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PubMed1996

Resuscitation of ischemically damaged pancreas during short-term preservation at 20 degrees C by the two-layer (University of Wisconsin solution/perfluorochemical) method.

We have shown that 24-hr preservation by a two-layer (University of Wisconsin solution [UW]/perfluorochemical [PFC]) cold storage method allows tissue ATP synthesis and makes it possible to resuscitate a canine pancreas subjected to 90 min of warm ischemia. The purpose of this study was to examine whether increasing preservation temperature to 20 degrees C makes it possible to shorten a preservation period for recovery of ischemically damaged pancreas grafts. After 90 min of warm ischemia, canine pancreas grafts were preserved using the two-layer (UW/PFC) method for 1 to 8 hr at 20 degrees C, and then autotransplanted. A K-value of intravenous glucose tolerance test more than 1.0 at 2 weeks after transplantation was considered graft survival. ATP tissue levels were measured by high performance liquid chromatography at the end of preservation. Pancreatic tissue perfusions were measured using an H2 clearance technique after 30 min to 4 hr of reperfusion. Pancreas grafts subjected to 90 min of warm ischemia were not viable (0/5, control group). However, 3- and 5-hr preservations made it possible to recover the ischemically damaged pancreas (3/5 and 5/5, respectively), although 1- and 8-hr preservations were not successful (0/3 and 0/3, respectively). ATP tissue levels in 1-hr-preserved grafts were 2.55 +/- 0.38 mumol/g dry weight and were significantly lower compared with the levels in 5- and 8-hr-preserved grafts, 9.40 +/- 2.09 (P < 0.01) and 7.37 +/- 1.06 (P < 0.01), respectively. On the other hand, pancreatic tissue perfusions in 8-hr-preserved grafts after 2 hr of reperfusion were 28.50 +/- 7.52 ml/100 g/min and were significantly lower than the values in 1- and 5-hr-preserved grafts, 66.0 +/- 11.22 (P < 0.01) and 57.10 +/- 4.40 (P < 0.01), respectively. It was suggested that 1-hr-preservation was not enough to synthesize ATP, which was essential to repair damaged cells, although vascular microcirculation at reperfusion was maintained and 8-hr preservation incurred microcirculatory disturbances, although ATP for repairing damaged cells was synthesized. We conclude that 3- to 5-hr preservation at 20 degrees C by the two-layer (UW/PFC) method accelerates ATP synthesis, which is essential for repairing damaged cells and protects vascular microcirculation. This makes it possible to resuscitate ischemically damaged pancreases faster. This method holds promise for pancreas-kidney transplantation from cardiac arrest donors.

Adenosine↗
PubMed2003

Successful surgical salvage of pancreas allograft.

BACKGROUND: Early and late complications related to the pancreas after simultaneous kidney-pancreas transplantation (SKPT) frequently result in graft loss. The authors describe a surgical rescue technique that allows salvage of the pancreatic graft when surgical complications appear after the transplant. METHODS: Of 158 patients who underwent SKPT, 7 were identified with posttransplant complications that required surgical salvage of the pancreas allograft. The surgical salvage technique consisted of the following: pancreatoduodenectomy with conversion from whole-pancreas transplant with bladder or enteric diversion to segmental graft with duct injection (three cases) and conversion from whole-pancreas transplant with duct injection (four cases). RESULTS: Five of seven pancreas allografts are still functioning, with a mean follow-up of 28 months (range, 6-42 months). CONCLUSION: The described surgical treatment may be useful for surgical salvage of the pancreatic allograft, without major impairment of endocrine function.

Humans↗
PubMed2003

Underutilization of pancreas donors.

BACKGROUND: Transplantation of the pancreas has become the treatment of choice for selected patients with type 1 diabetes mellitus. With the current shortage of cadaver donors and the increasing number of diabetic patients on the transplant waiting list, there is a critical need to optimally use all available pancreas grafts for transplantation. We have therefore explored the use of traditionally "less-than-ideal" pancreas donors, including pediatric (4-10 years), older (>or=45 years), obese (weight >or=200 lb), and non-heart-beating donors and donors with an elevated amylase (75% greater than normal values). METHODS: A total of 620 primary simultaneous pancreas-kidney transplantations were performed at our center. We analyzed the ratio of livers to pancreata transplanted at our center and compared this to the United Network for Organ Sharing database. Using univariate and multivariate analyses, we then assessed the impact of these less-than-ideal donors on patient survival, graft survival, and postsurgical complications after simultaneous pancreas-kidney transplantation. RESULTS: A substantial nationwide underutilization of pancreata from donor procurements is demonstrated in the United Network for Organ Sharing database. By using these less-than-ideal donors, the ratio of liver to pancreata procured can be reduced to 1.25:1. Graft survival was not significantly different in patients receiving transplants from obese, non-heart-beating, pediatric, or hyperamylasemic donors compared with grafts from ideal donors. However, grafts from donors 45 years of age or older had significantly lower 1- and 5-year graft survival rates (76% and 65% vs. 90% and 80%, P=0.006). CONCLUSIONS: This study demonstrates that utilization of pancreas grafts from selected, less-than-ideal donors results in good overall outcomes and could potentially expand the organ donor pool.

Adolescent↗
PubMedDate not supplied

The solution to hyperglucagonemia after pancreas transplantation in inbred rats.

BACKGROUND: We studied the possible role of the diseased host pancreas and site of venous graft drainage in the development of hyperglucagonemia after pancreas transplantation, to identify the crucial steps of the technique capable of eliminating hyperglucagonemia and its possible diabetogenic effect. METHODS: Therefore, we compared 4 groups of inbred rats: (1) heterotopic pancreas transplantation with either systemic (n = 9); or (2) portal (n = 5) venous drainage after prior induction of diabetes with streptozotocin; (3) orthotopic pancreaticoduodenal transplantation with portal venous drainage after prior pancreaticoduodenectomy (n = 7), and (4) sham-operation (Sham; n = 10). The postoperative period was 6 months. RESULTS: Only heterotopic transplantation with systemic venous drainage and loss of glucagon's first pass hepatic extraction, resulted in arterial hyperglucagonemia, whereas the arterial plasma insulin level was only slightly higher in comparison with the other groups. After either type of heterotopic transplantation the glucagon content of host pancreata remained unchanged, whereas the insulin content was approximately 5% of that in the pancreas of Sham rats. The insulin and glucagon contents of all grafts were similar to those of the control pancreas in Sham rats, and the insulin release was sufficient to normalize fasting plasma glucose and lipids after either type of transplantation. CONCLUSION: To remove the diseased host pancreas appears unnecessary, as the hyperglucagonemia and the concomitant slight hyperinsulinemia, capable of preventing glucagon's diabetogenic effects, are due to loss of the first pass hepatic extraction by systemic venous drainage alone. This disadvantage can be eliminated by portal venous graft drainage.

Animals↗
PubMedDate not supplied

Organ procurement in experimental pancreas transplantation with minimal microcirculatory impairment.

BACKGROUND: Ischemia-reperfusion injury has been shown to deteriorate microcirculation in experimental pancreas transplantation. However, minor concern was taken on the impact of organ procurement in this condition. We examined the impact of a standardized technique of organ procurement on microcirculation and apoptosis in experimental pancreas transplantation. METHODS: Male Lewis rats were divided into three groups: sham-operated animals without dissection of the pancreas served as controls (n = 5); animals undergoing nearly total process of organ procurement with the pancreas pedunculated on the aorta and the hepatoduodenal ligament (n = 7), and animals receiving pancreaticoduodenal transplantation. Pancreatic grafts were preserved for 6 h in cold University of Wisconsin solution (n = 7). At 1 and 2 h reperfusion and in time-matched controls, microcirculation was assessed by means of intravital fluorescence microscopy. Tissue samples were obtained after 2 h measurement and DNA breaks of acinar cells were detected by in situ nick end-labeling (TUNEL assay). The apoptotic index (apoptotic cells per high- power fields; hpf) was quantified by microscopic counting of at least 50 hpf. RESULTS: Assessment of functional capillary density (FCD) in animals undergoing subtotal process of organ procurement revealed a slight non-significant decrease at 1 and 2 h compared with controls. In addition, leukocyte sticking to postcapillary venules (LAV) as well as the apoptotic index were found slightly increased after organ procurement compared with controls (p > 0.05). However, after pancreas transplantation the apoptotic index and the LAV were significantly increased and the FCD significantly decreased compared with both groups of non-transplanted animals (p < 0.01). CONCLUSIONS: Our validated technique of organ procurement does not negatively impact microcirculation and apoptosis in experimental pancreas transplantation.

Anastomosis, Surgical↗
PubMed1989

Monitoring of pancreas-graft perfusion by radionuclide and digital subtraction angiography.

The vascularity of a kidney transplant can be evaluated by intravenous radionuclide angiography. A normal functioning transplant should have an isotope histogram with a well-defined peak. Accordingly, a transplanted pancreas may be evaluated in the same way. By intravenous digital subtraction angiography and small amounts of contrast medium, arterial and venous structures can be visualized without catheterization of the arterial system. Five patients had combined kidney and pancreas transplantation. Intravenous angiography with 99mTc-pertechnetate was performed three times a week for the first 5 postoperative wk. Digital subtraction angiography with an intravenous bolus of 80 ml of a low-osmolar nonionic contrast medium (iopamidol) was performed late in the postoperative course or when severe impairment of pancreas-graft perfusion was discovered by radionuclide angiography. One patient had two episodes and three patients one episode of rejection of both kidney and pancreas. Impairment of the pancreas-graft perfusion always preceded or was associated with deterioration of the graft function. In all patients, digital subtraction angiography demonstrated the graft vessels in sufficient detail. No thrombotic complications were observed. We conclude that these two methods can be used for monitoring the kidney and pancreas-graft perfusion. The methods may be of great value, especially in the early postoperative period, when problems with organ function are frequent and early intervention is essential.

Contrast Media↗
PubMed1994

Amelioration of rewarming ischemic injury of the pancreas graft during vascular anastomosis by increasing tissue ATP contents during preservation by the two-layer cold storage method.

Rewarming ischemic injury during vascular anastomosis severely compromises posttransplant pancreas graft survival because the graft has already been subjected to warm and cold ischemia before vascular anastomosis. We examined whether preservation of the pancreas graft by the two-layer method ameliorates rewarming ischemic injury of the graft during vascular anastomosis and also investigated the energy metabolism of the pancreas graft before, during and after rewarming ischemic period. After flushing with cold University of Wisconsin solution (UW), the pancreas grafts were preserved by the two-layer (UW/perfluorochemical [PFC]) method (group 1) or simple cold storage in UW (group 2) for 24-hr and then autotransplanted. In control, the pancreas grafts were flushed out with cold UW and immediately autotransplanted without preservation (group 3). After completion of vascular anastomosis, vascular clamp was not released until 90, 120, or 150 min of rewarming ischemia, including anastomosis time, has elapsed. After 90 min of rewarming ischemia, graft survival rates were 5/5, 100%, 5/5, 100%, and 5/5, 100% in groups 1, 2 and 3, respectively. After 120 min, all the grafts in groups 2 and 3 failed (0/5, 0%, and 0/5, 0%, respectively), however, all the grafts in group 1 survived (5/5, 100%). Even after 150 min, 1 of 3 grafts in group 1 survived (1/3, 33%). After 24 hr preservation, tissue adenosine triphosphate (ATP) and total adenine nucleotides (TAN) levels of the grafts in group 1 were about 2-fold the reference values before harvesting and significantly higher compared with group 2(p < 0.05; p < 0.05). After 120 min of rewarming ischemia, tissue ATP levels in group 1 were 84% of the reference values and significantly higher compared with group 2(p < 0.05). TAN levels of group 1 were also significantly higher compared with group 2(p < 0.05). Two hours after reperfusion, ATP and TAN levels in group 1 were significantly higher than group 2(p < 0.05). There were no remarkable difference between group 1 and group 2 concerning adenosine diphosphate (ADP), adenosine monophosphate (AMP) levels. We conclude that the two-layer (UW/PFC) method ameliorates rewarming ischemic injury of the pancreas graft during vascular anastomosis by increasing tissue ATP concentration and TAN levels during preservation and maintaining tissue ATP and TAN levels during vascular anastomosis. Consequently, ATP levels are rapidly recovered after reperfusion and the graft survives.

Adenosine Triphosphate↗
PubMed1995

The mechanism of action of the two-layer cold storage method in canine pancreas preservation--protection of pancreatic microvascular endothelium.

We have demonstrated that oxygenation of a pancreas during preservation by a two-layer method leads continued ATP production to maintain cellular integrity and produces an extended period of preserved pancreatic viability. The aim of this study is to examine the effect of ATP vs. oxygenation per se on viability of nonparenchymal cell (vascular endothelium), using 2.4 dinitrophenol, an uncoupler of mitochondrial oxidative phosphorylation. Mongrel dogs of both sexes, weighing 12-18kg were used. Under general anesthesia, a left lobectomy of the pancreas was performed. The segmental pancreas graft was autotransplanted immediately (group 1; control) or after 48-hour preservation (group 2; simple cold storage method with Euro-Collins' solution [EC], group 3; two-layer cold storage method using EC, group 4; two-layer cold storage method using EC with 0.2 mM DNP), and the remainder of the pancreas was excised at the time of autotransplantation. Graft viability was judged from graft survival after transplantation. A K-value of intravenous glucose tolerance test more than 1.0 at 2 weeks after transplantation was considered graft survival. Tissue concentration of ATP was determined after preservation using high-performance liquid chromatography. Viability of vascular endothelium was examined using trypan-blue perfusion/fixation test after preservation. Nuclear staining by trypan blue in eosin-counterstaining sections was indicative of loss of cell viability. Pancreatic tissue perfusions, which reflect pancreatic microcirculation, were also measured using H2 clearance technique after 30 to 240 min of reperfusion. Graft survival rates in groups 1, 2, 3 and 4 were 5/5, 0/4, 4/4 and 0/3 respectively. ATP tissue concentration was significantly higher in group 3 compared with group 2 (7.91 +/- 1.21 [n = 4] vs. 1.21 +/- 0.31 [n = 4] mumol/g dry weight, p < 0.01). DNP caused a significant decrease in tissue ATP in group 4 (0.61 +/- 0.07 [n = 3] vs. 7.91 +/- 1.21 [n = 4] mumol/g dry weight, p < 0.01). The percentage of nuclear trypan blue uptake of nonparenchymal cells in group 3 was significantly lower than group 2 (11.29 +/- 3.71 [n = 3] vs. 26.41 +/- 1.66 [n = 3] %, p < 0.01), and DNP (group 4) increased trypan blue uptake (30.10 +/- 4.08 [n = 3] vs. 11.29 +/- 3.71 [n = 3] %, p < 0.01). Tissue perfusions after 2hr-reperfusion in group 3 were significantly higher than group 2 (68.64 +/- 8.62 [n = 5] vs. 45.56 +/- 12.84 [n = 5] ml/min/100g, p < 0.01). Moreover, DNP (group 4) caused a significant decrease in pancreatic tissue perfusions (28.84 +/- 9.09 [n = 5] vs. 68.64 +/- 8.62 [n = 5] ml/min/100g. p < 0.001). It was clear that the two-layer method (group 3) protected microvascular endothelium against cold ischemic damage and inhibition of ATP production using DNP (group 4) caused endothelial damage, microcirculatory disturbance after reperfusion and consequently loss of graft viability. We conclude that microvascular endothelium of the pancreas graft is protected against cold ischemic injury by maintaining ATP tissue levels during preservation by the two-layer method. This is one of the mechanisms of action of the two-layer method in successful pancreas preservation.

Adenosine Triphosphate↗
PubMed2003

Duodenal-preserving resection of the head of the pancreas and pancreatic head resection with second-portion duodenectomy for benign lesions, low-grade malignancies, and early carcinoma involving the periampullary region.

HYPOTHESIS: Duodenal-preserving resection of the head of the pancreas (DPRHP) and pancreas head resection with segmental duodenectomy (PHRSD) can be alternatives to standard pancreaticoduodenectomy for benign periampullary lesions. DESIGN: Retrospective analysis of patients requiring surgery for benign and borderline malignant tumors of the periampullary region. SETTING: Tertiary care referral center. PATIENTS: Duodenal-preserving resection of the head of the pancreas (n = 8) and PHRSD (n = 7) were performed in 15 patients with a preoperative diagnosis of benign and borderline malignant tumors of the periampullary region (ie, 11 pancreas head lesions [2 intraductal papillary mucinous tumors, 4 serous cystadenomas, 2 insulinomas, 1 epidermal cyst, 1 metastatic renal cell carcinoma, 1 nonfunctioning islet cell tumor/parapaillary] and 4 duodenal lesions [3 adenomas and 1 adenocarcinoma]). MAIN OUTCOME MEASURES: Surgical factors (operation time and blood loss), postoperative complication, postoperative pancreatic insufficiency (eg, development of diabetes mellitus and steatorrhea or elevated stool elastase values), weight change, and recurrence of disease. RESULTS: No differences were noted in the mean operation time and estimated blood loss between the 2 procedures. Major postoperative complication constituted the following: bile duct stricture (n = 1) in DPRHP and delayed gastric emptying (n = 1) and postoperative bleeding (n = 1) in PHRSD. Newly developed diabetes mellitus occurred in 1 patient. Exocrine pancreatic insufficiency (steatorrhea) was observed in 1 patient after PHRSD. Patients with early duodenal carcinoma and intraductal papillary mucinous tumors with a borderline malignancy are still alive without evidence of recurrence. There was no hospital or long-term mortality. CONCLUSIONS: Duodenal-preserving resection of the head of the pancreas is recommended first for a benign or low-grade, early malignant pancreatic head lesion; PHRSD can be an option for a lesion of the ampullary-parapapillary duodenal area as well as the pancreatic head. Duodenal-preserving resection of the head of the pancreas can be converted to PHRSD if ischemia of the second portion of the duodenum occurs. We found benign periampullary lesions could be conservatively treated with DPRHP and PHRSD, which could substitute for classic pancreaticoduodenectomy.

Adult↗
PubMed1990

Combined kidney and pancreas transplantation. A safe and effective treatment for diabetic nephropathy.

Seventeen patients with type I diabetes and diabetic nephropathy underwent combined kidney and pancreas transplantation. Mean age was 32 +/- 6 years and average duration of diabetes was 21 +/- 6 years. Transplantation was performed through bilateral iliac fossa incisions, and graft duodenocystostomy was used to achieve exocrine pancreas drainage. The actuarial patient and kidney survival rate was 92% and the pancreas survival rate, 88% (follow-up of 3 to 28 months). One patient with functioning grafts died at 10 months owing to a cardiac arrhythmia and one pancreas was "lost" to early thrombosis. Major morbidity was due to pancreas wound infection (53%) that required reoperation, but all patients have had subsequent healing of their wounds. Rehabilitation with return to meaningful activity has been accomplished by 15 patients. This experience demonstrates that combined kidney and pancreas transplantation can be performed safely and successfully.

Adult↗
PubMed1997

Peripheral vascular disease after kidney-pancreas transplantation in diabetic patients with end-stage renal disease.

OBJECTIVE: To determine the long-term effect of a functioning pancreas transplant on peripheral vasculopathy. DESIGN: We compared the progression of peripheral vascular disease in 39 recipients of successful kidney-pancreas transplants (KPT) with 65 consecutive diabetic patients who received cadaver kidney transplants alone (KTA) during the same period in a nonrandomized, retrospective control study. The mean duration of follow-up was more than 4 years in both groups. SETTING: Academic subspecialty referral practice. PATIENTS: A consecutive sample of all KPT recipients with more than 6 months of pancreas allograft function performed between May 1, 1988, and April 30, 1995. All patients who received cadaver renal transplants for diabetic nephropathy during the same period and who maintained a functioning renal allograft for more than 6 months were included as controls. INTERVENTION: Kidney-pancreas transplantation. MAIN OUTCOME MEASURE: Progression of peripheral vascular complications (PVC) defined as any midfoot or limb amputation (AMP), any ischemic ulceration requiring treatment (ULCER), and lower-extremity bypass surgery or angioplasty (LEBP). Ulcers leading to amputation were considered as single events (AMP only). RESULTS: Thirty-five (90%) of 39 KPT recipients are insulin-free. The KTA recipients had more atherosclerotic risk factors, including a higher incidence of coronary artery disease (P = .008), higher serum cholesterol levels (P = .03), and higher triglyceride levels (P = .04) than KPT recipients. Peripheral vascular complications before transplantation were comparable (P = .94) between groups. After transplantation, there were 35 new PVC (9 AMP, 11 ulcers, and 15 LEBP) in 18 of 39 KPT recipients vs 32 PVC (10 AMP, 8 ulcers, and 14 LEBP) in 20 of 65 KTA recipients (P = .005), indicating that KPT recipients had more PVC than did KTA recipients, despite a functioning pancreas. Seven bypass grafts failed after KPT, resulting in 6 limb amputations. In contrast, only 3 limb amputations were performed in 14 patients undergoing lower-extremity bypass procedures after KTA. CONCLUSIONS: Despite fewer risk factors for peripheral vasculopathy and the presence of insulin independence, KPT recipients had a higher incidence of PVC than a cohort of uremic diabetic patients undergoing KTA during the same period. These data show that a functioning pancreas allograft performed with a renal transplantation not only does not alter the progression of peripheral vascular disease in patients with renal failure secondary to diabetic nephropathy but also may accelerate PVC.

Adult↗
PubMed1998

Effect of pancreas transplantation and immunosuppression on proinsulin secretion.

Insulin resistance and increased demand for insulin secretion occur after successful pancreas transplantation. To investigate the potential effects of immunosuppression and pancreas transplantation on fasting beta-cell function, we studied fasting proinsulin and 32,33 split proinsulin secretion cross-sectionally and longitudinally in segmental pancreatic graft recipients (SPx, n = 18); in whole-pancreas graft recipients (WPx, n = 13); in nondiabetic kidney transplant recipients (Kx, n = 14) and in normal subjects (Ns, n = 14). Basal insulin secretion rates were significantly increased in SPx 15.8 (1.7), WPx 24.4 (4.5) and Kx 22.1 (2.1) vs Ns 9.7 (1.6) pmol min(-1) l(-1), p < 0.05, mean (SEM). Total proinsulin, intact proinsulin and 32,33 split proinsulin concentrations were significantly higher in all the transplanted groups than in normal subjects (p < 0.05), whereas the total proinsulin to C-peptide ratio and the 32,33 split proinsulin ratio were higher in SPx than in WPx, Kx and Ns (< 0.05). In the longitudinal study, beta-cell function in terms of proinsulin secretion remained stable for 1 year. In conclusion, fasting glucose homeostasis in pancreas-kidney transplant recipients is obtained at the expense of increased proinsulin secretion and increased insulin secretion rates, primarily induced by immunosuppression. In segmental pancreas graft recipients, increased fasting proinsulin and 32,33 split proinsulin relative to the number of beta-cells transplanted indicate more stress on the residual beta-cell and therefore higher secretory demand than in whole pancreas transplant recipients.

Adult↗
PubMed1998

Localization of expression of human beta defensin-1 in the pancreas and kidney.

Defensins are antimicrobial peptides which play a key role in innate immunity. High levels of human beta defensin-1 (hBD-1) have previously been detected in the kidney and pancreas, but the cell-specific location of hBD-1 mRNA has not been determined. The expression of hBD-1 mRNA has been examined in fetal and adult pancreas and kidney by mRNA in situ hybridization. In fetal pancreas, hBD-1 expression was detected in the developing acini and in adult pancreas in the acini, but not in the pancreatic ducts. In both fetal and adult kidney, hBD-1 expression was detected in the collecting ducts and in the loops of Henle in adult kidney. Expression of hBD-1 mRNA in the pancreas and kidney from early development and in the acini of the adult pancreas, rather than in the pancreatic ducts, may indicate that in these tissues, hBD-1 fulfils physiological functions in addition to host defence.

Adult↗
PubMed1998

Size of pancreas in children and adolescents with type I (insulin-dependent) diabetes.

PURPOSE: The aim of this study was to evaluate the influence of insulin-dependent diabetes mellitus (IDDM) on the size of the pancreas in children. METHODS: Pancreas size was evaluated sonographically in a group of 60 diabetic children and adolescents, aged 3-15 years, and 60 sex- and age-matched healthy controls. RESULTS: A significant reduction in pancreatic area and other parameters was found in diabetic patients particularly in children aged 8-12 and 13-15 years. The pancreas was larger in children 3-7 years old who had had IDDM for 2 years of less (mean size, 8.61 cm2) than in children 8-12 and 13-15 years old who had had IDDM for more than 5 years (mean size, 8.06 and 8.40 cm2, respectively). An inverse correlation between area of the pancreas and duration of IDDM was seen in all age groups (p < 0.05). CONCLUSIONS: Diabetes affects the growth of the pancreas in children with IDDM. Sonography can be used to noninvasively evaluate the influence of the disease on pancreas size.

Adolescent↗
PubMed1993

Detection of the 5-HT1A receptor and 5-HT1A receptor mRNA in the rat bowel and pancreas: comparison with 5-HT1P receptors.

We tested the hypothesis that the rat bowel and pancreas contain 5-HT1A receptors. 3H-8-hydroxy-2-(di-n-propylamino)tetralin (3H-8-OH-DPAT) was used as a radioligand. Binding of 3H-8-OH-DPAT to membranes derived from the myenteric plexus and the pancreas was investigated by rapid filtration. Alternatively, radioautography was employed to locate 3H-8-OH-DPAT binding sites in frozen sections of unfixed bowel or pancreas. An excess of 5-HT (10 microM) was used to define nonspecific binding. Saturable, high affinity binding of 3H-8-OH-DPAT to enteric (Kd = 2.8 +/- 1.1 nM; Bmax = 83.8 +/- 4.3 fmol/mg protein) and pancreatic (Kd = 6.6 +/- 1.3 nM; Bmax = 44 +/- 2.2 fmol/mg protein) membranes was found. The binding of 3H-8-OH-DPAT to enteric and pancreatic membranes was inhibited by 8-OH-DPAT, NAN-190, and spiperone. In contrast, the binding of 3H-8-OH-DPAT to enteric and pancreatic membranes was not inhibited by 5-carboxyamidotryptamine, or by a variety of compounds known to bind to other subtypes of 5-HT receptor. Digoxigenin-labeled oligonucleotides were found to detect mRNA encoding the 5-HT1A receptor in a subset of neurons in myenteric and submucosal ganglia. In contrast, 5-HT1A mRNA was not found in the pancreas. Radioautography revealed that the highest density of 3H-8-OH-DPAT binding sites was found in the stomach. These sites were especially numerous in the lamina propria adjacent to gastric glands, and in myenteric ganglia. Pancreatic 5-HT1A receptors were located on nerves, lymphoid tissue (especially the capsule of nodes), and on cells scattered in the pancreatic parenchyma. The concentration of 3H-8-OH-DPAT binding sites in the rat bowel and pancreas was less than that of 3H-5-HT binding sites; however, the distribution of 3H-8-OH-DPAT binding sites was similar to that of sites that bind 3H-5-HT. It is concluded that the rat gut and its extension in the pancreas contains 5-HT1A receptors. Many, if not all, of the nerve cells and processes that express 5-HT1A receptors express 5-HT1P receptors as well. The function of these receptors in the physiology of the entero-pancreatic innervation remains to be determined.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2005

Ex vivo analysis of acinar and endocrine cell development in the human embryonic pancreas.

In contrast to the considerable body of data on pancreas development in rodents, information on pancreas development in humans is scant. We previously described a model in which mature beta cells developed from human embryonic pancreas: human embryonic pancreas was grafted under the kidney capsule of scid mice, beta cells were then seen to develop in the graft. Here, we showed that not only beta cells, but also other endocrine cells, acinar cells and ducts develop in this model. We then used this model to probe the mechanisms underlying acinar and beta cell development in the human embryonic pancreas. BrdU pulse/chase experiments produced evidence of clonal acinar cell development: the first acinar cells to appear proliferated, thereby expanding the acinar cell population. In contrast, beta cell development was regulated by the proliferation of pancreatic progenitor cells, followed by beta-cell differentiation. We then showed that early progenitors expressing PDX1 proliferated, whereas late endocrine progenitors expressing Ngn3 did not. This proliferative capacity of early endocrine progenitor cells in embryonic human pancreas may hold promise for obtaining human beta-cell expansion.

Animals↗
PubMed1995

Cellular and subcellular localization of transforming growth factor-alpha and epidermal growth factor receptor in normal and diseased human and hamster pancreas.

Four normal pancreas, 8 chronic pancreatitis specimens, and 30 non-endocrine pancreatic tumors from humans and 6 normal and 6 induced pancreatic cancers in hamsters were examined immunohistochemically by antibodies against human transforming growth factor-alpha (TGF-alpha) and epidermal growth factor receptor (EGFR). Two normal pancreas and two pancreatic cancer specimens from each species were also studied immunoelectron microscopically by the immunogold method. In chronic pancreatitis, the reactivity and intensity of the staining with both antibodies were much greater in ductal/ductular cells than in the normal pancreas. All 30 pancreatic cancers reacted with both antibodies with a variable degree of reactivity and staining intensity. No correlation was found between the histological type of tumors, the degree of tumor differentiation, and the incidence and patterns of reactivity of either antibody. Immunoelectron microscopically, both EGFR and TGF-alpha were demonstrated primarily on the basal membrane. In the normal hamster pancreas, TGF-alpha was overexpressed in the alpha-cells but not in any other islet cells. Both TGF-alpha and EGFR were marginally detectable in the exocrine pancreas and in induced pancreatic lesions. This is the first demonstration of subcellular localization of TGF-alpha and EGFR in the normal and diseased human and hamster pancreas.

Adult↗
PubMed1995

Mouse R-cadherin: expression during the organogenesis of pancreas and gastrointestinal tract.

Members of the cadherin protein family of cell adhesion molecules are thought to regulate many morphogenetic events during the development of multicellular organisms. We are interested in which cell-cell interactions cadherins regulate during pancreas morphogenesis. Expression and function of E-cadherin in the pancreas have previously been characterized. Recently, R-cadherin cDNA was isolated and the expression patterns of R- and N-cadherin cDNA was isolated and the expression patterns of R- and N-cadherin mRNAs in the pancreas have been described. In the present study, we have investigated the expression of R-cadherin in the pancreas and gastrointestinal tract using specific anti-R-cadherin antibodies. During early stages of pancreas development (E10.5) R-cadherin is expressed in most hormone-producing cells in addition to in primitive duct-like cells. Later, at E18.5, when islets start to form, R-cadherin is not expressed in intraislet endocrine cells, but is instead found in intraductule endocrine and exocrine cells. In adult islets of Langerhans R-cadherin is absent from endocrine cells, but is present in ductule-like cells. Furthermore, the molecule is expressed in exocrine cells: apically and basolaterally on epithelial duct and ductule cells and apically on acinar cells. Interestingly, there appears to be a correlation between the downregulation of R-cadherin expression in intraductule endocrine cells and the migration out of the duct epithelium to form islets. In the gastrointestinal tract R-cadherin is expressed in the pit region of gastric glands and in absorptive cells of the small intestine. The subcellular localization in these tissues is on both the apical and basolateral surfaces. The potential function of R-cadherin, in particular its role in pancreas development, is discussed.

Animals↗