Tracheal Glands Research Articles

Developmental expression of SP-A and SP-A mRNA in the proximal and distal respiratory epithelium in the human fetus and newborn.

We used immunolocalization and in situ hybridization to determine the distribution of SP-A and SP-A mRNA in lungs of human fetuses and normal newborn infants. Early in the second fetal trimester a few immunostained cells were observed in tracheal epithelium, often in mucosal folds near the origin of submucosal gland ducts. Non-mucous tracheal gland cells were immunostained for SP-A as they became differentiated. Expression of SP-A mRNA was similar to that of immunolocalization in the second trimester. Immunostained cells and SP-A mRNA also appeared about the same time in gestation in isolated cells of bronchial epithelium and glands. SP-A mRNA was seen in bronchiolar cells and pre-Type II cells lining terminal airways of fetuses at 19-20 weeks of gestation. Only in liveborn infants did cells of bronchioloalveolar portals and mature Type II cells contain SP-A mRNA or immunostain for SP-A. In postnatal infants, luminal material was also stained for SP-A. Although some alveolar macrophages contained immunoreactive material, SP-A mRNA was never detected. The abundance of SP-A in tracheal and bronchial glands and epithelium of conducting airways supports the importance of non-surfactant-associated functions for SP-A and may be related to a role in host defense.

Mucinlike glycoproteins from cat tracheal gland cells in primary culture.

In a recent study (D. J. Culp, D. K. P. Lee, D. P. Penney, and M. G. Marin. Am. J. Physiol. 263: L264-275, 1992), we reported that primary cultures of cat tracheal gland cells expressed histological, ultrastructural, and immunological characteristics of mucous cells when cultured on floating gels of rat tail collagen (released-gel cultures) compared with cells cultured on glutaraldehyde-fixed collagen gels (fixed-gel cultures). We therefore collected culture medium from gland cells grown under both culture conditions for determination and comparison of glycoconjugates with characteristics of mucin glycoproteins. Cells were cultured in the presence of [3H]glucosamine, and material of high molecular weight and density (HMD material) was isolated. HMD material from both culture conditions were each resistant to heparitinase and heparinase, whereas 72 and 25% of the radiolabel in released-gel and fixed-gel HMD material, respectively, was resistant to chondroitinase ABC. Material resistant to chondroitinase ABC was analyzed further. Both samples contained a single broad glycoprotein band [relative molecular weight (M(r)) > 250,000] after sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and had amino acid profiles similar to airway mucin. The sample from fixed-gel cultures had nearly equal amounts of carbohydrate and protein, was highly enriched in N-acetylglucosamine, contained mannose, displayed little blood group A immunoreactivity, and had few O-linked oligosaccharides. Conversely, the sample from released-gel cultures contained 80% carbohydrate, was composed of monosaccharides characteristic of airway mucins, displayed blood group A immunoreactivity, and contained oligosaccharides O-linked via N-acetylgalactosamine.(ABSTRACT TRUNCATED AT 250 WORDS)

A stimulatory role of protein kinase C in feline tracheal submucosal gland secretion

To determine the role of protein kinase C (PKC) in airway submucosal gland secretion, we examined the effect of a selective PKC stimulant, phorbol 12-myristate 13-acetate (PMA), on mucus glycoprotein (MGP) secretion, fluid secretion and intracellular Ca 2+ concentration ([Ca 2+]i) in isolated feline submucosal glands. MGP and fluid secretions were estimated by measuring trichloroacetic acid (TCA)-precipitable glycoconjugates and 22Na-efflux, respectively, from isolated glands. [Ca 2+]i was measured using a Ca 2+-sensitive fluorescent dye, Fura 2. PMA itself produced a significant increase in MGP secretion in a dose-dependent fashion (173% of control at 10 −5 M). PMA also produced a significant increase in 22Na-efflux (151% of baseline rate constant at 10 −5 M). Indomethacin failed to alter the increase in MGP secretion or in 22Na-efflux in response to PMA. Two PKC inhibitors, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) and sphingosine, inhibited both MGP secretion and 22Na-efflux stimulated by PMA; there was only a partial inhibition after stimulation by methacholine (MCh). PMA did not significantly alter [Ca 2+]i and H-7 did not alter the MCh-induced [Ca 2+]i rise. These findings indicate that PKC has a direct stimulatory role in stimulus-secretion coupling of airway submucosal gland secretion.

Calcium-dependent chloride secretion across cultures of human tracheal surface epithelium and glands.

Surface epithelium and gland cells from human trachea were cultured on porous-bottom inserts and loaded with fura 2 to permit measurement of the intracellular calcium concentration ([Ca2+]i). Short-circuit current (Isc), an index of transepithelial active ion transport, was measured on cells from the same cultures. Surface epithelial [Ca2+]i of 82 +/- 15 nM was increased transiently by isoproterenol, histamine, and bradykinin with maximal increases of 88 +/- 17, 480 +/- 149, and 978 +/- 214 nM (n = 15), respectively. Baseline [Ca2+]i in cultured gland cells of 68 +/- 11 nM was increased transiently by isoproterenol, histamine, methacholine, and bradykinin with maximal increases of 105 +/- 19, 233 +/- 47, 327 +/- 121, and 634 +/- 151 nM (n = 17-21), respectively. In both cell types, mediators that increased [Ca2+]i also increased Isc with a time course identical to the increase in [Ca2+]i. Pretreatment with the calcium chelator, 1,2-bis-(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid, acetoxymethyl ester (BAPTA-AM), had no effect on basal Isc or transepithelial resistance but markedly inhibited both the Isc and [Ca2+]i responses to agonists. Forskolin (10(-5) M), 3-isobutyl-1-methylxanthine (10(-3) M), dibutyryl adenosine 3',5'-cyclic monophosphate (10(-3) M), and 8-(4-chlorophenylthio)-cAMP (10(-3) M) had no or only trivial effects on Isc and [Ca2+]i. We suggest that mediators increase Isc across human airway epithelium by activating Ca-dependent basolateral K channels, resulting in hyperpolarization and an increased driving force for Cl exit through apical membrane Cl channels.

Epinephrine Promotes Growth and Differentiation of Human Tracheal Gland Cells in Culture

Submucosal gland cells isolated from human tracheas by enzymatic digestion and cultured in the absence or presence of epinephrine (E) were used to investigate the possible action of this catecholamine on the physiology of the gland secretory cells issued from the human trachea. A 3 x 10(-6) M concentration of E shortens the doubling time of growth and increases the cells' confluency rate. On the other hand, E appears to induce cell polarity in terms of differential secretion apically versus basolaterally. Furthermore, when human tracheal gland cells are cultured in the presence of E, a maximal cell stimulability by different agonists occurs from 8 days after confluency and then remains identical for 10 days, allowing us to compare the action of different adrenergic and cholinergic agonists on the proteinase bronchial inhibitor and the radiolabeled glycoconjugate secretion. As previously described, secretions of bronchial inhibitor and high molecular weight glycoconjugates were stimulated both by alpha- and beta-adrenergic and by cholinergic agonists but at a much higher rate when cells were cultured in the presence of E. These results indicate that E improves cultured human tracheal glandular cell growth and differentiation in that it increases their polarity and their ability to respond to adrenergic and cholinergic agonists.

Characterization of cAMP dependent CFTR-chloride channels in human trache gland cells

Human tracheal gland cells are believed to be a major site at the origin of cystic fibrosis. Since this disease is due to mutations in a protein called CFTR, we looked for the activity of CFTR in human tracheal gland cells in culture. We have identified CFTR-like chloride-selective channels as having a linear current-voltage relationship and unitary conductance of 7 pS in these cells. In cell-attached patches, theophylline (1 mM), IBMX (1 mM), or a cocktail of dibutyryl cAMP (1 mM) and IBMX (0.1 mM) promoted the opening of channels. The unitary current had a reversal potential close to the cell resting potential. Replacement of choline by K + or Na + in the pipette solution was without effect on the current-voltage relationship, the reversal potential or the unitary conductance, which is consistent with the chloride selectivity of the channel. Channels were always found clustered and their opening probability was not noticeably dependent on membrane potential. This work therefore represents the first observation of a CFTR-like channel activity in submucosal gland cells.

Dexamethasone modulation of ion transport and fluid movement across airway epithelium.

Electrolyte or fluid is secreted across airway mucosa by both superficial epithelium and submucosal glands. To understand the effect of glucocorticoid on fluid movement across airway mucosa, we examined the effects of dexamethasone (Dex) on bioelectric properties of canine and feline tracheal epithelium and on 22Na efflux from isolated feline tracheal submucosal glands. Potential difference (PD) and short-circuit current (SCC) across tracheal epithelium were measured using an Ussing chamber, and conductance (G) was calculated as the ratio SCC/PD. Isolated glands were loaded with 22Na, and the rate constant (RC) of Na2+ efflux was calculated by measuring the radioactivity of each effluent sample. After treatment with 10(-9) to 10(-5) M Dex for up to 6 h, the epithelium and isolated glands were stimulated with isoproterenol (ISP) and methacholine (MCh), respectively. Dex treatment did not alter significantly baseline values of PD, SCC, or RC. However, Dex treatment produced a dose-dependent attenuation of ISP-evoked epithelial PD and SCC and of MCh-evoked glandular RC. In canine epithelium, pretreatment with 10(-5) M Dex for 6 h reduced by 40% the ISP (10(-6) M)-evoked rise in PD and SCC, whereas G remained unchanged. After 10(-5) M Dex treatment for 6 h, MCh (10(-5) M)-evoked RC in isolated glands was significantly less than in control glands (MCh alone) by 23%. These findings suggest that glucocorticoid decreases the fluid secretion across the airway mucosa, especially when the mucosa are stimulated.

Retinoic acid and calcium regulation of p53, transforming growth factor-beta 1, and transforming growth factor-alpha gene expression and growth in adenovirus 12-SV40-transformed human tracheal gland epithelial cells.

Vitamin A and calcium are important regulators of growth and differentiation of epithelial cells and are intimately involved in preneoplastic and neoplastic transformation. It has been proposed that their effects are mediated by autocrine/paracrine positive and negative regulators of growth. The objectives of this investigation were to examine the effects of all-trans retinoic acid (RA) and Ca2+ on cell proliferation, anchorage-independent growth (AIG), and on the expression of transforming growth factor-alpha (TGF-alpha), transforming growth factor-beta 1 (TGF-beta 1), and p53 tumor suppressor genes in human tracheal gland epithelial (HTGE) cells immortalized by adenovirus 12-simian virus 40 (Ad12-SV40) hybrid. Cells exhibiting the transformed phenotype, AIG, were maintained in serum-free culture conditions. Calcium effects were examined at 0.15, 0.50, 1.0, and 2.0 mM concentrations. The effects of RA were determined with 10(-9), 10(-7), and 10(-6) M concentrations. Gene expression was examined by Northern and Western analyses. Ca2+ had no significant effect on cell proliferation, but it enhanced the expression of TGF-beta 1 gene and slightly inhibited p53 expression. Ca2+ had no effect on TGF-alpha. RA inhibited both cell proliferation and AIG growth, which was accompanied by enhanced expression of p53. RA had no significant effect on the expression of TGF-alpha and TGF-beta 1 genes. These results demonstrate that RA regulates growth of HTGE cells mainly by upregulating the p53 gene; Ca2+, which enhances TGF-beta 1 expression, had no effect on growth.

Epithelial myoepithelial tumour of the tracheal gland.

A case of epithelial myoepithelial tumour originating from the tracheal gland in a 57 year old woman is described. The tumour was removed by segmental tracheal resection and end-to-end anastomosis. Histologically, the tumour comprised clear cells and presented a monophasic pattern. Immunohistochemical analysis showed that the tumour cells were positive for both S-100 protein and smooth muscle actin. suggesting that this tumour resembles a subtype of epithelial-myoepithelial carcinoma described in the 1990 WHO international classification of salivary glands. Although some reports describe a clear cell dominant epithelial myoepithelial carcinoma, in this case local invasiveness or regional lymphnode metastasis was not proved through investigation. It is therefore concluded that this was an epithelial myoepithelial tumour rather than a carcinoma.

Localization of the cystic fibrosis transmembrane conductance regulator in airway secretory glands

Cystic fibrosis (CF) is caused by mutations in the gene coding for the CF transmembrane conductance regulator (CFTR). From human normal tracheal submucosal gland cells in culture, we identified endogenous CFTR as a 170 kDa protein, consistent with that of fully glycosylated, mature CFTR molecule. This observation led to the hypothesis that airway secretory glands could be an important site for the CFTR expression. Using anti-human CFTR polyclonal and monoclonal antibodies, we examined the cellular and subcellular localization of the CFTR protein in airway submucosal glands from human and bovine tracheal tissues as well as in tracheal gland cell cultures. In human tracheal tissue, CFTR immunolabelling was present along both the apical and basolateral plasma membranes of glandular mucous cells. In contrast, CFTR was associated with the secretory granules of glandular serous cells. Using immunogold electron microscopy, we demonstrated that CFTR protein was more specifically associated with the membrane of serous cell secretory granules. In bovine tracheal tissue CFTR labelling was also identified in the secretory granules of glandular serous cells. In contrast, when bovine and human tracheal gland cells were cultured, no mature secretory granules were present, but a predominantly intracytoplasmic distribution of CFTR was observed. Our data thus suggest that in airway tissues, CFTR could be involved in intracellular processes of the mucus exocytosis in submucosal secretory glands.

Development of immune response markers in the trachea in the fetal period and the first year of life

Immunoglobulin (Ig)-producing cells, T cells (CD3) and epithelial expression of secretory component (SC) and HLA class II determinants (DR, -DP, -DQ) were studied by immunohistochemistry in 16 fetal and 15 postnatal specimens from the tracheal wall. Small amounts of secretory component (SC) was present in the tracheal surface and gland epithelium in the fetal period and increased towards term. A few IgM-, IgD- and IgG-producing cells were present in some fetal specimens but no IgA- and IgE-producing cells were found. Only very few CD3+ T-cells were present in fetal specimens and intraepithelial T-cells were virtually absent until after birth. Premature infants that lived for 1 week had less SC epithelial expression than mature infants of the same age. The density of CD3+ T-cells, IgA-, IgM-producing cells as well as the epithelial SC expression increased rapidly after birth. Epithelial MHC class II expression was absent in fetal specimens. HLA-DR was detected on the apical border of the surface epithelium one week after birth and was extensively expressed throughout the remaining postnatal period. Epithelial DP and PQ expression were virtually absent during this same period. These features probably reflect local activation of the immune system in response to environmental factors.

Constitutive hypersecretion and insensitivity to neurotransmitters by cystic fibrosis tracheal gland cells.

Submucosal glands are the major mucus-secreting cells in the tracheobronchial tree, and they appear to be affected in cystic fibrosis (CF). To study the dysregulation of pulmonary secretion in CF, human tracheal glandular (HTG) cells were isolated from tracheal mucosa of CF patients undergoing bipulmonary transplantation and compared with normal HTG cells. The cells were cultured in Dulbecco's modified Eagle's-Ham's F-12 medium supplemented with Ultroser G, on collagen type 1-coated dishes. We observed that the secretion rates for the three specific serous secretory markers: bronchial inhibitor (BrI), lysozyme, and lactoferrin were 10, 20, and 50 times higher, respectively, in CF-HTG cells than in normal HTG cells. Furthermore, the two physiological neurotransmitters: acetylcholine and norepinephrine, which have opposite actions on the secretion of BrI (suggesting that these neurotransmitters acted as regulators of secretion) did not induce the significant modification of protein secretion observed with normal HTG cells. In combination with forskolin and calcium ionophore A23187, secretion of BrI was minimally modified, indicating a lack of responsiveness of CF-HTG cells to these agonists. In conclusion, CF-HTG cells in culture show a constitutive hypersecretion and an hyporesponsiveness to agonists. They provide a useful tool to study the regulation defect of bronchial secretion observed in CF.

Changes in serous acinar cells of the tracheal gland in diabetic rats

Histochemical and ultrastructural changes in tracheal glands of rats with artificially induced diabetes were studied. The diabetic condition was induced by streptozotocin. The tracheal gland is composed of a duct and secretory units, mucus tubules and serous acini in diabetic as well as normal rats. In normal rats, the serous acinar cells contained only neutral polysaccharides. In diabetic rats, on the other hand, the serous acinar cells contained not only neutral but also moderate amounts of what appeared to be sialic acid containing compounds. On the ultrastructural level, two kinds of serous cells were observed in diabetic rats, one of which contained homogeneous granules while the other containing heterogeneous granules. The ratio between the number of cells containing heterogeneous granules and cells with homogeneous granules increased with the duration of the diabetic condition in the rat. Changes within the serous cells of diabetic rats might depress tracheal host defense mechanisms and could explain why airway infections are common in patients suffering from diabetes.

モルモット気管における炭酸脱水酵素の局在について

The distribution of histochemical carbonic anhydrase (CA) activity was investigated in the trachea of a guinea pig. Activity was localized in the tracheal glands, and some epithelial cells and goblet cells in the mucosal epithelium. These cells were not observed in the upper trachea, but appeared in the middle or lower trachea as well as at the carina. The mucosal epithelial cells containing CA could be classified into four types according to their morphology; 1) cells showing long, slender cylindrical morphology (Type I ),2) cells showing bulging at the site corresponding to the nucleus and long, slender process pointing towards the epithelial surface (Type II ),3) cells which resembled Type II but had loop-like processes pointed towards the epithelial surface (Type M), and 4) cells with two types of processes (Type IV).

Mucus hypersecretion in bronchiectasis. The role of neutrophil proteases.

To investigate the role of neutrophil proteases in the pathogenesis of mucus hypersecretion in bronchiectasis, we collected sputum samples from seven patients with bronchiectasis and measured their secretagogue activity by examining secretion of radiolabeled macromolecules by bovine airway submucosal gland cells incubated with sputum supernatants. There was marked secretagogue activity in bronchiectasis sputum, reaching a maximum of 1,963 +/- 292% (mean +/- SEM) above baseline at 1:15 dilution. Addition of ICI 200,355 (10(-5) M), a selective human neutrophil elastase inhibitor, decreased the secretory response markedly (72.53 +/- 5.89% reduction). The combination of aprotinin, an inhibitor of cathepsin G, and ICI 200,355 caused significantly more reduction in the secretory response than ICI 200,355 alone (89.12 +/- 3.8 versus 72.53 +/- 5.89% reduction, p < 0.05). We conclude that bronchiectasis sputum causes a large secretory response from tracheal submucosal glands due mostly to neutrophil proteases.

Secretory proteins and glycoconjugates synthesized by human tracheal gland cells in culture.

To study the proteins and glycoconjugates synthesized by serous cells from human tracheal glands (HTG), isolated HTG cells were cultured in the presence of radiolabeled precursors 14C-proline, Na2(35)SO4, and 3H-fucose. The secretory 14C/35S/3H-radiolabeled proteins and glycoproteins, de novo synthesized by HTG cells, were analyzed by gel filtration chromatography. We observed the incorporation of 14C-proline into antileukoprotease and an unknown 30 kD protein, and the incorporation of 35SO4-- and 3H-fucose into high molecular weight glycoconjugates and sulfoconjugates (M(r) > 1,000,000) and into components with apparent M(r) of approximately 250 and 100 kD. After specific chemical and enzymatic treatment, the 35S- and 3H-glycoconjugates were shown to be -O-linked mucin-like glycoproteins and proteoglycans. These results show that cultured HTG cells synthesize some of the macromolecules identified in bronchial secretions.

Cellular sequence of tracheal repair in sheep after smoke inhalation injury.

The cellular repair process of injured tracheal epithelium is described for sheep after exposure to toxic smoke containing high concentrations of acrolein. Fourteen fasted 3-4-year-old ewes had a portion of their cervical trachea exposed to cotton smoke for 20 min and then were sacrificed at various time intervals ranging from 1 to 22 days after exposure. Within 1 day of injury, columnar epithelium sloughed intact from the trachea with a concomitant reduction of nearly 35% in the basal cell population. At 2 days of recovery, the cellularity of the epithelium had increased and mitotic figures were observed in some tracheal epithelial and gland cells. By 8 days, undifferentiated hyperplastic cells increased to 30/100 microns, differentiated nonciliated columnar cells first appeared, and the basal cell population returned to a normal count of 13 cells/100 microns. Thirteen days after exposure, the undifferentiated hyperplastic cell population had declined to 7 cells/100 microns, nonciliated columnar cells were at control values, and some ciliated cells were identified. At 18 and 22 days, epithelium was normal in appearance and the count was 13 cells/100 microns. Data suggest that because the columnar epithelium sloughs intact with the cilia remaining active, toxic smoke may affect their attachment to the basal lamina. Furthermore, the regeneration process involves differentiation of hyperplastic cells in which they elongate down to the basal lamina, thus re-establishing the integrity of tall epithelium in the sheep trachea.

The ontogeny and distribution of surfactant protein B in human fetuses and newborns.

The distribution of immunoreactive surfactant-associated protein B (IR-SP-B) was studied immunohistochemically in 120 subjects from 10 weeks of gestation to 7 postnatal months with a polyclonal antibody against human SP-B. Electron microscopy (EM) was done in 72 subjects to document the presence of Type II cells containing lamellar bodies. Fetuses of less than 18 weeks' gestation showed no immunostaining. Beginning at 18 weeks, non-mucous cells of tracheal glands immunostained in a few instances. Fetuses of 19 through 23 weeks showed progressive immunostaining of cells lining terminal airways. Infants 26-40 weeks who died with or without pulmonary pathology showed immunostaining of Type II cells and bronchioloalveolar (BA) portal cells of the respiratory bronchioles. In infants with hyaline membrane disease (HMD) who died less than 12 days after birth, occasional tracheal gland cells, BA portal cells, and mature and relining Type II cells immunostained. In bronchopulmonary dysplasia (BPD), BA portal cells, relining Type II cells, macrophages, and luminal material immunostained. Occasional tracheal and bronchial gland cells and Clara cells immunostained. The appearance of IR-SP-B at mid-gestation correlated with differentiation of Type II cells. There was good correlation of immunostaining with the presence of lamellar bodies on EM. Accelerated maturation of the lung was often associated with premature rupture of membranes (PROM).

Cat tracheal gland cells in primary culture.

Conditions for the primary culture of isolated cat tracheal gland cells were established. Cells plated onto glutaraldehyde-fixed gels of rat tail collagen grew to confluency after 8 days of culture forming a monolayer of cuboidal cells with ultrastructural characteristics of epithelial cells and immunoreactivity to antikeratins. Cultured cells synthesized and released radiolabeled high-molecular-weight glycoconjugates. Glycoconjugate secretion was increased approximately 10% in response to the cholinergic agonist, carbachol. Secretion of glycoconjugates was unrelated to regulated exocrine secretion, since these cells were devoid of secretion granules as assessed by light and electron microscopy. Confluent cultures also generated a spontaneous potential difference and short-circuit current, which were both inhibited by ouabain and increased by carbachol. This suggested gland cells contribute to fluid secretion by active ion-transport mechanisms. We also plated cells onto unfixed collagen gels that were released from the culture dish at confluency. Cells were columnar with apically oriented secretion granules that stained with alcian blue and for blood group A immunoreactivity. Secretion of radiolabeled high-molecular-weight glycoconjugates was increased 27% by carbachol. These cell culture systems may serve as models to investigate glandular secretory mechanisms and their regulation.

Arachidonic acid increases cholinergic secretory responsiveness of ferret tracheal glands.

The purpose of this study was to determine if arachidonic acid could alter ferret tracheal gland secretory responsiveness to a cholinergic agonist. We prepared glandular explants and incubated the explants in medium containing [3H]glucosamine. Secretory responsiveness was expressed as the percent change in basal secretion of acid-precipitable [3H]glucosamine-labeled glycoconjugates induced by the addition of agonist with and without arachidonic acid [mean +/- SE (n)]. Addition of 10(-3) M arachidonic acid caused a significant increase in secretion [28 +/- 6% (n = 6)] compared with untreated control tissues [-10 +/- 4% (n = 7), P less than or equal to 0.05]. Carbachol (10(-7) M) increased secretion 39 +/- 9% (n = 7). The combination of 10(-3) M arachidonic acid and 10(-7) M carbachol elicited a significantly greater change in secretion compared with either agent alone [173 +/- 50% (n = 5)]. The addition of nordihydroguaiaretic acid (10(-6) M) or indomethacin (10(-6) M) partially attenuated the arachidonic acid-enhanced secretory responsiveness to carbachol. Treatment with both blockers completely inhibited the arachidonic acid-enhanced secretory responsiveness to carbachol. The effect of arachidonic acid on cholinergic stimulation was also abolished by treating the explant cultures with tetrodotoxin (10(-7) M). This hypersecretory state is most likely mediated by eicosanoid-induced release of neurotransmitters from nerve terminals.