gastrins and Cystic-Fibrosis

The duodenum is abnormally acidic in cystic fibrosis (CF) due to decreased bicarbonate ion secretion that is dependent on the CF gene product CFTR. In the CFTR null mouse, the acidic duodenum results in increased signaling from the intestine to the exocrine pancreas in an attempt to stimulate pancreatic bicarbonate ion secretion. Excess stimulation is proposed to add to the stress/inflammation of the pancreas in CF. DNA microarray analysis of the CF mouse revealed altered pancreatic gene expression characteristic of stress/inflammation. When the duodenal pH was corrected genetically (crossing CFTR null with gastrin null mice) or pharmacologically (use of the proton pump inhibitor omeprazole), expression levels of genes measured by quantitative RT-PCR were significantly normalized. It is concluded that the acidic duodenal pH in CF contributes to the stress on the exocrine pancreas and that normalizing duodenal pH reduces this stress.

Topics: Acids; Amylases; Animals; Chimera; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Duodenum; Enzyme Inhibitors; Gastrins; Gene Expression; Hydrogen-Ion Concentration; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligonucleotide Array Sequence Analysis; Omeprazole; Pancreas; Pancreatitis; Reverse Transcriptase Polymerase Chain Reaction

The number of peptide hormones which have been localized in the gut and in neurons of the central and peripheral nervous system has increased considerably. As there is almost no information about their importance in children with gastrointestinal diseases, we developed highly sensitive radioimmunoassays and measured postprandial serum/plasma levels of gastrin, secretin, vasoactive intestinal polypeptide (VIP) and motilin in 112 healthy children (N), 28 patients with cystic fibrosis (CF) and 17 children with Crohn's disease (CD). Gastrin values were not pathologic in children with CF nor those with Crohn's disease (N = 56.2 +/- 29.6 pg/ml; CF = 57.0 +/- 34.2 pg/ml; CD = 43.6 +/- 26.6 pg/ml). A significant age dependency was established for secretin and VIP. These peptides were elevated in CF-patients. In children with Crohn's disease only Secretin was increased. Motilin was elevated in all patients: N = 78.0 (49.1-124.0) pg/ml; CF = 148.0 (70.8-309) pg/ml; CD = 153.0 (87.6-266).

Topics: Adolescent; Adult; Child; Child, Preschool; Crohn Disease; Cystic Fibrosis; Gastrins; Humans; Infant; Motilin; Radioimmunoassay; Secretin; Vasoactive Intestinal Peptide

It has been claimed that plasma cholecystokinin (CCK) concentrations are raised in patients with pancreatic insufficiency. We have measured plasma CCK concentrations in 32 patients with pancreatic insufficiency (22 alcoholic pancreatitis and 10 cystic fibrosis) and in 30 normal subjects by radioimmunoassays using antibodies with different specificities. Antibody 1703 binds to COOH-terminal forms of CCK containing at least 14 amino acid residues and does not cross-react with gastrins. Antibody T204 binds to all CCK-peptides containing the sulfated tyrosyl region and shows low cross-reactivity with sulfated gastrins but no binding to nonsulfated gastrins. Antibody 5135 binds to all COOH-terminal CCK-peptides and shows full cross-reactivity with gastrins. In patients with pancreatic insufficiency, plasma CCK concentrations (1.2 +/- 0.1 pmol/liter, antibody 1703; 2.0 +/- 0.2 pmol/liter, antibody T204; 12.5 +/- 1.4 pmol/liter, antibody 5135) were not significantly different from those in normal subjects (1.1 +/- 0.1 pmol/liter, antibody 1703; 2.2 +/- 0.3 pmol/liter, antibody T204; 10.5 +/- 0.9 pmol/liter, antibody 5135). Furthermore, plasma CCK concentrations in patients with pancreatic insufficiency due to alcoholic pancreatitis (1.2 +/- 0.1 pmol/liter, antibody 1703; 1.9 +/- 0.2 pmol/liter, antibody T204; 14.0 +/- 1.9 pmol/liter, antibody 5135) were not significantly different from those in patients with cystic fibrosis (1.2 +/- 0.2 pmol/liter, antibody 1703; 2.4 +/- 0.4 pmol/liter, antibody T204, 9.1 +/- 1.0 pmol/liter, antibody 5135). Cross-reactivity with gastrin accounted for almost all CCK-like-immunoreactivity measured with antibody 5135.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Alcoholism; Antibodies; Antibody Specificity; Binding Sites, Antibody; Cholecystokinin; Cross Reactions; Cystic Fibrosis; Diabetes Mellitus; Exocrine Pancreatic Insufficiency; Female; Gastrins; Humans; Male; Middle Aged; Pancreatitis; Radioimmunoassay

Increased basal and/or pentagastrin-stimulated gastric acid secretion was observed in 31 of 40 cystic fibrosis (CF) patients as compared to 13 age-matched control volunteers. Fasting serum gastrin level for 20 CF patients of 67.7 +/- 11.1 pg/ml (ranging from 10 to 145 pg/ml) was normal. Meal-stimulated serum gastrin concentrations were not significantly higher for seven CF patients as compared to nine normal subjects. In a rat bioassay, serum extracts from six CF patients produced gastric acid secretion comparable to 250 ng/ml of pentagastrin; significantly (p less than 0.01) greater than the responses produced by serum extracts from six normal subjects. There was no significant correlation of severity of pulmonary disease or steatorrhea with acid secretory results. Fourteen of 16 CF patients biopsied had evidence of proximal small intestinal injury which correlated with basal acid output elevation. Gastric acid hypersecretion in CF patients is due to nongastrin secretagogues and is a cause of proximal small intestinal injury.

Topics: Adolescent; Adult; Animals; Celiac Disease; Child; Child, Preschool; Cystic Fibrosis; Duodenum; Female; Gastric Acid; Gastrins; Humans; Infant; Intestinal Diseases; Lung Diseases, Obstructive; Male; Pentagastrin; Rats; Rats, Inbred Strains; Time Factors

Topics: Adult; Child; Child, Preschool; Cystic Fibrosis; Gastrins; Humans; Infant; Infant, Newborn; Infant, Premature; Intestine, Small; Radioimmunoassay

Topics: Adolescent; Calcium; Child; Chlorides; Cystic Fibrosis; Gastric Acidity Determination; Gastric Juice; Gastric Mucosa; Gastrins; Humans; Hydrogen; Hydrogen-Ion Concentration; Injections, Subcutaneous; Potassium; Secretory Rate; Sodium

Topics: Age Factors; Animals; Chronic Disease; Cystic Fibrosis; Depression, Chemical; Dogs; Gastrins; Injections, Intravenous; Pancreatitis; Secretin; Sex Factors; Vagus Nerve