AIM: To elicit the role of cholecistokinin (CCK), biogenic amines, bile acids (BA) in development of functional pancreatic insufficiency (PI) in chronic pancreatitis (CP). MATERIAL AND METHODS: Blood concentrations of CCK, serotonin and acetylcholin, fecal concentration of elastase (E-1), BA spectrum in the blood and duodenal content were studied in 46 CP patients (20 patients with alcoholic pancreatitis--AP and 26 patients with biliary pancreatitis--BP) and 15 healthy controls. RESULTS: In AP patients E-1 fell to 78.4 +/- 6.3 mcg/g (severe exocrine PI), while in BP patients E-1 was 170.0 +/- 28.9 mcg/g. CCK in AP and BP decreased to 0.33 +/- 0.03 and 0.45 +/- 0.03 ng/ml, respectively (control--1.60 +/- 0.02 ng/ml, respectively, p < 0.05). AP and BP patients had a rise in the absolute concentration and percentage of the total fraction of the taurodioxicholanic acids to 10.2 +/- 1.6 and 15.0 +/- 2.3%, respectively,(control 9.5 +/- 1.2%) in duodenal bile. The concentration of glycocholic acid fell to 24.1 +/- 1.6 and 23.7 +/- 3.7%, respectively,(control--36.4 +/- 2.4%, p < 0.05). AP patients had more significant decrease of taurocholic acid--to 4.5 +/- 0.7%(control--9.2 +/- 0.7%, p < 0.05). In the peripheral blood of AP patients there was an elevated basal level of serotonin and acetylcholine in the presence of low cholinesterase activity. After meal, acetylcholine concentration lowered in high secretion of serotonin. CONCLUSION: Depending on severity of destructive changes in the pancreas, AP and BP patients had different degree of exocrine insufficiency which may be secondary to the absence of acetylcholine rise in the blood after meal. Alterations in the composition of the conjugates of cholic and taurodioxicholanic BA lead to alterations of CCK blood concentration and, therefore, to changes in exocrine pancreatic secretion. Imbalance between serotonin and acetylcholine levels after meal evidences for defects in conventional regulatory interrelations. Decreased threshold of nociceptors activation in simultaneous enhancement of afferent nociceptive flows may entail pain syndrome in CP.

Fluid and macromolecule secretion by submucosal glands in mammalian airways is believed to be important in normal airway physiology and in the pathophysiology of cystic fibrosis (CF). An in situ fluorescence method was applied to measure the ionic composition and viscosity of freshly secreted fluid from airway glands. Fragments of human large airways obtained at the time of lung transplantation were mounted in a humidified perfusion chamber and the mucosal surface was covered by a thin layer of oil. Individual droplets of secreted fluid were microinjected with fluorescent indicators for measurement of [Na(+)],[Cl(-)], and pH by ratio imaging fluorescence microscopy and viscosity by fluorescence recovery after photobleaching. After carbachol stimulation, 0.1--0.5 microl of fluid accumulated in spherical droplets at gland orifices in approximately 3--5 min. In gland fluid from normal human airways,[Na(+)] was 94 +/- 8 mM,[Cl(-)] was 92 +/- 12 mM, and pH was 6.97 +/- 0.06 (SE, n = 7 humans, more than five glands studied per sample). Apparent fluid viscosity was 2.7 +/- 0.3-fold greater than that of saline. Neither [Na(+)] nor pH differed in gland fluid from CF airways, but viscosity was significantly elevated by approximately 2-fold compared to normal airways. These results represent the first direct measurements of ionic composition and viscosity in uncontaminated human gland secretions and indicate similar [Na(+)],[Cl(-)], and pH to that in the airway surface liquid. The elevated gland fluid viscosity in CF may be an important factor promoting bacterial colonization and airway disease.

Cystic fibrosis is a common, fatal disorder caused by abnormalities in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR encodes a chloride channel that regulates secretion in many exocrine tissues. The presentation of cystic fibrosis is highly variable as measured by the age of onset of disease, the presence of pancreatic insufficiency, or the progression of lung disease. Over 400 mutations in the CFTR gene have been described in cystic fibrosis patients and considerable effort has focused on the correlation between specific mutations and genotypes and clinical characteristics. Individual tissues display variation in their sensitivity to CFTR mutations. The vas deferens is functionally disrupted in nearly all males, whereas mild and severe pancreatic involvement is determined by the patient's genotype. The severity of pulmonary disease is poorly correlated with genotype, suggesting that there are other important genetic and/or environmental factors that contribute to lung infections and the subsequent disruption of lung function.

Airflow limitation is a frequent finding in patients with rheumatic diseases. We have previously suggested that it is associated with autoimmune exocrinopathy in Sjögren's syndrome. To compare clinical features of patients with and without airways dysfunction and to further test the hypothesis of a link between airways disease and exocrinopathy, we prospectively studied 2 groups of 15 lifetime nonsmoker female patients with seropositive rheumatoid arthritis (RA). The 2 groups were similar in their clinical and immunologic features, but differed in terms of airways function. Salivary, lacrimal, and sweat gland dysfunction were significantly more prevalent or severe in the group with airways disease. Antinuclear antibodies were also more prominent in the patients with airways disease, but antibodies against RNP, SS-A, SS-B, and double-stranded DNA were not present in these patients. HLA-DR4 was found in 80% of the RA patients with airways disease and in 57% of those without airways disease. HLA-B8 and DR3 were equivalently distributed in both groups. This prospective study further documents the existence of small airways disease in RA and supports the view that autoimmune exocrinopathy predisposes to its expression.

NF-kappaB/Rel transcription factors and IkappaB kinases (IKK) are essential for inflammation and immune responses, but also for bone-morphogenesis, skin proliferation and differentiation. Determining their other functions has previously been impossible, owing to embryonic lethality of NF-kappaB/Rel or IKK-deficient animals. Using a gene targeting approach we have ubiquitously expressed an NF-kappaB super-repressor to investigate NF-kappaB functions in the adult. Mice with suppressed NF-kappaB revealed defective early morphogenesis of hair follicles, exocrine glands and teeth, identical to Eda (tabby) and Edar (downless) mutant mice. These affected epithelial appendices normally display high NF-kappaB activity, suppression of which resulted in increased apoptosis, indicating that NF-kappaB acts as a survival factor downstream of the tumor necrosis factor receptor family member EDAR. Furthermore, NF-kappaB is required for peripheral lymph node formation and macrophage function.

The development of the tracheal submucosal glands has been determined quantitatively in 22 infants with cystic fibrosis and in 25 control infants, all under 4 months of age. In cross-sections of normal trachea significant relationships were found between postconceptional age (PCA) and gland area (P less than 0.001), submucosal area (P less than 0.02), tracheal airway diameter (P less than 0.05), and acinar diameter (P less than 0.001). In infants with cystic fibrosis the pattern of development was similar to that of the control infants. No statistically significant differences were found between three subgroups of infants with cystic fibrosis, which included those with meconium ileus with no lung infection, those with meconium ileus with lung infection, and those with lung infection and no history of meconium ileus. The normal pattern of development of tracheal submucosal glands in infants with cystic fibrosis was in contrast to the deficiency of normal maturation seen in the exocrine pancreas of these infants. The lumen fraction, an index of dilatation of acinar lumina, showed no significant relationship with PCA in either the control group or the group with cystic fibrosis. However, statistically significant dilatation of acini was observed in the tracheal submucosal glands of infants with cystic fibrosis (0.14, P less than 0.005).

Hypersecretion of mucus is a feature of several clinical diseases and in some is associated with mucous gland hypertrophy and goblet cell increase. In a variety of species these changes have been produced by irritants, by infection, or by administration of drugs. While the end result may appear the same, differences emerge in the type and amount of glycoprotein secreted and in the amount retained within the cell. Organ culture can be used to ascertain functional activity. The use of animal models has not only established that these environmental changes cause hypertrophy but indicated some of the intracellular events associated with their development. When new types of granules appear within a cell, they appear first at the apex: a flow chart is offered of the way of which individual cells change and hence the population. The nature of glycoprotein elaborated by a secretory cell can change within hours. A Clara or serous cell can develop into a mucus-secreting or goblet cell. The pattern of reversibility is emerging.