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PubMed2001

Predicting the severity of acute pancreatitis by rapid measurement of trypsinogen-2 in urine.

BACKGROUND: Early identification of patients at risk of developing a severe attack of acute pancreatitis (AP) is of great importance because rapid therapeutic interventions improve outcome. At a cutoff of 50 microg/L, trypsinogen-2 measured by a rapid urinary dipstick is a sensitive and specific diagnostic test in AP. The trypsinogen-2 concentration correlates with the severity of the disease, and a test with a higher cutoff might therefore be useful for prediction of disease severity. METHODS: We increased the detection limit of the urinary trypsinogen-2 test strip (Actim Pancreatitis) from 50 microg/L to 2000 microg/L and evaluated the prognostic value of this test. The results were compared with those obtained with serum C-reactive protein and the acute physiology and chronic health evaluation II (APACHE II) score. The study population consisted of 150 consecutive patients with AP (42 with severe disease). RESULTS: The sensitivity of the rapid urinary test strip (detection limit, 2000 microg/L) for prediction of severe AP, both on admission and at 24 h, was 62%; specificities were 87% and 85%, respectively, positive predictive values were 65% and 62%, and negative predictive values were 85% and 85%. C-Reactive protein had a sensitivity of only 38% on admission, but at 24 h, it was 83%; specificities were 90% and 70%, respectively, whereas positive predictive values were 59% and 52%, and NPVs were 79% and 91%, respectively. On admission the positive-likelihood ratio for the urinary trypsinogen-2 test strip was 4.8, and at 24 h it was 4.2; for C-reactive protein, the values were 3.7 and 2.7, respectively. CONCLUSIONS: The urinary trypsinogen-2 dipstick is a simple and rapid method for prediction of severe acute pancreatitis.

Acute Disease↗

PubMed2003

Identification of a trypsinogen activity stimulating factor produced by pancreatic cancer cells: its role in tumor invasion and metastasis.

Trypsinogen/trypsin is one of the major serine proteases and is produced by pancreatic acinar cells. Tumor-associated trypsinogen (TAT) has been reported to be produced by several cancer cell lines. The biological roles and activation mechanisms of both TAT and pancreatic acinar trypsinogen (PAT) have not been elucidated in the context of cancer extension, in particular at the stage of invasion and metastasis. In this study, we investigate the roles played by PAT and TAT in pancreatic cancer invasion. In addition, we determined their mechanisms of activation and identified a trypsinogen activity-stimulating factor (TASF) produced by pancreatic cancer cells. TAT expression and high TAT activity were associated with high invasive and liver metastatic potential in SW1990 and CAPAN-2 cells. Moreover, a trypsinogen activating effect and activity prolonging effect was observed in a mixture of these supernatants with trypsinogen. These cells revealed significantly enhanced invasiveness upon invasion assay and in the presence of PAT. TAT and PAT were activated by TASF, active u-PA, produced by pancreatic cancer cells. Activated TAT and PAT can degrade not only ECM proteins but they can also activate other latent proteases. This ECM-protease-network may form a vicious cycle, thereby promoting tumor cell invasion.

Enzyme Activators↗

PubMed1988

[Inhibition of pancreatic secretion by trypsin and trypsinogen].

In dogs, trypsinogen inhibited the secretion of proteases more selectively and for a longer period than trypsin, whereas trypsin reduced tryptic activity of the blood to a lesser extent than trypsinogen. In contrast to trypsinogen, trypsin increased renal excretion of amylase and lipase. The difference between the effects may be due to the action of the trypsinogen hexapeptide formed during its turning into trypsin. Dynamic self-regulation of pancreatic secretion seems to depend on the ratio of trypsin, trypsinogen, its hexapeptide and products of alimentary proteins hydrolysis in duodenal contents.

Amylases↗

PubMed1978

Human cationic trypsinogen. Purification, characterization, and characteristics of autoactivation.

Human pancreatic cationic trypsinogen has been purified to homogenity from an acetone powder of pancreatic tissue. After an initial ion exchange chromatography step on sulfopropyl (SP)-Sephadex at pH 2.6, cationic trypsinogen was separated from the majority of trypsin activity by passage through an affinity column of lima bean trypsin inhibitor-agarose at high ionic strength. The zymogen was then further purified by affinity chromatography on the same material at low ionic strength. Highly purified trypsinogen was resolved from containing chymotrypsinogen by ion exchange chromatography on SP-Sephadex at pH 6.0. The purified zymogen was shown to be homogeneous by polyacrylamide gel electrophoresis at pH 2.1 and at pH 4.3 as well as by discontinuous sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The autoactivation of human trypsinogen was investigated at pH 5.6 and at pH 8.0. The rate of autoactivation of the human zymogen is rapid at pH 5.6 and is maximal in approximately 1 mM Ca2+. These results are in marked contrast to those previously reported for autoactivation of bovine trypsinogen, which is extremely slow at pH 5.6 and which shows a dependence on at least 50 mM Ca2+ for maximum rate of activation (MacDonald, M. R., AND Kunitz, M. (1941) J. Gen. Physiol. 25, 53-73).

Calcium↗

PubMed1996

Molecular cloning and sequence analysis of two cDNAs coding for putative anionic trypsinogens from the colonial Urochordate Botryllus schlosseri (Ascidiacea).

Botryllus schlosseri is a colonial marine invertebrate that belongs to the subphylum Urochordata. Previously we analyzed the activity of a serine protease in this species, and cloned a tunicate chymotrypsin-like molecule. In the present study we further analyzed the protease activity of this animal, and found biochemical evidence also for specific trypsin-like activity. Subsequently we utilized a degenerate polymerase chain reaction (PCR) primer to clone two B. schlosseri cDNAs coding for two different putative trypsinogens, each 243 amino acids long, that differ within the coding region in 42 amino acids and 99 nucleotides. Both clones feature the characteristics of animal anionic trypsinogens. Sequence analysis of the tunicate putative trypsinogens revealed the invertebrate characteristics of three disulfide bridges, and higher similarity to invertebrate than to vertebrate trypsinogens. We therefore propose that the typical characteristics of vertebrate trypsinogens evolved after the divergence of Urochordates and Cephalochordates.

Amino Acid Sequence↗

PubMed2000

Mutations of the cystic fibrosis gene, but not cationic trypsinogen gene, are associated with recurrent or chronic idiopathic pancreatitis.

OBJECTIVE: We investigated whether mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and cationic trypsinogen gene are associated with recurrent acute, or chronic idiopathic pancreatitis. METHODS: Twenty patients with idiopathic pancreatitis (11 women, nine men; mean age, 30 yr) were studied for the presence of a CFTR mutation by screening the genomic DNA for more than 30 mutations and variants in the CFTR gene. Selected mutations of the cationic trypsinogen gene were screened by Afl III restriction digestion or by a mutation-specific polymerase chain reaction (PCR). In each patient exons 1, 2, and 3 of the cationic trypsinogen gene were sequenced. Patients with a CFTR mutation underwent evaluation of further functional electrophysiological test (intestinal current measurement). RESULTS: No mutation of the cationic trypsinogen gene was detected. A CFTR mutation was detected in 6/20 (30.0%) patients. Three patients (15.0%) had a cystic fibrosis (CF) mutation on one chromosome (deltaF508, I336K, Y1092X), which is known to cause phenotypical severe cystic fibrosis. One patient was heterozygous for the 5T allele. In addition, two possibly predisposing CFTR variants (R75Q, 1716G-->A) were detected on four patients, one of these being a compound heterozygous for the missense mutation I336K and R75Q. No other family member (maternal I336K; paternal R75Q; sister I1336K) developed pancreatitis. An intestinal current measurement in rectum samples of patients with a CFTR mutation revealed no CF-typical constellations. CONCLUSIONS: CFTR mutations are associated with recurrent acute, or chronic idiopathic pancreatitis, whereas mutations of the cationic trypsinogen mutation do not appear to be a frequent pathogenetic factor.

Adult↗

PubMed1998

Enhanced GFAP expression in astrocytes of transgenic mice expressing the human brain-specific trypsinogen IV.

We recently identified a cDNA encoding a human brain specific trypsinogen (trypsinogen IV). In order to test whether trypsinogen IV is involved in CNS diseases of, or injury response in, mammalian brain, a mouse model was developed in which the human trypsinogen IV was expressed specifically in neurons. Immunocytochemical analysis of the brains of transgenic mice revealed a striking enhancement of glial fibrillar acidic protein (GFAP) expression in astrocytes. This remarkable astrocytic reaction was detected in the brains of mice as young as 2 months and did not diminish in the older animals we tested. However, we did not find gross evidence for neurodegeneration, nor for reactive microglial cells. The long-term survival of these animals should provide a model with which to study the mechanism of nerve-astroglia interactions. In addition, the possible participation of trypsin IV in the metabolism of the Alzheimer precursor protein (APP) was investigated by immunostaining brains from transgenic mice with beta-amyloid (betaA4) antibodies. Immunocytochemical staining of brains from one year old transgenic mice revealed an intense intracellular betaA4-like signal in neurons.

Amyloid beta-Peptides↗

PubMed2000

Mutation analysis of the cystic fibrosis and cationic trypsinogen genes in patients with alcohol-related pancreatitis.

Cationic trypsinogen and cystic fibrosis mutations have been identified in pancreatitis patients, although no study has looked for mutations in both genes in the same patient. Pancreatitis can be induced by alcohol, although not all alcoholics develop pancreatitis. We hypothesize that this phenomenon is due to a genetic predisposition in persons with alcohol-related pancreatitis. We performed sequence analysis of the cationic trypsinogen-coding region in 46 alcohol-related pancreatitis patients and 16 patients with pancreatitis due to causes other than alcohol. We also screened for 40 cystic fibrosis mutations including the 5T allele. No cationic trypsinogen mutations were identified. Cystic fibrosis mutation screening identified the DeltaF508 mutation in two Caucasian alcoholic patients (P<0.025). The cystic fibrosis mutation carrier frequency in African-American alcoholic patients was 3%, which was not significantly increased compared with the normal carrier frequency. The frequency of the 5T allele was not significantly increased compared with the normal population carrier frequency in either racial group. These results may suggest a role for the cystic fibrosis gene in alcohol-related pancreatitis but indicate that cationic trypsinogen mutations are not a common predisposing risk factor for alcohol-related pancreatitis. A multicenter study is necessary to attain sufficient numbers to come to a conclusion.

Adult↗

PubMedDate not supplied

Pancreatitis in fibrocalculous pancreatic diabetes mellitus is not associated with common mutations in the trypsinogen gene.

BACKGROUND: A distinct type of pancreatitis associated with diabetes, termed fibrocalculous pancreatic diabetes (FCPD), has been reported in tropical developing countries including Bangladesh. The molecular basis for autosomal dominant hereditary pancreatitis (HP) has recently been attributed to mutations in exons 2 and 3 of the trypsinogen gene. We have investigated the hypothesis that mutations in the aforementioned exons of this gene might also predispose to FCPD. METHODS: Seventy Bangladeshi and 50 South Indian unrelated FCPD patients and seven South Indian families with FCPD probands were studied. Pancreatic calcification was confirmed by abdominal X-ray, ultrasound and/or ERCP. Established mutations of exons 2 and 3 of the trypsinogen gene were studied in these subjects by PCR-RFLP analysis and DNA sequencing. RESULTS: The mutations found in hereditary pancreatitis were not observed in this collection of FCPD subjects, and complete DNA sequencing of exons 2 and 3 of the fourth cationic trypsinogen gene also excluded any new mutations. CONCLUSIONS: These results indicate that chronic pancreatitis of FCPD is unlikely to be caused by common mutations in the trypsinogen gene.

Adult↗

PubMed2005

Gene conversion between functional trypsinogen genes PRSS1 and PRSS2 associated with chronic pancreatitis in a six-year-old girl.

Gene conversion--the substitution of genetic material from another gene--is recognized as the underlying cause of a growing number of genetic diseases. While in most cases conversion takes place between a normal gene and its pseudogene, here we report an occurrence of disease-associated gene conversion between two functional genes. Chronic pancreatitis in childhood is frequently associated with mutations of the cationic trypsinogen gene (serine protease 1; PRSS1). We have analyzed PRSS1 in 1106 patients with chronic pancreatitis, and identified a novel conversion event affecting exon 2 and the subsequent intron. The recombination replaced at least 289 nucleotides with the paralogous sequence from the anionic trypsinogen gene (serine protease 2; PRSS2), and resulted in the PRSS1 mutations c.86A > T and c.161A > G, causing the amino acid substitutions N29I and N54S, respectively. Analysis of the recombinant N29I-N54S double mutant cationic trypsinogen revealed increased autocatalytic activation, which was solely due to the N29I mutation. In conclusion, we have demonstrated that gene conversion between two functional paralogous trypsinogen genes can occur and cause genetically determined chronic pancreatitis.

Adolescent↗

PubMed2006

Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis.

Ten years ago, the groundwork for the discovery of the genetic basis of chronic pancreatitis was laid by linkage analyses of large kindreds with autosomal dominant hereditary chronic pancreatitis. Subsequent candidate gene sequencing of the 7q35 chromosome region revealed a strong association of the c.365G > A (p.R122 H) mutation of the PRSS1 gene encoding cationic trypsinogen with hereditary pancreatitis. In the following years, further mutations of this gene were discovered in patients with hereditary or idiopathic chronic pancreatitis. In vitro the mutations increase autocatalytic conversion of trypsinogen to active trypsin and thus probably cause premature, intrapancreatic trypsinogen activation in vivo. The clinical presentation is highly variable, but most affected mutation carriers have relatively mild disease. In this review, we summarize the current knowledge on trypsinogen mutations and their role in pancreatic diseases.

DNA Mutational Analysis↗

PubMed1995

Quantitative assay of trypsinogen by measurement of cleaved activation peptide after activation with enterokinase.

Measurement of trypsinogen by quantitative immunosorbent assay of the highly specific and inert trypsinogen activation peptide following complete activation of trypsinogen by enterokinase offers a simple and sensitive method that provides reliable results over a wide range of trypsinogen concentrations. This method offers a significant advantage in being applicable to complex biological tissues.

Animals↗

PubMed1999

Crystal structure of enteropeptidase light chain complexed with an analog of the trypsinogen activation peptide.

Enteropeptidase is a membrane-bound serine protease that initiates the activation of pancreatic hydrolases by cleaving and activating trypsinogen. The enzyme is remarkably specific and cleaves after lysine residues of peptidyl substrates that resemble trypsinogen activation peptides such as Val-(Asp)4-Lys. To characterize the determinants of substrate specificity, we solved the crystal structure of the bovine enteropeptidase catalytic domain to 2.3 A resolution in complex with the inhibitor Val-(Asp)4-Lys-chloromethane. The catalytic mechanism and contacts with lysine at substrate position P1 are conserved with other trypsin-like serine proteases. However, the aspartyl residues at positions P2-P4 of the inhibitor interact with the enzyme surface mainly through salt bridges with the Nzeta atom of Lys99. Mutation of Lys99 to Ala, or acetylation with acetic anhydride, specifically prevented the cleavage of trypsinogen or Gly-(Asp)4-Lys-beta-naphthylamide and reduced the rate of inhibition by Val-(Asp)4-Lys-chloromethane 22 to 90-fold. For these reactions, Lys99 was calculated to account for 1.8 to 2.5 kcal mol(-1) of the free energy of transition state binding. Thus, a unique basic exosite on the enteropeptidase surface has evolved to facilitate the cleavage of its physiological substrate, trypsinogen.

Amino Acid Sequence↗

PubMed1985

Predictive value of a low serum trypsinogen.

Previous studies, in selected populations, have determined that a low serum trypsinogen can be seen in chronic exocrine pancreatic disorders (CP) and primary diabetes mellitus (DM). In this study, we investigated the predictive value of a low serum trypsinogen. The study population consisted of 488 consecutive emergency room patients admitted to our hospital on whom a serum amylase was drawn by the emergency room staff. Of the sera drawn, 418 were saved and tested for immunoassayable trypsinogen. Ten of 418 (2.4%), had a low level of this marker (less than 10 ng/ml). Of these 10, four had obvious historical or clinical evidence of CP during their initial hospitalization. Six patients, however, had no initial evidence of CP. Follow-up was obtained in three of the six, and all three had evidence of CP despite absence of symptoms. Of the 418 patients, 37 had DM. A low trypsinogen was found in three of these 37, and all three had concomitant CP. We conclude that this new assay has excellent predictive value in diagnosing chronic exocrine pancreatic disorders.

Adult↗

PubMed1995

Cholecystokinin-8 induces edematous pancreatitis in dogs associated with short burst of trypsinogen activation.

To study the early pathogenesis of acute edematous pancreatitis in dogs, we examined the relationship of pancreatic hyperstimulation with cholecystokinin-8 (10 micrograms/kg/hr intravenously for 6 hr) to alterations in circulating pancreatic enzymes and pancreatic morphology with special reference to trypsinogen activation. Cholecystokinin-8 infusion was associated with increases in plasma amylase, lipase, trypsin-like immunoreactivity, and plasma and urine trypsinogen activation peptide. Pancreatic parenchymal swelling and interlobular and subcapsular fluid accumulations were detected ultrasonographically within 2 hr of cholecystokinin-8. Circulating trypsin-like immunoreactivity and trypsinogen activation peptide in urine reached a peak at 2 and 4 hr, respectively, then declined despite progressive increases in circulating amylase and lipase and intrapancreatic fluid. No significant changes were observed in dogs receiving a saline infusion. This study illustrates that cholecystokinin-8 induces edematous pancreatitis in dogs that is associated with a short-lived burst of trypsinogen activation.

Acute Disease↗

PubMed1984

Proteolysis of human trypsinogen 1. Pathogenic implication in chronic pancreatitis.

SDS electrophoresis on polyacrylamide gels of purified trypsinogen 1 has shown the occurrence of a proteolysis in some molecules during long storage at -20 degrees C. This proteolyzed trypsinogen gives a positive reaction with an antiserum directed against the precipitate protein, major protein of about 14 000 molecular weight extracted from precipitates present in the pancreatic juice of patients with chronic pancreatitis. The autoactivation of proteolyzed trypsinogen 1 liberates a polypeptide of 14 000 molecular weight which is immunologically identical to the precipitate protein. These results show that the major protein present in pancreatic precipitates (and pancreatic stones) of patients with chronic pancreatitis is a degradation product of trypsinogen 1 liberated by a proteolysis which necessarily requires a premature zymogen activation in the disease.

Chronic Disease↗

PubMed1991

Characterization of trypsinogens 1 and 2 in two human pancreatic adenocarcinoma cell lines; CFPAC-1 and CAPAN-1.

Proteins with trypsin-like immunoreactivity (first detected by a specific immunoenzymatic assay) were isolated from CAPAN-1 and CFPAC-1 cell culture-conditioned media by chromatography on an immunoadsorbent prepared with a polyclonal antibody directed against trypsin 1. The adsorbed proteins were devoid of free trypsin activity but trypsin activity was present after enterokinase activation demonstrating that the immunoreactive trypsin present in cell supernatants corresponds to trypsinogens. When characterised by Western blotting using a monoclonal antibody directed against human trypsin 1 two protein bands corresponding to trypsinogen 1 (23 kDa) and trypsinogen 2 (25 kDa) gave a positive reaction. These results demonstrate the presence of trypsinogens 1 and 2 in CAPAN-1 and CFPAC-1 cells and in their culture-conditioned media.

Adenocarcinoma↗

PubMed1988

Limited proteolyses in pancreatic chymotrypsinogens and trypsinogens.

In the 1950's, the specific cleavages of the peptide bonds occurring in bovine cationic chymotrypsinogen and trypsinogen were among the first examples of limited proteolyses. According to the split bond(s), the precursor is transformed into enzyme or different forms of zymogen or again into inert protein. The conversion of trypsinogen into trypsin triggers the activations of all the other enzyme precursors of pancreatic juice. In the pancreas, several factors oppose trypsinogen autoactivation, whereas, in the duodenum, all the conditions are favorable for trypsinogen activation by enteropeptidase.

Amino Acid Sequence↗