Dogma destroyed: colonic crypts absorb.
Explore the source record for details and available documents.
Colon↗
Biomedical subjects
D W Powell
Publications and source records attributed to D W Powell.
Neuroimmunophysiology of the gastrointestinal mucosa: implications for inflammatory diseases.
In conclusion, studies of the neuroimmunophysiology of the intestinal mucosa of the past 5-8 years have demonstrated an important role for the immune system in modulating water and electrolyte transport as well as intestinal motility in the gut. Activation of mast cells and phagocytes leads to heightened Cl- and water secretion, as well as changes in intestinal motility which leads to diarrheal states. These diarrheal responses are self-protective; they rid the intestine of offending microorganisms and antigens. Our investigation of this response has uncovered a new immune accessory cell Cz, the intestinal myofibroblast. This cell seems to play an important role in amplifying the immune signal. This cell is probably also important for the secretion of growth factors onto the epithelium and also the secretion of collagen which results in fibrosis under diseased states. These intestinal myofibroblasts are prolific prostaglandin producers, an important finding because prostaglandin synthesis inhibition has been shown to decrease the development of neoplasia in the gut. Thus, these intestinal myofibroblasts may have other important roles in addition to just modulating water and electrolyte secretion or gut motility. Our laboratory is now engaged in studying these intestinal myofibroblasts in some detail hoping to better understand the biology of these interesting cells.
Animals↗
Presentation of the Julius Friedenwald Medal to Basil I. Hirschowitz, M.D.
Explore the source record for details and available documents.
Awards and Prizes↗
Epithelial secretory responses to inflammation. Platelet activating factor and reactive oxygen metabolites.
Explore the source record for details and available documents.
Animals↗
Fibroblasts modulate intestinal secretory responses to inflammatory mediators.
Cultured colonic epithelial cells and fibroblasts were used to examine the interaction between these cell types during intestinal secretion. Secretory responses of T84 colonic epithelial cells, measured as changes in the short-circuit current in modified Ussing chambers to bradykinin, serotonin, hydrogen peroxide, and histamine, were enhanced in the presence of fibroblasts, either in cocultures or when separate cultures of fibroblasts were acutely juxtaposed with the T84 cultures. This effect was abolished by pretreatment with indomethacin and the fibroblasts were found to release prostaglandin E2 in response to these inflammatory mediators. Fibroblasts may exert a paracrine regulation on the secretory response of intestinal epithelial cells via the generation and release of cyclooxygenase products in response to inflammatory mediators. These studies suggest a novel function for the intestinal fibroblastic sheath: that of amplification of the inflammatory response through mesenchymal/epithelial interaction.
Animals↗
Immune system control of intestinal ion transport.
Explore the source record for details and available documents.
Animals↗
Villous atrophy, crypt hyperplasia, cellular infiltration, and impaired glucose-Na absorption in enteric cryptosporidiosis of pigs.
Intestinal morphology and fluid and electrolyte transport were examined in a neonatal porcine model of cryptosporidiosis. Sections of jejunum, ileum, and colon were obtained for morphometric analysis on days 3, 6, 9, and 12 postinfection, and in vivo perfusion studies of jejunum and ileum were conducted on days 3 and 4 postinfection. The most severe morphologic lesion was seen in the ileum on day 3, and consisted of villous atrophy, crypt hyperplasia, and cellular infiltration. Villous surface area was reduced from 2.1 +/- 0.4 x 10(5) microns2 in control ileum to 0.8 +/- 0.1 x 10(5) microns2 in infected ileum, a result associated with enterocytes that were fewer in number and reduced in cross-sectional area. Conversely, the number of inflammatory cells in the lamina propria of the villus increased from 456 +/- 116 in control to 1014 +/- 187 in infected villus without a significant change in the volume of the lamina propria. At the height of infection, there was an approximate 1:2 ratio of both organisms and inflammatory cells to villous enterocytes. In contrast, organisms were not observed in the crypts, and the concentration of inflammatory cells in crypt lamina propria was unaltered. Disappearance of organisms and polymorphonuclear cells from the ileum was associated with restoration of normal structure and was complete by day 12. Although organisms were seen in the colon, the general architecture was not severely affected. On days 3 and 4 postinfection, there was a complete impairment of the glucose-stimulated Na and water absorption in both jejunum and ileum of infected pigs; however, absorption of electrolytes and water from a basic Ringer's solution, in the absence of glucose, was not significantly affected. These results are consistent with a malabsorptive diarrheal disease associated with the morphological damage and are very similar to those seen in enteric viral disease in pigs, except that the upper intestine is more severely affected in the latter.
Animals↗
Hydrogen peroxide stimulates rat colonic prostaglandin production and alters electrolyte transport.
The changes in short circuit current (electrogenic Cl- secretion) of rat colon brought about by xanthine/xanthine oxidase in the Ussing chamber were inhibited by catalase and diethyldithiocarbamate, but not by superoxide dismutase. These results, the reproduction of the response with glucose/glucose oxidase and with exogenous H2O2, and the lack of effect of preincubation with deferoxamine or thiourea implicate H2O2, and not O2- or OH., as the important reactive oxygen metabolite altering intestinal electrolyte transport. 1 mM H2O2 stimulated colonic PGE2 and PGI2 production 8- and 15-fold, respectively, inhibited neutral NaCl absorption, and stimulated biphasic electrogenic Cl secretion with little effect on enterocyte lactic dehydrogenase release, epithelial conductance, or histology. Cl- secretion was reduced by cyclooxygenase inhibition. Also, the Cl- secretion, but not the increase in prostaglandin production, was reduced by enteric nervous system blockade with tetrodotoxin, hexamethonium, or atropine. Thus, H2O2 appears to alter electrolyte transport by releasing prostaglandins that activate the enteric nervous system. The change in short circuit current in response to Iloprost, but not PGE2, was blocked by tetrodotoxin. Therefore, PGI2 may be the mediator of the H2O2 response. H2O2 produced in nontoxic concentrations in the inflamed gut could have significant physiologic effects on intestinal water and electrolyte transport.
Animals↗
Serosal bicarbonate protects against acid injury to rabbit esophagus.
The role of serosal bicarbonate ions (HCO3-) in protection against acid injury was investigated in rabbit esophageal mucosa mounted in Ussing chambers. Luminal acidification reduced potential difference and resistance in tissues exposed serosally to HCO3- or (unbuffered) HCO3-free solution. Whereas resistance declined similarly in both groups, potential difference declined less in HCO3- solution. After washout, HCO3-bathed tissues also had a greater increase in resistance, lower permeability to mannitol, and less histologic damage. Furthermore, as protection by HCO3- was not blocked by pretreatment with either the anion exchange blocker, 4 acetamido-4'-isothiocyanatostilbene 2-2'-disulfonic acid, or the carbonic anhydrase inhibitor, acetazolamide, and replacement of HCO3- with N-2-hydroxyethylpiperazine-N'-2-ethane sulfonic acid, a buffer impermeant to cells, was protective, an extracellular site for protection by HCO3- was likely. Where in the extracellular space HCO3- buffers H+ is unclear, but the absence of change in luminal pH and the inability to prevent the acid-induced increase in permeability in HCO3-bathed tissues argue against a luminal (preepithelial) site. Also, rapid repair was not demonstrated, indicating that a luminal site for protection after surface cell damage was unlikely. We conclude that serosal HCO3- is important in esophageal protection against acid damage by buffering H+ within the intercellular compartment of the extracellular space.
4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
Colonic and esophageal transepithelial potential difference in cystic fibrosis.
To evaluate differences in the expression of cystic fibrosis (CF) transport defects in the gastrointestinal tract of subjects with CF, in vivo measurements of colonic and esophageal transepithelial electrical potential difference (PD) were performed before and during amiloride superfusion in CF and healthy subjects. Esophageal PD before (-16 +/- 2 vs. -16 +/- 3 mV) and after (-14 +/- 2 vs. -15 +/- 0.3 mV) superfusion with amiloride were similar for CF and healthy subjects. Basal rectosigmoid colon PD was also similar (CF: mean -23 +/- 6 and maximal -37 +/- 9 mV; normal: mean -26 +/- 5 and maximal -45 +/- 11 mV) in both groups. However, with amiloride superfusion (10(-4) M) the colonic PD in CF subjects was almost abolished (95% +/- 15% inhibition), whereas the PD in healthy subjects was only partially reduced (42% +/- 6%) (p less than 0.05). The greater inhibition with amiloride in CF, which was evident in absolute terms (26 +/- 4 vs. 16 +/- 3 mV for controls, p less than 0.05) as well as relative terms, could not be ascribed to a difference in mineralocorticoid secretion rates, because 24-h urine excretion of aldosterone and 17 hydroxy and 17 ketosteroids were similar in both groups. Freshly excised colonic epithelia from 1 CF and 3 non-CF subjects were studied in Ussing chambers, and a similar difference in amiloride responsiveness noted: PD and short-circuit current declined 33% +/- 2% and 37% +/- 4%, respectively, in seven tissues from the colons of 3 patients without CF, whereas both PD and short-circuit current were fully inhibited (100%) in all three tissues from the CF patient. As the presence of an amiloride-insensitive component of short-circuit current in non-CF colon is largely due to electrogenic Cl- secretion, the demonstration that this component was absent both in vivo and in vitro in CF colon establishes the presence of a defect in electrolyte transport in CF colon, a defect consistent with recent reports of absent electrogenic Cl- secretion in CF intestine.
Adult↗
Immune system control of rat and rabbit colonic electrolyte transport. Role of prostaglandins and enteric nervous system.
The role of the immune system in controlling intestinal electrolyte transport was studied in rat and rabbit colon in Ussing chambers. A phagocyte stimulus, the chemotactic peptide FMLP, and a mast cell stimulus, sheep anti-rat IgE, caused a brief (less than 10 min) increase in short-circuit current (Isc). Products of immune system activation, platelet-activating factor (PAF) and reactive oxygen species (ROS), caused a sustained, biphasic increase in the Isc. Ion replacement and flux studies indicated that these agonists stimulated electrogenic Cl secretion and inhibited neutral NaCl absorption; responses that were variably inhibited by the cyclooxygenase blockers indomethacin and piroxicam. Lesser degrees of inhibition by nordihydroguaiaretic acid could be accounted for by decreased prostaglandin synthesis rather than by lipoxygenase blockade. Tetrodotoxin, hexamethonium, and atropine also inhibited immune agonist-stimulated Isc, but had no effect on immune agonist-stimulated production of PGE2 or PGI2. These results indicate that immune system agonists alter intestinal epithelial electrolyte transport through release of cyclooxygenase products from cells in the lamina propria with at least 50% of the response being due to cyclooxygenase product activation of the enteric nervous system. The immune system, like the enteric nervous system and the endocrine system, may be a major regulating system for intestinal water and electrolyte transport in health and disease.
Animals↗
Effect of BW 942C, an enkephalinlike pentapeptide, on sodium and chloride transport in the rabbit ileum.
BW 942C is a novel enkephalinlike pentapeptide that has been shown to have antidiarrheal action in model systems. The effect of BW 942C on rabbit ileal electrolyte transport was studied to gain insight into the mechanism of the antidiarrheal action of opiate-like compounds. Multiple effects were observed, differing with the basal state of the tissue. BW 942C increased Na absorption in tissues that were not absorbing in the basal state, whereas it had little effect on Na absorption in tissues that were previously absorbing at moderate to high rates (greater than 1 microEq/h.cm2. It increased Cl absorption and caused a dose-related decrease in short-circuit current in all tissues. This effect was reversed or inhibited by naloxone (10(-5) M), suggesting that it is mediated by opiate receptors. No significant change in residual flux was noted. BW 942C was effective from both the serosal and mucosal side; however, it required a 2-log higher dose on the mucosal side (10(-4) M, maximal) to achieve a response similar to that observed with serosal application (10(-6) M, maximal). The ability of BW 942C to alter stimulated secretion was studied using theophylline, prostaglandin E2, vasoactive intestinal peptide, and bethanechol. There was significantly less Cl secretion in BW 942C-treated tissues than in control tissues after stimulation with prostaglandin E2 (10(-7) M). However, this effect was not apparent at higher doses of prostaglandin E2 and there was no inhibition of the short-circuit current response to any of the secretory stimuli by BW 942C. Loperamide was also found to be unable to inhibit the Cl secretion or change in short-circuit current stimulated by theophylline. Although opiates have been shown to be moderately effective antidiarrheal agents, their ability to influence mucosal electrolyte transport is weak and may only account for part of their antidiarrheal action.
Animals↗
Altered intestinal chloride transport in cystic fibrosis.
Sodium ion and chloride transport was studied in vitro in small intestinal and colonic tissue from patients with cystic fibrosis (CF) and from non-CF control subjects matched as to age and sex. Normal histological appearance and substantial response to mucosal glucose (5 mM, ileum) or mucosal amiloride (10(-5) M, colon) indicated normal tissue viability in both control and CF tissues. Electroneutral NaCl absorption was demonstrated in the small intestine of control subjects and CF patients. Small intestinal and colonic tissues of control subjects responded to four secretagogues (theophylline, 5 mM; prostaglandin E2, 10(-6) M; calcium ionophore (A23187), 10(-5) M; bethanechol, 5 x 10(-5) M), with electrogenic chloride secretion. The tissues of CF patients, however, did not respond to any of the test secretagogues. These studies demonstrate that an abnormality in chloride transport is present in the small intestinal and colonic epithelia of CF patients. Unlike airway epithelia, which secrete chloride in response to Ca ionophore, the intestinal epithelia of CF patients do not respond to either cAMP- or Ca-mediated secretagogues. This abnormality in intestinal electrolyte transport may play a role in the pathogenesis of meconium impactions in CF patients.
Adult↗
Mucosal protection by sucralfate and its components in acid-exposed rabbit esophagus.
Sucralfate has been reported to protect the esophageal epithelium of the rabbit and cat against acid injury. To determine the contribution of its components, aluminum hydroxide and sucrose octasulfate (SOS), rabbit esophageal epithelia were mounted in Ussing chambers to monitor changes in electrical resistance (R) upon exposure to HCl (pH 1.4-1.6). In untreated tissues, acidification of the luminal bath produced a progressive decline in R, indicating increased epithelial permeability. Sucralfate added to the luminal bath 45 min after acidification increased R to preexposure levels--an effect accompanied by increased luminal pH. Similar to sucralfate, aluminum hydroxide added to the acidified bath increased R and luminal pH. However, the effect of aluminum hydroxide could be abolished by titration with HCl to maintain pH similar to acid-treated control tissues. Tissues treated with sucralfate and whose luminal solutions were titrated with HCl to maintain pH similar to controls no longer exhibited an increase in R but, in contrast to aluminum hydroxide treatment, the acid-induced decline in R was prevented. This action of sucralfate was shown to be a property of its other component, SOS. Sucrose octasulfate, like acid-titrated sucralfate solutions, did not increase luminal bath pH, yet prevented the acid-induced decline in R. Confirmation of protection by SOS was shown by additional morphologic and flux studies. Thus 1 h after luminal bath acidification in the Ussing chamber, SOS-treated tissues demonstrated less damage (injury score 0.6 +/- 0.4 vs. 1.6 +/- 0.3, p less than 0.05) and lower permeability to mannitol (0.003 +/- 0.001 vs. 0.013 +/- 0.005 mumol/h X cm2, p less than 0.05) than untreated tissues. Similarly, 1 h of luminal perfusion with HCl in vivo produced less damage (injury score 1.3 +/- 0.5 vs. 3.5 +/- 0.4, p less than 0.05) and less H+ efflux from the lumen in SOS-treated than untreated tissues. These results indicate that sucralfate can protect against acid injury in esophagus and that this protection is mediated by (a) intraluminal pH buffering through its content of aluminum hydroxide and (b) enhancing mucosal defense against H+ entry and injury through its content of SOS.
Acids↗
Development of a scoring system to predict mortality from upper gastrointestinal bleeding.
Despite the widespread application of endoscopy in acute upper gastrointestinal bleeding, there is little evidence of improved survival among those who undergo the procedure. To select high-risk patients who might benefit most from diagnostic and therapeutic endoscopy, the authors developed and validated a scoring system based on prognostic indicators of increased mortality. The scoring system was developed from the best clinical predictors of mortality, determined in a prospective study of consecutive bleeding patients. The model was then tested in a prospective validation phase at three hospitals. Three main factors in the model predict mortality: bleeding, including hematochezia, drop in hematocrit of 5%, short duration of bleeding, absence of melena, and hypotension; liver disease, manifested by prolonged prothrombin time and encephalopathy; and renal disease. Patients determined to be at high risk for death using the scoring system might be candidates for aggressive management and for therapeutic endoscopy.
Adolescent↗
Bradykinin-stimulated eicosanoid synthesis and secretion by rabbit ileal components.
The eicosanoid profiles, sites of production, and response to bradykinin stimulation were determined in rabbit ileum and its various components by radioimmunoassay of various prostanoids and 5-lipoxygenase products in the incubation media. The profile of eicosanoid synthesis and secretion by the epithelial cell fraction was PGF2 alpha greater than 6-keto-PGF1 alpha greater than dihydro-keto-PCM = PGE2 greater than TxB2 much greater than 5-HETE greater than LTB4 and by the deepitheliated ileum was PGE2 = 6-keto-PGF1 alpha greater than PGF2 alpha greater than dihydro-keto-PGM greater than TxB2 much greater than LTB4 greater than 5-HETE. PGD2 was not sought in these studies. Rates of eicosanoid production by the deepitheliated ileum were over 200 times that of the epithelial cells. The epithelial cells accounted for 67% of the protein but only 0.2% of the PGE2 produced, while the lamina propria and submucosa contained only 12-30% of the protein but produced 80-90% of the PGE2. Bradykinin (1 microM), A23187 (10 microM), arachidonic acid (20 microM), and melittin (0.7 microM) stimulated PGE2 and 6-keto-PGF1 alpha production by 200% in deepitheliated (or subepithelial) ileum, but bradykinin failed to stimulate production of any eicosanoid by the epithelial cell fraction. Thus the subepithelium (predominantly the lamina propria) is the major eicosanoid producer of rabbit ileum and is the major site of bradykinin-stimulated eicosanoid synthesis and secretion. Eicosanoids released from subepithelial components may be important regulators of epithelial function.
1-Methyl-3-isobutylxanthine↗
Cytoprotection by sucralfate: role of sulfate ions.
Sucralfate and its component, sucrose octasulfate, are both SO4(2-)-containing compounds shown to protect against acid-peptic injury in rabbit and/or cat esophagi. To determine if sulfate ions (SO4(2-) contributed to this protection, a series of in vitro and in vivo experiments were performed in acid-exposed rabbit esophagi. In the Ussing chamber SO4(2-)-containing solutions significantly reduced the acid-induced decline in electrical resistance (R) observed in controls. This effect was unrelated to buffering of H+, accompanying cation or changes in luminal solution osmolality. Protection by SO4(2-) was specific since other divalent (HPO4(2-] or impermeant anions (gluconate-) failed to reduce the acid-induced decline in R. Protection was confirmed in vivo by showing that acid-perfused esophagi exposed to SO4(2-) had less morphologic damage, higher R and lower permeability to 14C-mannitol and H+ than controls. These results indicate that SO4(2-) have a unique protective action against acid injury to esophageal epithelia, and this action appears to explain the cytoprotective properties of sucralfate.
Animals↗
Effect of cigarette smoke on esophageal epithelium of the rabbit.
Cigarette smoking is a recognized risk factor for esophageal mucosal disease. For this reason we investigated the effects of smoke on esophageal epithelial electrolyte transport and barrier function in the rabbit. Studies were performed using an extract of cigarette smoke (EOCS) prepared from high-tar, high-nicotine cigarettes. Epithelia were exposed to EOCS in vivo or in vitro in the Ussing chamber. Acute in vivo exposure to EOCS lowered in vivo esophageal potential difference by 61%, and in vitro studies established that this was due to inhibition of active Na transport from mucosa to serosa. Exposure to an EOCS had no effect on net Cl transport or epithelial permeability, the latter reflected by the absence of change in electrical resistance or mannitol flux. The ability of an EOCS to lower potential difference (and inhibit Na transport) was dose-related and equally effective whether contact occurred with the luminal or serosal surface of the tissue. Similar studies performed with an EOCS prepared from filtered smoke established that the component(s) in EOCS responsible for the effects on transport resided in the particulate phase of smoke (i.e., nicotine and "tars"). However, nicotine only inhibited Na transport from the serosal side of the tissue, thus indicating that one or more tars either cause or contribute to the effect of an EOCS on transport. The inhibition by smoke of ion transport in esophageal epithelium may well be an early deleterious link in the pathophysiological chain between cigarette smoking and esophageal mucosal disease.
Animals↗