Pancreatic secretory trypsin inhibitor: More than a trypsin inhibitor

Kazal-type serine protease inhibitor is one of the most important and widely distributed protease inhibitor families. Pancreatic secretory trypsin inhibitor (PSTI), also known as serine protease inhibitor Kazal type I(SPINK1), binds rapidly to trypsin, inhibits its activity and is likely to protect the pancreas from prematurely activated trypsinogen. Therefore, it is an important factor in the onset of pancreatitis. Recent studies found that PSTI/SPINK1 is also involved in self-regulation of acinar cell phagocytosis, proliferation and growth of a variety of cell lines. In addition, it takes part in the response to inflammatory factor or injury and is highly related to adult type II citrullinemia.     

Pancreatic secretory trypsin inhibitor in gastrointestinal mucosa and gastric juice.

We studied the distribution of pancreatic secretory trypsin inhibitor (PSTI) in the epithelia of the gastrointestinal tract and determined whether PSTI is secreted into gastric juice. PSTI was measured by a specific radioimmunoassay in biopsy specimens taken from the upper (n = 8) and lower (n = 7) gastrointestinal tract of patients with normal endoscopies. PSTI was present in the stomach, small intestine, and colon. Concentrations (micrograms/g protein) were highest in the stomach, and significantly higher in the antrum (1240, 670-1700, median and range) than in the gastric body (370, 350-570) (p less than 0.01). Concentrations were similar in the duodenum (180, 80-210) and colon (160, 130-360). PSTI determined by immunohistochemistry was present in mucus secreting gastric foveolar cells, duodenal Paneth cells, and colonic non mucus cells. PSTI was present in gastric juice. The median (range) concentration of PSTI in basal gastric juice from 13 patients with duodenal ulcers was 9 (3-21) micrograms/l and did not change during stimulation with pentagastrin. The rate of secretion, however, did increase significantly (p less than 0.05) from 1430 (180-2810) ng/h to 4500 (1250-12,770) ng/h during pentagastrin stimulation. PSTI was labile in acid pepsin but stable in the neutral conditions present in the mucus layer. The presence of pancreatic secretory trypsin inhibitor throughout the gut and its secretion into the lumen suggests a hitherto unrecognised mechanism protecting gastrointestinal epithelia against luminal proteases.     

Pancreatic secretory trypsin inhibitor stimulates the growth of rat pancreatic carcinoma cells

Pancreatic secretory trypsin inhibitor was examined for growth-promoting activity on five cell lines using standard cell culture techniques. One cell line, AR4-2J, derived from a rat pancreatic acinar cell carcinoma, responded with significantly increased incorporation of [3H]thymidine and colony formation. Pancreatic secretory trypsin inhibitor stimulated the incorporation of [3H]thymidine in liquid culture; the maximal increase was 61 +/- 10% above control (P less than 0.001) and was seen at a concentration of 10(-9) mol/L. Using a soft agarose clonogenic assay, pancreatic secretory trypsin inhibitor also consistently stimulated (3 assays) colony formation: the peak activity occurred at a concentration of 10(-10) mol/L which caused a 150 +/- 55% (mean +/- SE, P less than 0.05) increase above control. Aprotinin had no effect on the growth of AR4-2J cells and pancreatic secretory trypsin inhibitor did not bind to the epidermal growth factor receptor. AR4-2J cells were shown to produce pancreatic secretory trypsin inhibitor. The study raises the possibility that pancreatic secretory trypsin inhibitor provides autocrine stimulation of tumor cell growth.     

Serum pancreatic secretory trypsin inhibitor in pancreatic diseases

To elucidate the diagnostic significance of serum pancreatic secretory trypsin inhibitor (PSTI) in pancreatic diseases, organ distribution of PSTI and abnormalities in serum PSTI were studied. The pancreas showed the highest content of PSTI, which was five times that of the stomach and almost 40 times that of the other organs. Serum PSTI and amylase were elevated in eight patients with acute pancreatitis, 27 and 11 patients of 47 with chronic pancreatitis, 31 and 13 of 36 with pancreatic cancer, and 67 and 62 of 109 with non-pancreatic disease, respectively. PSTI levels were more sensitive to the presence of pancreatic disease than were amylase levels. The specificities in serum of healthy controls and patients with non-pancreatic disease were similar for PSTI and amylase (69% vs 71%). In chronic pancreatitis and pancreatic cancer patients the efficiency of the PSTI assay was higher (P < 0.02) than the amylase assay (67% vs 63% for pancreatitis and 71% vs 66% for cancer). The sensitivity and efficiency of serum PSTI assay in chronic pancreatic diseases were superior to those of amylase.     

Hyperplasia of Brunner's glands

3 observations of hyperplasias of Brunner's glands are described. Such proliferations are not too frequent. The diagnostics is performed by means of radiology and endoscopy. The clinical symptomatology is multivarious, however, non-characteristic. Intestinal haemorrhages are possible. The therapy can be performed surgically and endoscopically.     

Adenoma of Brunner's glands

Brunner's glands adenomas represent the 10% of the benign duodenal tumours. The most frequent site is the first portion of the duodenum, and they are extremely rare distally to the ampulla of Vater. We present two cases, one of them associated with an adenocarcinoma of the ampulla. This association has not been previously described in the literature. The transformation of an adenoma into an adenocarcinoma has neither been reported. We believe that the term hyperplasia should be used only for diffuse proliferations.     

A radioimmunoassay for rat pancreatic secretory trypsin inhibitor

A radioimmunoassay for the detection of pancreatic secretory trypsin inhibitor (PSTI) in the rat is described. The sensitivity of the assay enables the specific measurement of this inhibitor in the serum of normal rats. The average base-line value for multiple animal serum specimens taken from fasting female Wistar rats being fed conventional diets was 11.6 +/- 6.2 micrograms/l. The inhibitor existed in its free form in serum, and PSTI immunoreactivity increased significantly within 2 h of the induction of experimental pancreatitis. The present assay will facilitate the study of PSTI in experimental diseases of the pancreas.     

Protective effect of human pancreatic secretory trypsin inhibitor on cerulein-induced acute pancreatitis in rats.

We examined the protective effect of human pancreatic secretory trypsin inhibitor (PSTI), a specific trypsin inhibitor secreted from pancreatic acinar cells into the pancreatic duct, on cerulein-induced acute pancreatitis in conscious rats. The protective effect of human PSTI-RS, an analogue of PSTI with Arg-44 to Ser substitution which has a longer half-life in vitro, was also examined. Intraperitoneal administration of a pharmacological dose of cerulein to conscious rats induced acute pancreatitis, characterized by light microscopy as cellular disorganization of the acini and interstitial edema. Intravenous infusion of human PSTI (10, 50 or 250 micrograms/rat/h) into rats with cerulein-induced acute pancreatitis decreased their pancreatic wet weight and plasma amylase concentration. It also caused a dose-dependent decrease in vacuoles in acinar cells and interstitial edema. Human PSTI-RS, which has a longer half-life in vivo, was more effective than native PSTI at the same dose rate (10 micrograms/rat/h) in reducing pancreatitis. These results suggest that human PSTI may have a beneficial effect on acute pancreatitis.     

Pancreatic exocrine secretion in the rat after chronic alcohol ingestion: nonparallel secretion of proteins and pancreatic secretory trypsin inhibitor

Pancreatic secretion was studied in rats given 20% (v/v) ethanol or water ad libitum for 7--8 months. Basal secretion samples were collected for 30 min, after which secretion was stimulated with secretin (1.1 U/h) and cholecystokinin-pancreozymin (2.8 U/h). Then, four successive 30-min samples were collected. The flow rate, protein concentration and output, pancreatic secretory trypsin inhibitor (PSTI) concentration and output, and chymotrypsinogen concentration increased significantly from basal levels during the first stimulation period in both groups, with no significant differences between the groups. During the second, third, and fourth stimulation periods gradual decreases of these parameters were observed in both groups, and the decrease of volume, protein output, and PSTI output were significantly greater in the alcohol group than in the control group. No significant differences were observed in the concentrations of chymotrypsinogen, protein, and PSTI, but the PSTI/protein ratio was significantly lower in the alcohol group at the end of the experiment. The concentrations of bicarbonate did not decrease during stimulation and were elevated in the alcohol group compared with the control group during the fourth period. It is suggested that the decreased PSTI/enzyme ratio caused by long-term alcohol ingestion might favour premature activation of the proenzymes in the pancreatic ducts.     

Isolation of pancreatic trypsin inhibitor from bovine pituitary glands.

A trypsin inhibitor has been isolated from bovine pituitary extracts. From its amino acid composition, NH2-terminal residue, mobility in paper electrophoresis, and behavior in high-performance liquid chromatography and from the tryptic pattern of the performic acid-oxidized material, it appears that the inhibitor is identical to the Kunitz and Northrop pancreatic trypsin inhibitor.     

Immunoreactive pancreatic secretory trypsin inhibitor in normal,inflammatory and neoplastic gallbladders

Operative specimens from normal, inflammatory and neoplastic gallbladders were analyzed for immunoreactive pancreatic secretory trypsin inhibitor (irPSTI) using a peroxidase-antiperoxidase method. In normal and inflammatory gallbladders no irPSTI was demonstrated, while irPSTI was found in neoplastic gallbladders. This study was supported by the Swedish Cancer Society (proj. no. 1300-B90-O5XB). the Medical Faculty of the University of Lund, the Foundation of Malm? General Hospital for Cancer, the Albert Pahlsson Foundation, the Torsten and Ragnar S?derberg Foundation and Agnes and Nils Nilssons Foundation.     

Immunoreactive pancreatic secretory trypsin inhibitor in normal, inflammatory and neoplastic gallbladders

Operative specimens from normal, inflammatory and neoplastic gallbladders were analyzed for immunoreactive pancreatic secretory trypsin inhibitor (irPSTI) using a peroxidase-antiperoxidase method. In normal and inflammatory gallbladders no irPSTI was demonstrated, while irPSTI was found in neoplastic gallbladders.