Howard A. Reber

Interleukin-10 prevents death in lethal necrotizing pancreatitis in mice.

BACKGROUND Cytokines derived from macrophages may play an integral role in the evolution of acute pancreatitis. Interleukin-10 (IL-10), a potent antiinflammatory cytokine, prevents the activation of macrophages and their release of inflammatory cytokines. The aim of this study was to determine whether treatment with IL-10 decreased the severity of experimental acute pancreatitis. METHODS Thirty female Swiss Webster mice were divided into three groups. Acute pancreatitis was induced by using a choline-deficient, 0.5% ethionine supplemented (CDE) diet. Group A (controls) received CDE diet alone. Group B was pretreated with 10,000 units of intraperitoneal IL-10 at the onset of feeding and every 8 hours thereafter. Group C received IL-10 33 hours after beginning the CDE diet and every 8 hours thereafter. One half of the animals in each group was killed at 54 hours; the remaining living animals were killed at 80 hours. Serum amylase levels (units per liter) were determined at 54 and 80 hours. Pancreata were harvested and fixed in formalin. Histologic characteristics were graded on a scale from 0 to 4 (normal to most abnormal) in a blinded fashion by two investigators. RESULTS Serum amylase level and histologic score (edema, inflammation, hemorrhage, and necrosis) were significantly reduced when IL-10 was administered either prophylactically or therapeutically (p < 0.01). At 54 hours all animals were alive. Mortality was reduced at 80 hours in both groups treated with IL-10 compared with those fed the CDE diet alone (p < 0.001). CONCLUSIONS These results suggested that macrophages play an integral role in determining the severity of acute pancreatitis in this animal model. The finding that IL-10 decreased inflammation and prevented death, even when given after acute pancreatitis was established, suggests that it may have potential for clinical use.

Interleukin-10 reduces the systemic inflammatory response in a murine model of intestinal ischemia/reperfusion

BACKGROUND Intestinal ischemia/reperfusion (I/R) is known to increase systemic cytokine levels, as well as to activate neutrophils in distant organs. This study was designed to investigate the effect of interleukin-10 (IL-10) on cytokine release, pulmonary neutrophil accumulation, and histologic changes in a murine model of I/R. METHODS Forty female Swiss-Webster mice were divided into four groups. Group 1 underwent 45 minutes of superior mesenteric artery occlusion followed by 3-hour reperfusion (I/R). Group 2 underwent laparotomy alone (Sham). Group 3 underwent I/R, but was treated with IL-10, 10,000 units IP every 2 hours, starting 1 hour before reperfusion (Pretreatment). Group 4 was treated with an equal dose of IL-10, starting 1 hour after reperfusion (Posttreatment). All animals were killed at 3 hours, standard assays were performed for serum cytokine levels, and lung myeloperoxidase activity and intestinal histology were scored. RESULTS Serum cytokines (TNF-alpha and IL-6), lung myeloperoxidase levels, and histologic score were significantly reduced when IL-10 was administered either before or after reperfusion. CONCLUSIONS IL-10 reduced the severity of local and systemic inflammation in a murine model of intestinal I/R when given before or after reperfusion injury. These observations suggest that IL-10 may exert its effect by blocking cytokine production and distant organ neutrophil accumulation.

Natural History of Intraductal Papillary Mucinous Neoplasms (IPMN): Current Evidence and Implications for Management

Intraductal papillary mucinous neoplasms (IPMNs) show varying degrees of dysplasia throughout the neoplasm that can range from adenoma to invasive carcinoma, with dysplastic changes of borderline neoplasms and carcinoma in situ in between. An understanding of the natural history, and especially the required time to transform into either carcinoma in situ or an invasive adenocarcinoma, is critically important for management policy. This topic serves as the rationale for the present analysis. At the beginning of February 2007, using the key word “IPMN” in PubMed, we initially selected 119 publications using the principal criteria as defined by the WHO classification. We identified 20 appropriate original reports and one consensus paper. Neither randomized control trials (RCT) or systematic reviews of RCTs (level 1 evidence) nor cohort studies or reviews of cohort studies (level 2 evidence) have been published. Only one report fit the criteria for level 3 evidence (case control study). Nineteen papers satisfied criteria for level 4 (cases series) and two for level 5 (expert opinion publication). After additional review and analysis, we considered only six reports to be “cornerstone papers” of merit for the final review. Clues to the natural history of IPMNs can be gained by using several methods to examine the articles: (a) to verify different prognoses between main and side branch duct subtypes; (b) to compare the average age of patients with benign vs. malignant IPMNs; (c) to summarize the findings of nonoperative, observational studies based on follow up by clinical, biochemical, and imaging techniques without operative resection; (d) to determine the prognostic importance of the status of the resection margin; and (e) to follow patients clinically after surgical resection. Although important aspects of the natural history of IPMN are still unknown, the following conclusions can be drawn: (1) Branch-duct IPMNs are less aggressive than main-duct IPMNs. (2) Malignancy is more common in older patients. (3) Malignancy (invasive or carcinoma in situ) is found in about 70% of resected main-duct IPMNs. (4) After resection of noninvasive IPMNs (branch- and main-duct varieties), recurrence is rare (<8%). (5) After resection of invasive IPMN, recurrence occurs in 50–65% of patients.

Prostate stem cell antigen is a putative target for immunotherapy in pancreatic cancer.

The prostate stem cell antigen (PSCA) is a glycosylphosphatidyl-inositol (GPI)-linked cell surface antigen expressed in normal prostate and overexpressed in the majority of prostate cancers and correlates with tumor grade and disease stage. Because PSCA has been described to be up-regulated in pancreatic cancer, the purpose was to evaluate the expression of PSCA in human pancreatic cancer. Furthermore, the therapeutic efficacy of a monoclonal anti-PSCA antibody in an in vivo pancreatic cancer model was determined. Methods: The expression of PSCA in human pancreatic cancer tissues was determined and compared with chronic pancreatitis and normal pancreas by quantitative reverse transcriptase-polymerase chain reaction. Therapeutic efficacy of the monoclonal anti-PSCA antibody 1G8 was examined in Capan-1 pancreatic tumors grown as subcutaneous grafts in athymic nude mice. Results: PSCA was strongly up-regulated in human pancreatic cancer compared with chronic pancreatitis and normal pancreas. In addition, the PSCA protein was expressed on the cell surface of pancreatic cancer cells. Treatment with 1G8 significantly reduced tumor growth initiation in an in vivo pancreatic cancer xenograft model. In addition, antibody treatment of established tumors reduced tumor progression. Conclusions: These results show a potential therapeutic role for anti-PSCA antibodies in the treatment of pancreatic cancer. Furthermore, PSCA might serve as a novel marker in the diagnosis of pancreatic cancer.

Interleukin-10 reduces circulating levels of serum cytokines in experimental pancreatitis

Over the past few years, evidence has accumulated that implicates proinflammatory cytokines as the mediators responsible for the escalation of acute pancreatitis into a multisystem disease. It has been shown that the degree of serum cytokine elevation, particularly the macrophage-derived cytokines interleukin-1, interleukin-6, and tumor necrosis factor-α, correlates with the severity and outcome of acute pancreatitis. Interleukin-10 is an anti-inflammatory cytokine that inhibits cytokine production from the macrophage. The aim of this study was to determine whether interleukin-10 would decrease both the severity of acute pancreatitis and the level of circulating proinflammatory cytokines. Ninety female mice were divided into three equal groups. Group 1 (controls) received intraperitoneal saline solution. Groups 2 and 3 received intraperitoneal cerulein (50 mg/kg/hr) for 7 hours. In addition, group 3 was given 1500 units of intraperitoneal interleukin-10, beginning 1 hour after the induction of acute pancreatitis and every 3 hours thereafter. Animals were killed at 3-hour intervals. Blood samples were pancreatitis and amylase and cytokine determinations (interleukin-1β, interleukin-6, and tumor necrosis factor-α). Pancreate were dissected free and fixed in formalin for blinded histologic scoring. Interleukin-10 reduced the serum levels of interleukin-1β, interleukin-6, tumor necrosis factor-α, and amylase in comparison, to untreated animals with pancreatitis (P<0.05). Pancreatic edema, necrosis, and inflammatory cell infiltrate were also reduced in those animals given interleukin-10 (P<0.05). Histologic score, serum cytokines, and amylase levels are elevated during acute pancreatitis. Interleukin-10 given therapeutically, that is,after the onset of acute pancreatitis, lessened the severity of disease, probably through inhibition of the macrophage. This was associated with a decrease in circulating cytokine levels.

Trophic effects of gastrin on the exocrine pancreas in rats

Abstract In three groups of hypergastrinemic rats with gastrojejunostomy and gastric antrum transplanted to the colon (AT), pancreatic structure and function were studied 2, 6, or 16 weeks postoperatively. Fasting serum gastrin was 658 ± 88 pg/ml in AT animals compared with 87 ± 12 pg/ml in sham-operated controls. Another group of rats prepared with antrectomy and gastrojejunostomy (A) had low serum gastrin concentrations; they were studied 12 weeks postoperatively. Pancreatic juice was collected after iv secretin or CCK and was analyzed for [HCO3−], [Cl−], and protein. Pancreas histology and DNA/RNA per milligram of pancreatic protein was the same in all groups. A twofold increase in [HCO3−] and volume of secretion at 2 weeks in AT animals suggested that gastrin exerted a trophic effect on the ducts. By 6 weeks pancreas weight had increased, probably reflecting acinar growth. By 16 weeks pancreatic secretion was qualitatively similar to the control group, but the pancreas weights were 35% greater and absolute secretory capacities were 50% greater. In the A animals, pancreas weights and protein secretion were unchanged, but HCO3− secretion was impaired. We conclude that chronic endogenous hypergastrinemia produced functionally significant hyperplasia of both the duct and acinar cells.

Endoscopic measurement of pancreatic tissue perfusion in patients with chronic pancreatitis and control patients

BACKGROUND Pancreatic blood flow is diminished in experimental models of acute and chronic pancreatitis. We attempted to develop a safe and reliable technique for its measurement in patients and to examine blood flow in patients with chronic pancreatitis and in control subjects. METHOD Pancreatic blood flow was measured using the hydrogen gas clearance technique and an endoscopically placed platinum ductal electrode. Pancreatic blood flow was measured in 12 patients with chronic pancreatitis diagnosed clinically and radiographically, and in 11 control patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) for non-pancreatic pathology. RESULTS Patients with chronic pancreatitis had a significantly lower pancreatic blood flow compared with control patients (51.5 versus 91.7 mL/min/100 gm, p < 0.01). With secretin stimulation pancreatic blood flow increased in two control patients, whereas this notable rise was not seen in three patients with chronic pancreatitis. CONCLUSIONS Measurement of pancreatic blood flow with an endoscopically placed electrode is relatively safe and simple to perform. The scarring and vascular fibrosis associated histologically with chronic pancreatitis is reflected in lower pancreatic blood flow.

Feline model of chronic obstructive pancreatitis : Effects of acute pancreatic duct decompression on blood flow and interstitial pH

BACKGROUND The mechanism by which duct decompression (DD) relieves pain in patients with chronic pancreatitis (CP) is unknown. CP is associated with increased tissue pressure (IP), low pancreatic microvascular blood flow (PMBF), and interstitial pH (pH(I)). The aims of this study were to examine the effects of acute DD on PMBF, increased IP, and pH(I) in cats with CP. METHODS The main pancreatic duct was partially obstructed. At 6 weeks PMBF (ml/min/100g H2 gas clearance), IP (mmHg needle electrode), and pH(I) (microelectrode) were measured before and after secretin stimulation. The duct was then opened, and the studies were repeated. RESULTS PMBF normally increased with secretin stimulation (118 +/- 20 versus 271 +/- 52, P < 0.05). IP was unaltered, and pH(I) decreased as hydrogen ions produced during bicarbonate secretion were dissipated (7.41 +/- 0.01 versus 7.38 +/- 0.01, P < 0.05). In CP, basal PMBF was lower than normal (51 +/- 6 versus 118 +/- 20, P < 0.05) and decreased with stimulation (51 +/- 3.5 versus 31 +/- 3.5, P < 0.05). Basal pancreatic IP was increased (3.47 +/- 0.7 versus 0.05 +/- 0.3, P < 0.05) and increased further with secretory stimulation (3.47 +/- 0.7 versus 4.41 +/- 0.7, P < 0.05) (a compartment syndrome). The low basal pancreatic pH(I) (7.23 +/- 0.02) did not change with secretin stimulation, since bicarbonate secretion was minimal. DD decreased IP (3.66 +/- 0.5 versus 2.81 +/- 0.5, P < 0.05) and increased PMBF (50 +/- 6 versus 79 +/- 6, P < 0.05) and pH(I) (7.24 +/- 0.02 versus 7.34 +/- 0.02, P < 0.05). The normal increase in PMBF after stimulation was restored (79 +/- 6 versus 218 +/- 54, P < 0.05). pH(I) now increased with stimulation (7.34 +/- 0.002 versus 7.37 +/- 0.002, P < 0.05), perhaps due to the marked hyperaemic response. CONCLUSIONS DD acutely restored basal and stimulated PMBF and IP towards normal. Basal pancreatic pH(I) also improved and reflects the underlying ischaemia.

Stenting does not decompress the pancreatic duct as effectively as surgery in experimental chronic pancreatitis

BACKGROUND In humans with chronic pancreatitis (CP), pancreatic interstitial pressure (IP) is elevated and pancreatic blood flow (PBF) is reduced. The efficacy of surgical decompression (SD) of the pancreatic duct (ie, pancreaticojejunostomy) is believed to be due to its ability to decrease IP and pancreatic vascular resistance (Rp), which increases PBF. Pancreatic duct stenting (STE) also probably reduces IP and Rp, which may explain its efficacy. The purpose of this study was to compare the efficacy of SD with STE. METHODS CP in cats was created by narrowing the main pancreatic duct. Six weeks later, CP and normal pancreata were isolated and perfused ex vivo under basal conditions and after secretin stimulation. In normal and CP glands, IP and perfusion pressure were measured and Rp (U) was calculated. In two additional groups, the pancreatic duct was decompressed, either by stenting or by complete transection of the duct with a longitudinal capsulotomy. RESULTS In CP glands, IP and Rp were increased and secretory output was markedly reduced compared with the normal (0.65 +/- 0.30 mm Hg and 0.46 +/- 0.04 U vs 3.90 +/- 0.80 mm Hg and 1.68 +/- 0.05 U; P < .05). Secretin administration (2 units) increased IP and Rp in CP glands (6.60 +/- 1.10 mm Hg and 2.87 +/- 0.07 U; P < .05), but these values did not chang in normal glands (0.81 +/- 0.20 and 0.53 +/- 0.03 U; NS). STE and SD decreased IP and Rp in CP glands (2.20 +/- 0.20 to 1.0 +/- 0.40 mm Hg and 1.20 +/- 0.015 to 0.90 +/- 0.01 U, respectively; P < .05). Both methods prevented an increase of IP and Rp after secretin administration. IP and Rp decreased to a greater degree following SD, compared with STE (P < .05). CONCLUSIONS Both STE and SD decreased IP and Rp in this experimental model of CP. However, SD was significantly more effective than STE.

The antiinflammatory effect of dopamine in alcoholic hemorrhagic pancreatitis in cats. Studies on the receptors and mechanisms of action.

Hemorrhagic pancreatitis was induced in cats by perfusing pancreatic enzymes through a pancreatic duct after the administration of intragastric ethanol. Dimethyl prostaglandin E2 was administered concurrently. In the first study, dopamines antiinflammatory effect on the pancreas was determined in the presence of haloperidol, propranolol, or both. Next, dopamines effects on blood flow in the normal and inflamed pancreas were compared using a hydrogen gas-clearance technique. In the final study, the effect of dopamine on fluorescein isothiocyanate-labeled dextran leakage from the pancreatic duct to portal venous blood was investigated. It was found that blockade of either dopamine or beta-adrenergic receptors reduced, and blockade of both receptors completely eliminated, the antiinflammatory effect. Dopamine had no effect on pancreatic blood flow in normal cats. In pancreatitis, although dopamine transiently reduced blood flow, after an hour flow had returned to normal. Dopamine reversed the leakage of fluorescein isothiocyanate-labeled dextran from the pancreatic duct caused by ethanol and by ethanol and prostaglandin E2. It was concluded that dopamine ameliorated pancreatitis by reducing pancreatic ductal and/or microvascular permeability rather than by altering pancreatic blood flow. The antiinflammatory effect was mediated by both dopamine and beta-adrenergic receptors.