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PubMed1985

Elastase in tissue injury.

This article surveys elastinolytic proteinases in man, excluding enzymes of the pancreas and digestive tract. Special emphasis is placed on the elastase of polymorphonuclear neutrophils (PMN). The properties of this latter enzyme, its target molecules in plasma and connective tissues, and its endogenous regulators are briefly discussed. Persistent activity of the enzyme, even in the presence of its regulatory inhibitors, is explained. The chapter closes with a brief discussion of several pulmonary diseases in which elastase-mediated tissue injury is thought to play a role.

Blood Platelets↗

PubMed1995

Polycystic kidney disease: etiology, pathogenesis, and treatment.

Once viewed as hopelessly incurable disorders and the dustbin for careers in academic medicine, the polycystic kidney diseases have emerged as prime targets of pathophysiologic study and palliative and definitive treatment in the era of molecular medicine. Polycystic kidney disease (PKD) may be hereditary or acquired. The major inherited types are autosomal dominant (AD) and autosomal recessive (AR). ADPKD is caused by at least two (and possibly three) genes located on separate chromosomes, while ADPKD-1 is due to a 14 kb transcript in a duplicated region on the short arm of chromosome 16 very near the alpha-globin gene cluster and the gene for one form of tuberous sclerosis. ADPKD-2 has been assigned to the long arm of chromosome 4. ARPKD is due to a mutated gene on both copies of the long arm of chromosome 6. Cysts originate in renal tubules. Proliferation of tubule epithelial cells modulated by endocrine, paracrine, and autocrine factors is a major element in the pathogenesis of renal cystic diseases. In addition, fluid that is abnormally accumulated within the cysts is derived from glomerular filtrate and, to a greater extent, by transepithelial fluid secretion. Abnormal synthesis and degradation of matrix components associated with interstitial inflammation are additional features in the pathogenesis of renal cystic diseases. The ADPKD genotypes are characterized by bilateral kidney cysts, hypertension, hematuria, renal infection, stones, and renal insufficiency. ADPKD is a systemic disorder; cysts appear with decreasing frequency in the kidneys, liver, pancreas, brain, spleen, ovaries, and testis. Cardiac valvular disorders, abdominal and inguinal hernias, and aneurysms of cerebral and coronary arteries and aorta are also associated with ADPKD. Treatment is supportive: dietary regulation of salt and protein intake, control of hypertension and renal stones, and dialysis and transplantation at the end stage. ARPKD is a relatively rare disease that causes clinical symptoms at birth, with significant mortality in the first month of life. The cysts develop primarily in the collecting ducts because of a failure in the maturation process. Early complications include Potter's syndrome; excessive size of the kidneys, causing respiratory dysfunction; hypertension; and renal insufficiency. Hepatic fibrosis is an associated extrarenal problem that results in significant morbidity in young children and adolescents. Treatment includes supportive care, dialysis, and renal transplantation. Acquired cysts (solitary/simple) are commonplace in older persons. Multiple cysts may be seen in association with potassium deficiency, congenital disorders, metabolic diseases, and toxic renal injury.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2006

Pathophysiology of SPINK mutations in pancreatic development and disease.

The endogenous pancreatic trypsin inhibitor, SPINK, is believed to limit enzyme activity in the pancreas and reduce the risk of pancreatitis. Recently, mutations in the SPINK1 gene have been associated with development of both acute and chronic pancreatitis. In most patients with SPINK1 mutations, the genetic variants do not cause the disease independently, but may act in concert with other genetic or environmental factors. Recent studies, using mice in which the trypsin inhibitor gene has been deleted or overexpressed, provide novel insights into the role of SPINK in pancreatic development and pancreatitis.

Animals↗

PubMed2006

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas: its histopathologic difference between 2 major types.

Intraductal papillary mucinous neoplasm (IPMN) is a unique pancreatic neoplasm developing in the ductal system. Two major histologic subtypes have been reported, that is the gastric type and the intestinal type. However, their histopathologic features, especially those of the gastric type, have not been fully described. To evaluate the features of these two types and refine their differences, we analyzed 80 IPMNs including 50 cases of the gastric type and 30 cases of the intestinal type with mucin immunohistochemistry. By defining a main duct-type lesion as predominantly involving the main pancreatic duct with or without branch ducts, and a branch duct-type lesion as exclusively centered on branch ducts or consisting of a collection of small cystic lesions, gastric-type IPMNs were mostly branch duct-type lesions (98%), whereas the intestinal-type IPMNs were usually main duct type (73%). The histologic grade of the intestinal type was generally higher than that of the gastric type. The intestinal type was also characterized by frequent intraluminal nodular growth, and severe atrophy and fibrosis of the surrounding parenchyma with mucous lake formation. In contrast, pyloric glandlike structures at the base of the papillae and pancreatic intraepithelial neoplasia (PanIN)-like complexes were more frequently observed in the gastric type. A significant difference was observed between the gastric type and the intestinal type with regard to all the above features (P<0.05). Seven cases (23%) of the intestinal type were associated with an invasive adenocarcinoma (6 mucinous and 1 ductal), versus only 1 case (2%) of the gastric type (invasive ductal carcinoma). All cases of both gastric and intestinal types expressed MUC5AC; however, high immunolabeling scores for MUC2 were mostly observed in the intestinal type (P<0.05). In conclusion, gastric and intestinal types of IPMNs have distinct histopathologic features and mucin profiles, suggesting that they may follow different biologic pathways.

Adenocarcinoma, Mucinous↗

PubMed1986

Hyperplastic and neoplastic endocrine cells of the pancreas in aspiration biopsy.

Aspiration biopsy of four primary endocrine tumors of the pancreas showed single and large sheets of tumor cells. Tumor cells were polygonal in shape with ill-defined, filmy or granular cytoplasm and regular round nuclei containing a finely granular chromatin pattern and inconspicuous or prominent nucleoli. Focal gland-like arrangement was seen in several sheets of tumor cells. Aspirate from liver metastases of an endocrine tumor of the pancreas showed single and clustered oval cells with granular cytoplasm and eccentrically located round and hyperchromatic nuclei. Smears prepared from aspirates of three fibrotic pancreata containing nodules of hyperplastic endocrine cells showed smaller fragments of endocrine-cell epithelium with focal gland-like arrangement. Individual hyperplastic endocrine cells displayed granular, filmy, and ill-defined cytoplasm and round to oval hyperchromatic nuclei showing a finely granular chromatin pattern. Nuclear pleomorphism was noted in some cell groups.

Adenoma, Islet Cell↗

PubMed1999

Giant solid cystic tumor of the pancreas with a fibrous septum caused by extracapsular growth in middle-aged woman: report of a case.

We report herein the case of a 57-year-old female who was admitted to our hospital for treatment of rectal carcinoma and incidentally found to have a giant cystic tumor, 20 cm in diameter, in the body and tail of the pancreas. Several imaging procedures, including ultrasonography, computed tomography, and magnetic resonance imaging, showed that this tumor was round and hypovascular, and had a septum with protuberant lesions. The capsule was 3-4 mm thick with partial calcification. A preoperative diagnosis of a solid cystic tumor (SCT) of the pancreas was made, even though these tumors are rarely found in females in their fifties. Moreover, few reports of SCT with a septum have been described. Distal pancreatectomy and splenectomy were performed, and the tumor was found to be filled with massive necrotic tissue. Microscopically, the tumor was confirmed to be a SCT with a fibrous septum. We present this case due to the atypical findings, including the age of the patient and the existence of a septum caused by extracapsular growth.

Biopsy, Needle↗

PubMed1976

[Changes of the pancreatic duct system associated with aging: their relations to parenchyma (author's transl)].

A postmortem study by ductography and histology was carried out in 50 macroscopically normal human pancreata. The alterations of the pancreatic duct system, their relations to the parenchyma, and their changes depending on age were studied. The most frequent changes of the ducts are epithelial hyperplasia (88%) and periductal fibrosis (74%). In the ducts they produce cystic widening (62%) and intraluminal protein precipitates (40%), within the parenchyma an intralobular fibrosis up to total fibrosis of lobules (88%). All these alterations increase with aging both in frequency and intensity. But they are already visible before the age of 50 and sometimes before the age of 30. The pathogenetic connexions between the changes of the duct system and the alterations of parenchyma were studied by serial sections and ceroplasty. This investigation revealed that the small branches of the larger ducts, which drain small periductally situated lobules, play an important role in the development of the parenchymal alterations. No connections were found between the pancreatic alterations and diseases of the bile duct system.

Adult↗

PubMed2002

Chronic pancreatitis.

The pathogenesis of idiopathic chronic pancreatitis remains poorly understood despite the high expectations for ascribing the pancreatic damage in affected patients to genetic defects. Neither mutations in the cationic trypsinogen gene nor mutations of the cystic fibrosis conductance regulator gene account for the chronic pancreatitis noted in most patients with idiopathic chronic pancreatitis. Attempts to find an autoimmune basis for the pancreatitis in these patients have not been very successful. The diagnosis of small duct idiopathic chronic pancreatitis remains a great source of frustration for clinicians. Such patients with negative results of radiographic studies often cannot be diagnosed unless a hormone stimulation test such as a secretin test is performed. Although the porcine biologic form of secretin, which has been used to diagnose chronic pancreatitis, became unavailable because of widespread use in the treatment of children with autism, a synthetic form of porcine secretin has now been approved by the US Food and Drug Administration and is available. The true value of endoscopic ultrasonography in diagnosing small duct chronic pancreatitis remains to be fully defined. Endoscopic ultrasonography is becoming the test of choice in detecting radiographic abnormalities in both the parenchyma and ducts of the pancreas. Endoscopic ultrasonography-guided celiac plexus block can be performed relatively easily and very safely. It can provide excellent short-term pain relief in some patients, but reliable predictors of which patients will be successful with this therapy are not yet available. Because long-term follow-up data on the use of endoscopic ultrasonography in this respect are not available, and because the pain of chronic pancreatitis is, indeed, chronic, the role of endoscopic ultrasonography-guided celiac plexus block should be limited to treating those patients with chronic pancreatitis whose pain has not responded to other modalities.

Journal Article↗

PubMed1994

Enzyme therapy for pancreatic insufficiency: present status and future needs.

Pancreatic enzyme extracts have been used for several decades to decrease maldigestion of macro- and micronutrients due to pancreatic insufficiency and to alleviate various abdominal symptoms, including the pain of alcohol-induced chronic pancreatitis and distal intestinal obstruction. Decreasing nutrient maldigestion and malabsorption in pancreatic insufficiency is of additional critical importance because improvement in nutritional status reduces morbidity and mortality. For example, pancreatic sufficient patients with cystic fibrosis (CF) demonstrate a slower decline in pulmonary function. In spite of the recognized importance of pancreatic enzymes, several problems exist with current preparations, and as newer enzyme preparations are marketed, proper evaluation becomes critical. There is a clear need to optimize the constituents of enzyme preparations, improve manufacturing processes, and find better sources of enzymes. Other issues that need addressing include standardization of the ratios of enzymes (lipase, amylase, protease) in these products; the stability of the enzymes at room temperature; the shelf life of the finished product; whether there are significant batch-to-batch differences; and the need for a USP reference standard.

Enzyme Therapy↗

PubMed1998

Malignant transformation of duct-like cells originating from acini in transforming growth factor transgenic mice.

BACKGROUND & AIMS: In transgenic mice overexpressing transforming growth factor (TGF)-alpha in the exocrine pancreas, progressive pancreatic fibrosis and a transdifferentiation of acinar cells to duct-like cells occurs. The present study was undertaken to analyze this transdifferentiation process. METHODS: Pancreatic specimens were characterized using light microscopy and immunohistochemistry. Expression of the epidermal growth factor receptor (EGFR) and TGF-alpha was evaluated with slot blot and Western analysis. To identify other generic events, K-ras mutations were screened with an enriched polymerase chain reaction approach and p53 expression was detected with immunohistochemistry. RESULTS: Morphological examination revealed an aggregation of interlobular fibroblasts and a decrease in acinar cell height starting at day 14 after birth. In older animals, these acinar cells change to duct-like cells, which form tubular structures and express ductal markers. Evidence for dysplastic changes was found in 12 of 21 TGF-alpha transgenic mice older than 1 year. We also observed four malignant pancreatic tumors, which were multicentric and originated from dysplastic tubular complexes. They displayed a mixed cystic-papillary phenotype strongly positive for carbonic anhydrase activity. EGFR expression progressively increased in the transition from acinar to duct-like and transformed cells. Activating K-ras mutations could not be detected; however, tubular complexes and tumors displayed increased immunoreactivity for nuclear p53. CONCLUSIONS: These data suggest an involvement of the TGF-alpha/EGFR pathway in conjunction with other yet unknown events in pancreatic tumor development. Furthermore, these observations are in favor of an acinar-ductal carcinoma sequence. Thus, these transgenic animals will be useful to define genetic alterations associated with a transition from acinar cells to a neoplastic ductal phenotype.

Animals↗

PubMed1991

Pseudocysts in chronic pancreatitis: a morphological analysis of 57 resection specimens and 9 autopsy pancreata.

The pathology of chronic pancreatitis is reviewed in order to study the histology and incidence of pseudocysts in relation to the degree of pancreatic fibrosis and calcification. The series consisted of 57 resection specimens (49 partial pancreatectomy specimens and 8 total pancreatectomy specimens) and 9 autopsy pancreata. The histology of cystic lesions observed in the specimens was found to be identical to that of pseudocysts in acute pancreatitis. In 19 of 57, there was concomitant occurrence of focal autodigestive (fat) necrosis and pseudocysts. Pseudocysts were more common in specimens with focal fibrosis and few calcifications (13/25) than in those with diffuse advanced fibrosis and numerous calcifications (15/41). The findings indicate that sequelae of acute pancreatitis are frequently present in chronic pancreatitis, particularly in an early stage when fibrosis is still focal and calcification rare. This suggests that chronic pancreatitis may result from relapses of severe acute pancreatitis. A pathogenetic concept that relates acute pancreatitis with chronic pancreatitis is proposed.

Adult↗

PubMed1997

Cloning and characterization of a novel human DNase.

The therapeutic significance of recombinant human DNase I in treating the patients with cystic fibrosis has risen our interests in identifying other human DNase I-like enzymes to study their biological significance. Here we described our work of cloning and characterization of a novel gene, which encodes a human protein homologous to human DNase I. A full length cDNA clone of this gene consists of 1290 bp, encoding a polypeptide of 306 amino acids. The deduced amino acid sequence of this novel human DNase (nhDNase) is 45% identical to that of human DNase I. Among sixteen human tissues examined by Northern Blot, high level expression of nhDNase was found in human liver and spleen. Recombinant protein of nhDNase was produced in a Baculovirus expression system and purified by chromatography and reverse-phase HPLC. Purified recombinant nhDNase migrated as a single band of about 33 kD molecular weight analyzed by SDS-PAGE. The DNase activity of nhDNase was demonstrated by assay of hydrolysis of S.S.DNA. Its activity was dependent upon the presence of divalent metal irons, calcium and magnesium. However, unlike bovine pancreas DNase I, nhDNase was not inhibited by G-actin of bovine muscle, which indicates the physiological significance of this enzyme in clinical implication.

Actins↗

PubMed1998

Indomethacin and pancreatic enzymes synergistically damage intestine of rats.

The use of high-dose pancreatic enzymes by patients with cystic fibrosis was associated with the development of fibrosing colonopathy. Preliminary studies indicated that the infusion of high-dose pancreatic enzymes alone did not cause intestinal damage. We hypothesized that cystic fibrosis patients that developed fibrosing colonopathy had increased intestinal permeability. Our goal was to develop a rat model for pancreatic enzyme-induced fibrosing colonopathy by increasing intestinal permeability with the use of indomethacin. Pancreatic enzymes, 150,000 units/kg/day, and indomethacin, 3 mg/kg/day, alone and in combination were administered via duodenal catheter to rats for 10 days. Indomethacin and pancreatic enzymes caused intestinal damage, resulting in significant increases in the total number of ulcers (P < 0.007), the number of severe ulcers (P < 0.003), and ulcers in the cecum and colon (P < 0.0007). We conclude that the combination of indomethacin and pancreatic enzymes acts synergistically to cause damage to the intestine.

Animals↗

PubMed2001

Gastric acid suppression and treatment of severe exocrine pancreatic insufficiency.

Adding either H(2)-receptor antagonists (cimetidine or ranitidine) or proton pump inhibitors to an adequate amount of lipolytic activity improves fat malabsorption in most cases and abolishes steatorrhoea in up to 40% of children and adults with cystic fibrosis and in adults with chronic pancreatitis. Acid suppression improves fat absorption because the resultant increase in pH within the upper gastrointestinal tract improves the survival of lipolytic activity, reduces duodenal volume flow and prevents the precipitation of bile acids. These effects increase the concentration of intraduodenal lipolytic activity and promote the aggregation of bile acids and the micellar solubilization of lipid. The amount of lipase that should be recommended is controversial, but we interpret our studies as indicating that at least 90 000 United States Pharmacopeia (USP) units should be ingested with meals. This amount of lipolytic activity taken with an agent that suppresses gastric acid secretion improves fat absorption in most patients and may even abolish steatorrhoea.

Anti-Ulcer Agents↗

PubMed2001

Coordination of pancreatic HCO3- secretion by protein-protein interaction between membrane transporters.

Increasing evidence suggests that protein-protein interaction is essential in many biological processes including epithelial transport. In this report, we discuss the significance of protein interactions to HCO(3)(-) secretion in pancreatic duct cells. In pancreatic ducts HCO(3)(-) secretion is mediated by cystic fibrosis transmembrane conductance regulator (CFTR) activated luminal Cl(-)/HCO(3)(-) exchange activity and HCO(3)(-) absorption is achieved by Na(+)-dependent mechanisms including Na(+)/H(+) exchanger 3 (NHE3). We found biochemical and functional association between CFTR and NHE3. In addition, protein binding through PDZ modules is needed for this regulatory interaction. CFTR affected NHE3 activities in two ways. Acutely, CFTR augmented the cAMP-dependent inhibition of NHE3. In a chronic mechanism, CFTR increases the luminal expression of Na(+)/H(+) exchange in pancreatic duct cells. These findings reveal that protein complexes in the plasma membrane of pancreatic duct cells are highly organized for efficient HCO(3)(-) secretion.

Animals↗

PubMed2002

Isoforms of SLC26A6 mediate anion transport and have functional PDZ interaction domains.

The solute carrier gene family SLC26 consists of tissue-specific anion exchanger genes, three of them associated with distinct human recessive disorders. By a genome-driven approach, several new SLC26 family members have been identified, including a kidney- and pancreas-specific gene, SLC26A6. We report the functional characterization of SLC26A6 and two new alternatively spliced variants, named SLC26A6c and SLC26A6d. Immunofluorescence studies on transiently transfected cells indicated membrane localization and indicated that both NH(2)- and COOH-terminal tails of the SLC26A6 variants are located intracellularly, suggesting a topology with an even number of transmembrane domains. Functional expression of the three proteins in Xenopus oocytes demonstrated Cl(-) and SO(4)(2-) transport activity. In addition, the transport of SO(4)(2-) and Cl(-) was inhibited by DIDS and HCO(3)(-). We demonstrated also that the COOH terminus of SLC26A6 binds to the first and second PDZ domains of the Na(+)/H(+) exchanger (NHE)3 kinase A regulatory protein (E3KARP) and NHE3 regulatory factor (NHERF) proteins in vitro. Truncation of the last three amino acids (TRL) of SLC26A6 abrogated the interaction but did not affect transport function. These results demonstrate that SLC26A6 and its two splice variants can function as anion transporters linked to PDZ-interaction pathways. Our results support the general concept of microdomain organization for ion transport and suggest a mechanism for cystic fibrosis transmembrane regulator (CFTR)-mediated SLC26A6 upregulation in pancreatic duct cells.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1991

[Clinical and pharmacological aspects of pancreatic enzyme substitution therapy].

The adequate therapy of pancreatic enzyme replacement in patients with exocrine pancreatic insufficiency is still a difficult clinical problem especially in patients following pancreatectomys, with chronic alcoholic pancreatitis or cystic fibrosis. The substitution of lipase to eliminate steatorrhoea is the most important aim but due to its acid lability even the most serious problem in pancreatic enzyme replacement therapy. Various different medications are meanwhile available: conventional preparations from porcine pancreatin or fungal enzymes as rizolipase, enteric-coated tablets or even enteric-coated microspheres or adjunctive therapy with H2-receptor antagonists. While dosage requirements vary widely and therefore have to be tried out individually, the choice of the adequate preparation should be influenced by the realization of the physiological and pathophysiological characteristics of the individual patient and the pharmaceutical characteristics of the different supplements. The advantages and disadvantages of the various medications for enzyme replacement therapy in patients with exocrine pancreatic insufficiency are reviewed in this article.

Alcoholism↗

PubMed1998

Pneumatosis intestinalis: a review.

This review illustrates the changing paradigms in the understanding of the pathogenesis of pneumatosis intestinalis. Although many theories have been evoked, pragmatically there appear to be four major clinical and diagnostic imaging considerations. The most common and most emergent life-threatening cause of intramural bowel gas is the result of bowel necrosis due to bowel ischemia, infarction, necrotizing enterocolitis, neutropenic colitis, volvulus, and sepsis. In the stomach, intramural gas can be caused by emphysematous gastritis or ingestion of caustic agents. These situations represent surgical emergencies. Pneumatosis is found secondary to mucosal disruption presumably due to over-distention from peptic ulcer, pyloric stenosis, annular pancreas, and even to more distal obstruction. Disruption can also be caused by ulceration, erosions, or trauma, including the trauma of child abuse. Disruption can also be iatrogenic from intracatheter jejunal feeding tubes, stent perforation, sclerotherapy, or surgical or endoscopic trauma. In these cases, the gas may be focal or linear. Treatment depends on the extent of the disruption and the underlying cause. A more subtle form of mucosal disruption may occur due to mucosal erosions and also to defects in intestinal crypts secondary to acute and subclinical enteritides that allow intraluminal bacterial gas under pressure to percolate into the bowel wall layers, particularly the submucosa (29). Pneumatosis, often linear or cystic in appearance, is seen with increased frequency in patients who are immunocompromised because of steroids, chemotherapy, radiation therapy, or AIDS. In these cases, the pneumatosis may result from intraluminal bacterial gas entering the bowel wall due to increased mucosal permeability caused by defects in bowel wall lymphoid tissue. Clinical and imaging findings are important in the differentiation of this transient pneumatosis from fulminant life-threatening causes in this subset of patients. A pulmonary cause must still be considered in cases of chronic obstructive pulmonary disease, asthma, and cystic fibrosis. It can occur with barotrauma and after chest tube placement. It may relate to increased intrathoracic pressure associated with retching and vomiting. The possibility remains that occasionally the origin of pneumatosis intestinalis will remain cryptogenic--caused but unexplained.

Humans↗