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At least 1,207 records · Page 67Linked to original sources
PubMed2006

Primary cilia deletion in pancreatic epithelial cells results in cyst formation and pancreatitis.

BACKGROUND & AIMS: Defects in cilia formation or function have been implicated in several human genetic diseases, including polycystic kidney disease (PKD), Bardet-Biedl syndrome, and primary ciliary dyskinesia. Pancreatic lesions are found in approximately 10% of PKD patients, suggesting a connection between cilia defects and pancreatic pathologies. Here, we investigate the role of cilia in pancreas formation and function by analyzing mice that lack cilia in pancreatic cells. METHODS: Using Cre/lox technology, we conditionally inactivated Kif3a, the gene encoding for a subunit of the kinesin-2 complex that is essential for cilia formation, in pancreatic epithelia. Kif3a mice were studied by immunohistochemical and biochemical methods to assess the morphology and differentiation status of pancreatic cells. RESULTS: Tissue-specific loss of Kif3a in pancreatic cells resulted in severe pancreatic abnormalities including acinar-to-ductal metaplasia, fibrosis, and lipomatosis. Ductal metaplasia appears to be due to expansion of ductal cells rather than transdifferentiation of acinar cells. Cyst formation, aberrant ductal morphology, and extensive fibrosis associated with severe adhesion to adjacent organs were commonly observed in aged Kif3a mutant mice. Deletion of Kif3a using different pancreas-specific Cre strains suggests that these pancreatic phenotypes might be caused by the absence of cilia in ductal cells. Activation of transforming growth factor beta and Mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathways may play a role in these phenotypes. CONCLUSIONS: These results demonstrate that the absence of cilia in pancreatic cells produces pancreatic lesions that resemble those found in patients with chronic pancreatitis or cystic fibrosis.

Animals↗
PubMed1989

The hypervitaminosis-A rat: a model for mucin hypersecretion in cystic fibrosis?

Cystic fibrosis is a devastating disease with pathognomonic features typically displayed in the exocrine system. An obvious drawback with human clinical studies of the disease is the relative inaccessibility of its "target-tissues," i.e., the salivary glands, intestine, pancreas, and tracheobronchial tree. Thus, little is known about its underlying cellular mechanisms. For this reason, physiologically relevant animal models for the disease are vitally needed. At present, there are animal models available for certain salivary gland biochemical aspects of the disease and for bicarbonate ion secretory alterations. However, no adequate model exists for excessive mucus production, an aspect of the disease which sets the stage for life-threatening infections and digestive disorders. This manuscript examines morphological and biochemical changes occurring in various biological systems exposed to high levels of vitamin A and correlates such changes with abnormalities commonly seen in cystic fibrosis.

Animals↗
PubMed1990

Essential fatty acid deficient rats in the study of cystic fibrosis: an X-ray microanalytical and ultrastructural study in chronically reserpinized rats.

Essential fatty acid (EFA) deficiency has been proposed as a major pathogenic mechanism for cystic fibrosis (CF) and EFA-deficient animals have been proposed as an animal model for CF. In the present study, the elemental composition and ultrastructure of the acinar cells of the submandibular and parotid gland of the pancreas of EFA-deficient rats were investigated by X-ray microanalysis and electron microscopy. The effects of EFA-deficiency were compared to changes in these exocrine glands in chronically reserpine-treated rats, an established animal model for CF. EFA-deficiency did not cause any significant changes in the elemental composition of the acinar cells of the submandibular or parotid gland, or of the pancreas. The changes in elemental composition induced by reserpine treatment were only slightly modified by EFA-deficiency, mainly towards normalization. EFA-deficiency resulted in the presence of abnormal, electron translucent, zymogen granules in the parotid gland and in a reduction of the number of zymogen granules in pancreatic acinar cells. Since EFA-deficiency in rats only causes minor changes in structure and elemental composition of salivary glands and pancreas, and does not potentiate the effect of chronic reserpine treatment on these tissues, it is concluded that EFA-deficiency is likely to be of minor importance in the exocrine gland disturbances in CF.

Animals↗
PubMed1996

Regulation of epithelial ion channels by the cystic fibrosis transmembrane conductance regulator.

In most epithelia ion transport is tightly regulated. One major primary target of such regulation is the modulation of ion channels. The present brief review focuses on one specific example of ion channel regulation by the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR functions as a cAMP-regulated Cl- channel. Its defect leads to the variable clinical pictures of cystic fibrosis (CF), which today is understood as a primary defect of epithelial Cl- channels in a variety of tissues such as the respiratory tract, intestine, pancreas, skin, epididymis, fallopian tube, and others. Most recent findings suggest that CFTR also acts as a channel regulator. Three examples are discussed by which CFTR regulates other Cl- channels, K+ channels, and epithelial Na+ channels. From this perspective it is evident that CFTR may play a major role in the integration of cellular function.

Animals↗
PubMed1996

Magnetic resonance imaging for diagnosis of Shwachman's syndrome.

Shwachman's syndrome is a rare disease characterized by the association of chronic diarrhea due to exocrine pancreatic insufficiency, metaphyseal dysostosis, and neutropenia. The diagnosis requires demonstration of lipomatosis, or fatty replacement of the pancreas, which is the typical pathological feature of the disease. Magnetic resonance imaging (MRI) was performed in 13 patients with exocrine pancreatic insufficiency, 7 with Shwachman's syndrome, 2 with Pearson's syndrome, 1 with normal sweat test later diagnosed as cystic fibrosis, and 3 without identified syndrome, and in 7 control children. Ultrasonography in the patients did not differentiate between atrophy and lipomatosis and could not be performed in 3. MRI visualized the pancreas in all. The same image was noted in all patients with Shwachman's syndrome with a normal-sized or enlarged pancreas, a hyperintense signal on T1- and T2-weighted image, and a null signal on short time inversion recovery (STIR)-weighted image, characteristic of fat. In all other patients, the findings were very different: The pancreas was a small structure surrounded with fat. In 1 patient without identified syndrome, the pancreas appeared to be partially replaced with fat. MRI is an excellent imaging technique to correlate the nature of a tissue and its radiological representation, especially fat, which gives a very typical signal. In our brief series of patients with Shwachman's syndrome, MRI had 100% positive predictive value in demonstrating lipomatosis. In atypical cases of pancreatic insufficiency in which some of the clinical features of Shwachman's syndrome are absent. MRI is an invaluable aid in the diagnostic procedure.

Adolescent↗
PubMed1994

Clinical pharmacology of pancreatic enzymes in patients with cystic fibrosis and in vitro performance of microencapsulated formulations.

Improving protein and fat absorption in patients with cystic fibrosis relates to the amount of biologically active enzyme reaching the duodenum. Microencapsulated formulations are more effective than conventional products but differ in content, ability to retard acid inactivation and the pH at which they release enzymes. Contaminants in these products contribute to hyperuricosuria.

Adolescent↗
PubMed2006

Diagnosis and treatment of intestinal malabsorption in cystic fibrosis.

Intestinal malabsorption is severe and of early onset in virtually all people who have cystic fibrosis. The main cause is deficiency of pancreatic enzymes. Bicarbonate deficiency, abnormal bile salts, mucosal transport problems, motility differences, and anatomical structural changes are other contributory factors. Effective treatment should allow a normal to high-fat diet to be taken, control symptoms, correct malabsorption, and achieve a normal nutritional state and growth. Appropriate pancreatic enzyme replacement therapy will achieve normal or near-normal absorption in most people with cystic fibrosis. Early identification and treatment of intestinal malabsorption is critical to achieving optimal nutritional status. The occurrence of fibrosing colonopathy in a few patients on very high doses of those enzymes which have the copolymer Eudragit L30 D55 in their covering resulted in guidelines in the UK to avoid doses equivalent to more than 10,000 IU lipase per kg per day, and also to avoid preparations containing this copolymer in children and adolescents. For patients not responding to 10,000 IU lipase per kg per day review of adherence to treatment, change of enzyme preparation, variation in time of administration, and reduction in gastric acid may improve absorption. The importance of early investigation to exclude other gastrointestinal disorders as a cause of the patient's symptoms, rather than merely increasing the dose of enzymes, is stressed. With modern pancreatic enzymes in doses up to or only slightly in excess of 10,000 IU lipase per kg per day, adequate control of gastrointestinal symptoms and absorption can be achieved, and a normal nutritional state and growth rate maintained in most people with cystic fibrosis.

Adolescent↗
PubMed2005

Pancreatic exocrine function in patients with cystic fibrosis.

Pancreatic insufficiency in cystic fibrosis (CF) is associated with more severe disease and requires replacement therapy. Outcome measures such as growth and number of stools, frequency of abdominal pain, and flatulence have often been used to identify pancreatic-insufficient patients and to adjust the dose of replacement enzymes. Unfortunately, some patients with CF are misclassified, and approximately 9% do not receive therapy appropriate for their pancreatic exocrine functional status. Growth, number of stools, frequency of abdominal pain, and flatulence cannot be used to adjust enzyme doses.

Cystic Fibrosis↗
PubMed1986

Abnormalities of circulating immunoreactive pancreatic anionic trypsinogen in cystic fibrosis: an assay artifact due to cross-reacting serum antibodies.

In patients with CF, serum pancreatic cationic trypsinogen has proven to be useful for newborn diagnostic screening and also as a test of pancreatic function in the older patient. However, an assay for serum anionic trypsinogen is of no value as a test of pancreatic function in CF due to an apparent artifactual elevation of this enzyme in some patients. In this study, we evaluated the extent of the abnormality in the anionic trypsinogen assay and also elucidated the nature of the interfering material. CF patients were grouped according to the presence (pancreatic insufficiency) or absence (pancreatic sufficiency) of steatorrhea. In CF infants, both serum cationic and anionic trypsinogen levels were greatly elevated. Serum cationic trypsinogen declined with age in patients with pancreatic insufficiency, reaching low or undetectable levels after 6 years. In contrast, serum anionic trypsinogen levels remained normal or elevated in 33% of those over 6 years of age. There was no age-related change in either cationic or anionic trypsinogen among the CF patients with pancreatic sufficiency, and the majority had normal or elevated levels. Serum samples from selected CF patients were separated into IgG and non-IgG fractions using Staph. Protein A columns. Immunoreactive cationic and anionic trypsinogen were detectable in the non-IgG fractions of sera from CF infants and older patients with pancreatic sufficiency. In older CF patients with undetectable serum cationic and anionic trypsinogen, no immunoreactive material was detectable in either the IgG or non-IgG fractions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗