that both of these conditions are propagated by interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha, which are produced in large quantities within these organs. Because the generation of these cytokines occurs in a predictable manner early in the development of acute pancreatitis, we aimed to determine whether cytokine gene processing could be inhibited in vivo and what effects this would have on pancreatitis severity. Mild [caerulein, 50 micrograms/kg/hour intraperitoneally (IP) x 4; n = 40] or severe (choline-deficient diet; n = 40) necrotizing pancreatitis was induced in NIH swiss mice. Animals were randomly given a novel small molecule (CNI-1493; 10 mg/kg IP) known to inhibit macrophage production of TNF and IL-1 in vitro by inhibiting translation of TNF mRNA into protein. Control animals received IP vehicle. All animals with acute pancreatitis showed dramatic up-regulation of the IL-1 beta and TNF-alpha genes. Those animals receiving CNI-1493 demonstrated attenuated production of both species of mRNA in pancreatic as well as pulmonary tissue (P < 0.01). Markers of pancreatitis severity such as serum amylase and lipase, as well as pancreatic necrosis, were decreased in animals treated with CNI-1493 (all P < 0.05). Posttranscriptional blockade of TNF production precludes induction of the proinflammatory cytokine cascade that normally occurs during acute pancreatitis. This lack of cytokine gene processing in the pancreas and lungs results in dramatic reductions in tissue damage and pancreatitis severity, which is not model dependent. This is the first time that a small molecule has been shown to influence this disease.

Potential new therapies for the treatment of acute pancreatitis.

The treatment of acute pancreatitis has remained virtually unchanged for the past 50 years, in large part due to a poor understanding of the initial intracellular events. Furthermore, there is a lack of knowledge regarding the mediator(s) responsible for the progression of the disease from local pancreatic inflammation to a systemic inflammatory disease, as well as the mediator(s) responsible for distant organ dysfunction and failure. With recent advances in the pathophysiology of pancreatitis, in particular the role of the inflammatory mediators interleukin-1 beta, tumour necrosis factor alpha and platelet-activating factor, the potential for new effective therapies has been realised. At present, a number of inflammatory mediator antagonists are being tested in humans, with the hope that we may soon develop a specific treatment for a disease, which thus far, has none.

Gene targeting demonstrates additive detrimental effects of interleukin 1 and tumor necrosis factor during pancreatitis.

BACKGROUND & AIMS: During severe pancreatitis, interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha are produced in large quantities. The aim of this study was to determine whether either one plays a more dominant role and if their detrimental effects are additive. METHODS: Necrotizing pancreatitis was induced in transgenic (-/-) knockout mice deficient in either IL-1 type 1 receptors, TNF type 1 receptors, or both IL-1 and TNF type 1 receptors. Wild-type mice served as controls. Mortality was assessed for 10 days. Additional animals were killed on days 0, 1, 2, 3, and 4 for determination of pancreatitis severity. RESULTS: All three knockout groups showed decreased amylase and lipase, histological score, serum IL-6, and mortality compared with wild-type groups. Animals devoid of receptors for both cytokines showed improved survival and decreased IL-6 levels compared with those devoid of either IL-1 or TNF receptors individually, yet they failed to show a further decrease in pancreatitis severity. CONCLUSIONS: Preventing the activity of IL-1beta or TNF-alpha has a nearly identical beneficial effect on the severity and mortality of acute pancreatitis. Preventing the activity of both cytokines concurrently has no additional effect on pancreatitis severity but further attenuates the systemic stress response and is associated with an additional but modest decrease in mortality.

TNF but not IL-1 decreases pancreatic acinar cell survival without affecting exocrine function: a study in the perfused human pancreas.

Substantial quantities of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) are produced within the pancreatic parenchyma during acute pancreatitis. Recent evidence suggests that IL-1 beta and TNF-alpha propagate acute pancreatitis and intensify the resulting pancreatic acinar cell death. This study examines the direct effect of IL-1 beta and TNF-alpha on pancreatic acinar cells. Human pancreata (n = 6), harvested during organ procurement, were perfused ex vivo through the splenic artery using a sterile, oxygenated colloid solution. Each pancreas was perfused with either recombinant human IL-1 beta or TNF-alpha for 2 h and subsequently with the cholecystokinin analogue caerulein (positive control). Venous effluent was collected continuously and amylase and lipase were determined at 15-min intervals. Pancreatic histology was graded at baseline and following cytokine and caerulein perfusion. To examine the long-term effects of these cytokines on acinar cell viability, additional in vitro studies utilized the AR42J acinar cell line which was exposed to either IL-1 beta or TNF-alpha with survival determined daily by MTT assay. Perfusion of the human pancreas with either IL-1 beta or TNF-alpha did not alter amylase, lipase, or histology. Caerulein did induce pancreatitis as measured by increased amylase, lipase, and pancreatic histology. Survival of pancreatic acinar cells decreased when they were incubated with TNF-alpha but not IL-1 beta. Although present in large amounts within the pancreas during acute pancreatitis, IL-1 beta and TNF-alpha have no direct effect on acinar cell viability or exocrine function acutely nor do they induce pancreatitis. When present for more than 24 h, however, TNF-alpha but not IL-1 beta has a dramatic effect on acinar cell survival.

Macrophage pacification reduces rodent pancreatitis-induced hepatocellular injury through down-regulation of hepatic tumor necrosis factor alpha and interleukin-1beta.

Overproduction of tumor necrosis factor (TNF-), interleukin-1beta (IL-1beta), and nitric oxide (NO) is believed to be detrimental during the progression of acute pancreatitis, yet little is known about the hepatic production of these mediators and their role in mediating pancreatitis-induced hepatic dysfunction. Rats were randomized to receive a single intraperitoneal injection of the macrophage-pacifying compound, CNI-1493 (1.0 mg/kg), or vehicle 1 hour before the induction of retrograde bile salt pancreatitis. Sham-operated animals served as controls. Animals were killed 18 hours later, with serum and livers harvested to determine the degree of hepatocellular injury and the induction of TNF-, IL-1beta, and inducible nitric oxide synthase (iNOS). In addition, serum TNF- and nitrites (end-product of NO breakdown) were determined in each group to assess the mechanism of action of CNI-1493. TNF-, IL-1beta, and iNOS gene expression (by reverse-transcription polymerase chain reaction) as well as aspartate transaminase (AST), alanine transaminase (ALT), and lactic dehydrogenase (LDH) (but not alkaline phosphatase [ALP]) increased following the development of pancreatitis (all P < .05). Macrophage pacification significantly prevented the induction of TNF- and IL-1beta mRNA (but not iNOS), resulting in lessened serum AST, ALT, and LDH (all P < .05). Serum TNF- protein and nitrites correlated with gene induction in that both were increased following the onset of pancreatitis, and TNF- protein production was significantly attenuated in animals receiving CNI-1493. Hepatocellular, but not bile duct, injury occurs during experimental pancreatitis that is associated with hepatic TNF-, IL-1beta, and iNOS mRNA gene induction, as well as TNF- protein and nitrite production. Preventing the production of TNF- and IL-1beta by macrophage pacification attenuates the hepatocellular damage, suggesting that these mediators play a role in pancreatitis-induced hepatic injury.