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PubMed1999

Pathophysiology of gene-targeted mouse models for cystic fibrosis.

Pathophysiology of Gene-Targeted Mouse Models for Cystic Fibrosis. Physiol. Rev. 79, Suppl.: S193-S214, 1999. - Mutations in the gene causing the fatal disease cystic fibrosis (CF) result in abnormal transport of several ions across a number of epithelial tissues. In just 3 years after this gene was cloned, the first CF mouse models were generated. The CF mouse models generated to date have provided a wealth of information on the pathophysiology of the disease in a variety of organs. Heterogeneity of disease in the mouse models is due to the variety of gene-targeting strategies used in the generation of the CF mouse models as well as the diversity of the murine genetic background. This paper reviews the pathophysiology in the tissues and organs (gastrointestinal, airway, hepatobiliary, pancreas, reproductive, and salivary tissue) involved in the disease in the various CF mouse models. Marked similarities to and differences from the human disease have been observed in the various murine models. Some of the CF mouse models accurately reflect the ion-transport abnormalities and disease phenotype seen in human CF patients, especially in gastrointestinal tissue. However, alterations in airway ion transport, which lead to the devastating lung disease in CF patients, appear to be largely absent in the CF mouse models. Reasons for these unexpected findings are discussed. This paper also reviews pharmacotherapeutic and gene therapeutic studies in the various mouse models.

Animals↗
PubMed2002

Genotype-phenotype correlation in cystic fibrosis: the role of modifier genes.

More than 1,000 mutations have been identified in the cystic fibrosis (CF) transmembrane regulator (CFTR) disease gene. The impact of these mutations on the protein and the wide spectrum of CF phenotypes prompted a series of Genotype-Phenotype correlation studies. The CFTR genotype is invariably correlated with pancreatic status-in about 85% of cases with pancreatic insufficiency and in about 15% of cases with pancreatic sufficiency. The correlations between the CFTR genotype and pulmonary, liver, and gastrointestinal expression are debatable. The heterogeneous phenotype in CF patients bearing the same genotype or homozygotes for nonsense mutations implicated environmental and/or genetic factors in the disease. However, the discordant phenotype observed in CF siblings argued against a major role of environmental factors and suggested that genes other than CFTR modulate the CF phenotype. A locus that modulates gastrointestinal expression was identified in mice and subsequently in humans. By analyzing nine CF patients discordant for meconium ileus we were able to show that this locus had a dominant effect. Moreover, in a collaborative study we found a higher rate of polymorphisms in beta-defensin genes 1 and 2 in CF patients and in controls. In another multicenter study mutations in alpha-1 antitrypsin (A1AT) and mannose binding lectin genes were found to be independent risk factors for liver disease in CF patients. The body of evidence available suggests that the variegated CF phenotype results from complex interactions between numerous gene products.

Animals↗
PubMed1990

The age-related incidence of meconium ileus equivalent in a cystic fibrosis population: the impact of high-energy intake.

During the decade from 1976 to 1986, the age-related incidence of meconium ileus equivalent (MIE) was calculated on the basis of 240 Danish cystic fibrosis (CF) patients. In the first 5 years, the patients were given enteric-coated granules of pancreatic enzymes (Pancreatin, Rosco, Denmark), and a low fat diet was recommended. In the last 5 years, the Center recommended supplementation with acid-resistant, enteric-coated, encapsulated microspheres (Pancrease, Cilag, Birkerød, Denmark), and high-energy intake with a 40% fat content and no dietary restrictions. There was no difference in the incidence of MIE when these two 5-year periods were compared, and the overall incidence of MIE was low (5.4 MIEs/1,000 patient years). This may, at least in part, be due to the rather high intake of exocrine pancreas enzyme supplementation (EPES) (a mean intake of 0.9 capsules/kg/day). MIE occurred almost exclusively among patients greater than 15 years old and peaked in young adults aged 20-25 years (35.5 MIEs/1,000 patient years). The daily intake of EPES/kg of body weight declined significantly with age, and the patients who developed MIE received even less than average per day. Both of these points strengthen the view that a low enzyme dosage is likely to have an effect on the incidence of MIE.

Acetylcysteine↗
PubMed1993

A severe phenotype in mice with a duplication of exon 3 in the cystic fibrosis locus.

To develop an animal model for cystic fibrosis (CF), targeted gene disruption in embryonic stem (ES) cells was used to generate a duplication of exon 3 (cftrm1Bay allele) of the mouse CF gene. ES cells containing this mutation were used to generate chimeric animals that transmitted the mutant allele through the germline. Homozygous mutant animals display a severe phenotype, with approximately 40% dying within 1 week from intestinal obstruction. RNAase protection analysis of the cftrm1Bay allele did not detect any normal mRNA (< 1-2% of wild-type) in mutant animals. Pathologic changes in the intestines from mutant mice included mucus accumulation in the crypts and intestinal lumen, dilatation of the bases of the crypts, enlargement of goblet cells, and the presence of concretions in the crypts or between the villi. Changes were also present in the mucosal glands of the pharynx and the minor sublingual glands, where dilatation of acini and accumulation of eosinophilic material were evident. Atrophy of acinar cells that may be secondary to nutritional deficiency and mild inflammation in the main pancreatic duct were present in the pancreas of mutant animals. No changes were noted in the lung, trachea, liver, or male reproductive tract of mutant animals, and mutant males were fertile. Homozygous mutant mice showed defects in cAMP-mediated ion transport both in ileum and in cultured fetal tracheal explants. Thus, an additional mouse model for CF has been generated that should prove useful for the understanding of the pathogenesis and the development of treatments for CF.

Alleles↗
PubMed2006

Genetic issues in pediatric pancreatitis.

The number of hospitalizations in children with acute and chronic pancreatitis is increasing and accounts for significant morbidity. Acute pancreatitis is a reversible event involving diffuse inflammation of the pancreas with variable involvement of other regional tissues, remote organs, or both, whereas chronic pancreatitis is a process that produces irreversible changes in the pancreatic structure and function. Mutations in the gene encoding cationic trypsinogen have recently been identified to be associated with hereditary pancreatitis. Genetic mutations in the pancreatic secretory trypsin inhibitor and the cystic fibrosis transmembrane conductance regulator have been described to play a role in the development of pancreatitis as well. Mutations in the cytokine target genes relating to regulation of inflammation are likely to be important in determining the severity of pancreatitis. These findings, along with the advances in cell biology, have contributed to a better understanding of the pathophysiology of pancreatic diseases.

Carrier Proteins↗
PubMedDate not supplied

Pancreatitis-associated protein (PAP) in patients with pancreatic cancer.

BACKGROUND: Pancreatitis-associated protein (PAP) is known as a marker for pancreatitis and cystic fibrosis. The aim of our study was to evaluate PAP in patients with pancreatic cancer, to assess its correlation to the extent of the disease and to compare it to CA19-9. PATIENTS AND METHODS: This prospective study comprised 75 individuals. Thirty had pancreatic cancer, 30 were healthy controls and 15 had benign lesions of the pancreas. PAP was determined by enzyme-linked immunosorbent assay. Statistical analysis was by Wilcoxon test and Spearman correlation coefficients. RESULTS: As compared to healthy individuals and using a cut-off of 18 micrograms/l corresponding to a sensitivity of 90%, the specificity of PAP for pancreatic cancer was 82.8%. PAP elevation in cancer patients could not be explained by concomitant pancreatitis (p = 0.649). PAP did not show correlation to tumour size (p = 0.14), T-stages (p = 0.706) or tumour grading (p = 0.105), but was significantly correlated to the overall extent of the disease according to the UICC stages (p = 0.002). No correlation between PAP and CA19-9 was seen. Jaundice was not found to influence PAP values (p = 0.4). CONCLUSION: Elevation of PAP in patients with pancreatic cancer is not merely explainable by concomitant pancreatitis, but seems to be due to increased PAP production by the cancer cells and is also correlated to tumour load as expressed by the UICC stages.

Acute-Phase Proteins↗
PubMed2004

Paraduodenal pancreatitis: a clinico-pathologically distinct entity unifying "cystic dystrophy of heterotopic pancreas", "para-duodenal wall cyst", and "groove pancreatitis".

A distinct form of chronic pancreatitis occurring predominantly in and around the duodenal wall (near the minor papilla) has been reported under various names, including cystic dystrophy of heterotopic pancreas, pancreatic hamartoma of duodenum, para-duodenal wall cyst, myoadenomatosis, and groove pancreatitis. Our experience with these lesions and the review of the literature show that these lesions have the following common characteristics: (1) The duodenal wall contains dilated ducts, some with inspissated secretions, and pseudocystic changes as well as adjacent stromal reactions including hypercellular granulation tissue, foreign-body type giant cell reaction engulfing mucoprotein material, and myofibroblastic proliferation. (2) Brunner's gland hyperplasia is typically present. (3) Dense myoid stromal proliferation, with intervening rounded lobules of pancreatic acinar tissue, creates a histologic picture reminiscent of "myoadenomatosis," "pancreatic hamartoma," or even leiomyoma in some cases. (4) Spillover of fibrosis into the adjacent pancreas and soft tissue occurs, especially in the "groove" area (between the pancreas, common bile duct and duodenum), including the region around the common bile duct. (5) Clinically, these lesions often mimic "pancreas cancer" or periampullary tumors, because of marked scarring as well as the ill-defined borders of the process. Patients with these findings are predominantly males, 40-50 years old, with a history of alcohol abuse. That the process is often centered in the region of minor papilla (and the adjacent pancreas) suggests that an anatomic variation of the ductal system may render this area particularly susceptible to the effects of alcoholic injury, and the myo-adenomatoid and cystic changes on the duodenal wall may in turn represent changes related to a localized recurrent pancreatitis. In conclusion, these clinicopathologic findings characterize a distinctive process that can be referred to as paraduodenal pancreatitis.

Choristoma↗
PubMed2004

No indications for altered essential fatty acid metabolism in two murine models for cystic fibrosis.

A deficiency of essential fatty acids (EFA) is frequently described in cystic fibrosis (CF), but whether this is a primary consequence of altered EFA metabolism or a secondary phenomenon is unclear. It was suggested that defective long-chain polyunsaturated fatty acid (LCPUFA) synthesis contributes to the CF phenotype. To establish whether cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction affects LCPUFA synthesis, we quantified EFA metabolism in cftr-/-CAM and cftr+/+CAM mice. Effects of intestinal phenotype, diet, age, and genetic background on EFA status were evaluated in cftr-/-CAM mice, DeltaF508/DeltaF508 mice, and littermate controls. EFA metabolism was measured by 13C stable isotope methodology in vivo. EFA status was determined by gas chromatography in tissues of cftr-/-CAM mice, DeltaF508/DeltaF508 mice, littermate controls, and C57Bl/6 wild types fed chow or liquid diet. After enteral administration of [13C]EFA, arachidonic acid (AA) and docosahexaenoic acid (DHA) were equally 13C-enriched in cftr-/-CAM and cftr+/+CAM mice, indicating similar EFA elongation/desaturation rates. LA, ALA, AA, and DHA concentrations were equal in pancreas, lung, and jejunum of chow-fed cftr-/-CAM and DeltaF508/DeltaF508 mice and controls. LCPUFA levels were also equal in liquid diet-weaned cftr-/-CAM mice and littermate controls, but consistently higher than in age- and diet-matched C57Bl/6 wild types. We conclude that cftr-/-CAM mice adequately absorb and metabolize EFA, indicating that CFTR dysfunction does not impair LCPUFA synthesis. A membrane EFA imbalance is not inextricably linked to the CF genotype. EFA status in murine CF models is strongly determined by genetic background.

Animals↗
PubMed2003

Genetic polymorphisms in alcoholic pancreatitis.

Chronic, excessive alcohol consumption is clearly associated with acute and chronic pancreatitis. However, both clinical and laboratory studies have demonstrated that alcohol consumption alone does not directly cause pancreatitis. Growing evidence suggests that environmental and possibly genetic cofactors must also be present before the mechanisms protecting the pancreas from pancreatitis are circumvented and pancreatitis develops. The discovery that mutations in the cationic trypsinogen gene (R122H, N29I) predisposed to acute and chronic pancreatitis focused attention on possible genetic predispositions. Mutations in the cationic trypsinogen gene, however, are rarely associated with alcoholic chronic pancreatitis. Mutations in the SPINK1 gene (e.g. N34S) provide a threefold increased risk, and cystic fibrosis transmembrane conductance regulator (CFTR) mutations continue to be investigated. However, the major cofactor associated with alcoholic chronic pancreatitis is yet to be identified.

Acute Disease↗
PubMed1990

[Primary interstitial pancreatitis or dyschylic pancreatitis in children. Apropos of 13 cases].

During a retrospective review of more than 1,000 pediatric pancreas specimens obtained by autopsy or biopsy, 13 cases of primitive interstitial pancreatitis (PIP) were identified. The morphologic diagnosis of PIP is based on the following histological features: presence of abundant, inspissated, PAS-negative intraductal secretions, overdistension and focal rupture of the intrapancreatic ducts, and presence of a focal, extensive inflammatory infiltrate. PIP should be distinguished from cystic fibrosis, necrotizing pancreatitis, and passive secondary interstitial infiltrates associated with extensive retroperitoneal cellulitis caused by septicemia or abdominal surgery. Clinical diagnosis is difficult and was not considered in the ten children under four years of age. In the three children over five, the presence of recurrent abdominal pain with mild ascitis and jaundice led to the correct diagnosis. Pathological findings suggest two possible pathophysiologic hypotheses: lesions may develop proximal to a mechanical malformative obstruction that is, however, only very rarely found, according to a more likely alternative, quantitative and qualitative modifications of pancreatic secretions may occur as a result of severe dehydration or use of drugs (corticosteroids, diuretics), justifying the term "dyschylic pancreatitis" coined by G. Seifert.

Child↗
PubMed1996

Inhibition of human pancreatic proteinases by mucus proteinase inhibitor, eglin c and aprotinin.

The kinetic investigation of the inhibition of human pancreatic trypsin 1, trypsin 2 and chymotrypsin A by mucus proteinase inhibitor, eglin c and aprotinin reveals that (i) the first protein is a potent inhibitor of chymotrypsin A (kass. = 1.4 x 10(6) M-1.s-1, Ki = 71 pM) but forms loose complexes with trypsin 1 (Ki = 0.5 microM) and trypsin 2 (Ki = 18 nM), (ii) eglin c does not inhibit the two trypsins but forms a tight complex with chymotrypsin A (kass. = 3.3 x 10(6) M-1.s-1, Ki < 0.1 nM) and (iii) aprotinin is a potent inhibitor of trypsin 1 (kass. = 1 x 10(6) M-1.s-1, Ki < 0.2 nM) and trypsin 2 (kass. = 2.4 x 10(5) M-1.s-1, Ki < 1 nM) but forms a loose complex with chymotrypsin A (Ki = 0.17 microM). These data, together with those published previously on human pancreatic elastase, suggest that a cocktail of aprotinin + eglin c might be a better intensive-care drug for acute pancreatitis than aprotinin alone, because it will efficiently inhibit all four human pancreatic proteinases. On the other hand, human gastric juice inactivates mucus proteinase inhibitor by pepsin-mediated cleavage. This indicates that the fraction of mucus proteinase inhibitor that reaches the stomach following aerosol delivery to cystic fibrosis patients does not reach the duodenum in an active form and, therefore, does not aggravate the pancreatic insufficiency of these patients.

Amino Acid Sequence↗
PubMed1993

Genetic determinants of airways' colonisation with Pseudomonas aeruginosa in cystic fibrosis.

Exocrine pancreatic insufficiency and lung infection with Pseudomonas aeruginosa are major features of cystic fibrosis (CF). This monogenic disease is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. 267 children and adolescents with CF who were regularly seen at the same centre were assessed for an association of the CFTR mutation genotype with exocrine pancreatic function and the age of onset of chronic colonisation with P aeruginosa. The major mutation delta F508 accounted for 74% of CF alleles; 33 further CFTR mutations had been detected on the CF chromosomes of the study population by June, 1992. With the exception of delta F508/R347P compound heterozygotes, patients of the same mutation genotype were either pancreas insufficient (PI) or pancreas sufficient (PS). The age-specific colonisation rates with P aeruginosa were significantly lower in PS than in PI patients. The missense and splice site mutations that are "mild" CF alleles with respect to exocrine pancreatic function were also "low risk" alleles for the acquisition of P aeruginosa. On the other hand, the proportion of P aeruginosa-positive patients increased most rapidly in the PI delta F508 compound heterozygotes who were carrying a termination mutation in the nucleotide binding fold-encoding exons. Pancreatic status and the risk of chronic airways' colonisation with P aeruginosa are predisposed by the CFTR mutation genotype and can be differentiated by the type and location of the mutations in the CFTR gene.

Adolescent↗
PubMed1994

Developmental expression of mucin genes MUC1 and MUC2.

The mucin gene MUC1, is expressed in a number of human ductal epithelia in vivo including those within the pancreas, mammary gland, kidney and genital ducts. Further it is expressed at a high level in certain tumours and tumour-derived cell lines. MUC2 was initially isolated from a human jejunum cDNA library and is thought to be one of the major intestinal mucin genes, though it is also expressed in the trachea. We have examined the developmental expression of these two mucin genes in human tissues. High level expression of MUC1 has been seen by 12.5 weeks of gestation in the epithelial of the distal respiratory tract and the collecting ducts in the kidney. By 18 weeks MUC1 mRNA is detectable in the colon but pancreatic expression of MUC1 is not seen until late in gestation. MUC2 mRNA is seen by 12 weeks of gestation in the jejunum, ileum and colon, and in large bronchioles of the lung by 18 weeks. The pattern of expression of MUC1 suggests that this mucin may not be involved in early ductal obstruction in the CF pancreas, but both MUC1 and MUC2 may play a role in the development of intestinal disease and MUC1 in early respiratory disease associated with CF.

Cystic Fibrosis↗
PubMed1976

Serum isoamylases in cystic fibrosis.

Salivary and pancreatic isoamylases were determined in the sera of 33 patients with cystic fibrosis (CF) and in 34 CF-parents. Pancreatic serum isoamylase activities were greatly decreased in patients with CF, and only two values from this group fell within the normal range. Salvary isoamylases, however, were markedly increased so that the total serum amylase activities were normal. We interpret the low pancreatic isoamylase levels in serum to reflect reduced exocrine masses in the pancreas of CF-children. In heterozygotes, the mean activity of the pancreatic isoamylase was significantly higher than in the reference group, while salivary isoamylases were within the normal range. Due to a genetic polymorphism pancreatic isoamylase may occur in two main fractions. This variant type of pancreatic isoamylase appeared more frequently in CF-heterozygotes than was expected from a reference group of blood donors.

Adolescent↗
PubMed1998

Pancreatic mucin-producing adenocarcinoma associated with a pancreatic stone: report of a case.

We present an autopsy case of an 83-year-old Japanese man with a mucin-producing adenocarcinoma accompanied by pancreatolithiasis in the head of the pancreas. He suffered from obstructive jaundice and died of disseminated intravascular coagulation. He did not normally drink alcohol and had no history of chronic pancreatitis. The autopsy findings revealed a mucinous cystic tumor, composed of multiple dilatated branches, in the head of the pancreas. Histological examinations showed papillary adenocarcinoma, which scirrhously infiltrated the distal common bile duct with perineural invasion and lymph node involvement. He was thus diagnosed to have mucin-producing branch-type cancer in the head of the pancreas. The main pancreatic duct was dilated, and the residual pancreatic tissue showed moderate fibrosis and parenchymal atrophy. A stone was observed in a dilated branch of the primary lesion. To the best of our knowledge, there have only been five previously reported cases of mucin-producing tumor associated with pancreatolithiasis. Intraductal calcification is a major characteristic of chronic pancreatitis, but it is clinically important not to misdiagnose cancers associated with pancreatolithiasis such as chronic pancreatitis.

Adenocarcinoma, Mucinous↗
PubMed1979

[Meconial peritonitis. Recordings about six observations. Diagnostic and prognostic value of calcifications. Therapeutic given off (author's transl)].

The authors report six cases of meconium peritonitis with intra-abdominal calcifications; surgical intervention was successful in four. In five patients, fibrocystic desease of pancreas was eliminated. Presenting this report, it is their intention to underline the good prognosis of calcifications which generally eliminate the meconium ileus.

Calcinosis↗
PubMed2002

[Uncommon types of chronic pancreatitis].

Alcoholic chronic pancreatitis and obstructive chronic pancreatitis are the most frequent and the better characterized types of pancreatitis. Recent advances in biology and genetics have brought new insights into the understanding of rare forms of chronic pancreatitis such as tropical chronic pancreatitis, hereditary chronic pancreatitis and chronic pancreatitis in cystic fibrosis. Some other rare forms of chronic pancreatitis have been identified: eosinophilic chronic pancreatitis, chronic pancreatitis after radiotherapy or during hypercalcemia, minimal change chronic pancreatitis and chronic pancreatitis associated with gut diseases or connectivitis. Recently, a particular form of non alcoholic chronic pancreatitis with duct destruction has been described often presenting as a pancreatic mass, leading in some cases to surgical resection of the pancreas. New insights into the understanding of chronic pancreatitis lead to new physiopathological concepts, and many arguments suggest that combined factors may lead to chronic inflammatory lesions of the pancreas.

Autoimmune Diseases↗