Potential Role for Interleukin-1 in the Pathophysiology of Ulcerative Colitis

1994 ◽  
Vol 86 (5) ◽  
pp. 619-626 ◽  
Author(s):  
T. D. Wardle ◽  
L. A. Turnberg
Keyword(s):  
Ulcerative Colitis ◽  
Prostaglandin E2 ◽  
Inflammatory Mediators ◽  
Colonic Mucosa ◽  
Short Circuit ◽  
Interleukin 1 ◽  
Platelet Activating Factor ◽  
Short Circuit Current ◽  
Normal Mucosa ◽  
Leukotriene C4

1. Biopsies of colonic mucosa from patients with ulcerative colitis liberated more interleukin-1β, prostaglandin E2, leukotriene C4 and platelet-activating factor into the medium in which they were cultured than biopsies from patients with irritable bowel syndrome and histologically normal mucosa. 2. Addition of interleukin-1 stimulated release of greater quantities of all these inflammatory mediators, including interleukin-1 itself, from inflamed and normal mucosa. 3. Blockade of cyclo-oxygenase with indomethacin or of lipoxygenase with ICI 207968 or of phospholipase A2 with mepacrine inhibited release of prostaglandin E2 or leukotriene C4 or both of these plus platelet-activating factor, respectively. 4. Interleukin-1 stimulated the short-circuit current across isolated rat colonic mucosa mounted in flux chambers in a dose-dependent manner (Km 2 × 10−11 mol/l). This stimulation was markedly inhibited by the removal of chloride from the bathing media. 5. Indomethacin or ICI 207968 inhibited the short-circuit current response to interleukin-1 and a combination of these antagonists produced a greater inhibition. Mepacrine caused an even greater inhibition whereas tetrodotoxin plus mepacrine inhibited the current completely. 6. These data indicate that interleukin-1, released in excess from inflamed colonic mucosa, stimulates the release of a range of inflammatory mediators as well as of more interleukin-1. It probably acts by stimulating phospholipase A2 in inflammatory cells, probably lymphocytes, and can do so in normal and inflamed mucosa. Since, in rat colonic mucosa it stimulated an electrical response in very low concentrations, it is feasible that it is involved in the chloride secretion, and hence the diarrhoea, which may occur in inflammatory reactions. Hence treatment with mepacrine seems a prospect worth pursuing.

Neuromodulation of ion transport in porcine distal colon: NPY reduces secretory actions of leukotrienes

1995 ◽  
Vol 269 (2) ◽  
pp. R426-R431 ◽  
Author(s):  
T. R. Traynor ◽  
D. R. Brown ◽  
S. M. O'Grady
Keyword(s):  
Ion Transport ◽  
Colonic Mucosa ◽  
Short Circuit ◽  
Short Circuit Current ◽  
Distal Colon ◽  
Effective Concentration ◽  
Leukotriene C4 ◽  
Ussing Chambers ◽  
Cl Secretion ◽  
Half Maximal Effective Concentration

Electrical transmural stimulation (ETS) was used to examine the neuroregulation of electrolyte transport in the porcine distal colon. ETS of the colonic mucosa-submucosa mounted in Ussing chambers produced rapid and transient increases in short-circuit current (Isc) that were inhibited 36% by serosal bumetanide, suggesting that a portion of the response may be attributed to Cl secretion. ETS actions were dependent upon stimulus intensity and frequency and were inhibited by tetrodotoxin and omega-conotoxin. Prazosin and pyrilamine had no effect on the mucosal responses to ETS, whereas atropine reduced the responses by 32%. Neuropeptide Y (NPY) also reduced the mucosal responses to ETS up to 60% (half-maximal effective concentration = 17 nM). In addition, the effects of leukotriene C4, previously shown to stimulate Cl secretion via a neuronal pathway, were also inhibited by NPY. These results indicate that cholinergic submucosal neurons play a role in the regulation of epithelial ion transport and that NPY acts as an inhibitory neuromodulator, particularly on leukotriene-sensitive neurons in the porcine distal colon.

Colitis reduces short-circuit current response to inflammatory mediators in rat colonic mucosa

Inflammation ◽  
1995 ◽  
Vol 19 (2) ◽  
pp. 245-259 ◽  
Author(s):  
J. F. Kachur ◽  
A. Keshavarzian ◽  
R. Sundaresan ◽  
M. Doria ◽  
R. Walsh ◽  
...  
Keyword(s):  
Inflammatory Mediators ◽  
Colonic Mucosa ◽  
Short Circuit ◽  
Short Circuit Current ◽  
Current Response

HCl-induced inflammatory mediators in cat esophageal mucosa and inflammatory mediators in esophageal circular muscle in an in vitro model of esophagitis

2006 ◽  
Vol 290 (6) ◽  
pp. G1307-G1317 ◽  
Author(s):  
Ling Cheng ◽  
Weibiao Cao ◽  
Claudio Fiocchi ◽  
Jose Behar ◽  
Piero Biancani ◽  
...  
Keyword(s):  
Inflammatory Mediators ◽  
Platelet Activating Factor ◽  
Circular Muscle ◽  
Muscle Layer ◽  
Normal Mucosa ◽  
Esophageal Mucosa ◽  
Mrna Levels ◽  
Physiol Gastrointest Liver ◽  
Krebs Buffer

Platelet-activating factor (PAF) and interleukin-6 (IL-6) are produced in the esophagus in response to HCl and affect ACh release, causing changes in esophageal motor function similar to esophagitis (Cheng L, Cao W, Fiocchi C, Behar J, Biancani P, and Harnett KM. Am J Physiol Gastrointest Liver Physiol 289: G418–G428, 2005). We therefore examined HCl-activated mechanisms for production of PAF and IL-6 in cat esophageal mucosa and circular muscle. A segment of normal mucosa was tied at both ends, forming a mucosal sac (Cheng L, Cao W, Fiocchi C, Behar J, Biancani P, and Harnett KM. Am J Physiol Gastrointest Liver Physiol 289: G860–G869, 2005) that was filled with acidic Krebs buffer (pH 5.8) or normal Krebs buffer (pH 7.0) as control and kept in oxygenated Krebs buffer for 3 h. The supernatant of the acidic sac (MS-HCl) abolished contraction of normal muscle strips in response to electric field stimulation. The inhibition was reversed by the PAF antagonist CV3988 and by IL-6 antibodies. PAF and IL-6 levels in MS-HCl and mucosa were significantly elevated over control. IL-6 levels in mucosa and supernatant were reduced by CV3988, suggesting that formation of IL-6 depends on PAF. PAF-receptor mRNA levels were not detected by RT-PCR in normal mucosa, but were significantly elevated after exposure to HCl, indicating that HCl causes production of PAF and expression of PAF receptors in esophageal mucosa and that PAF causes production of IL-6. PAF and IL-6, produced in the mucosa, are released to affect the circular muscle layer. In the circular muscle, PAF causes production of additional IL-6 that activates NADPH oxidase to induce production of H2O2. H2O2 causes formation of IL-1β that may induce production of PAF in the muscle, possibly closing a self-sustaining cycle of production of inflammatory mediators.

Corticosteroid alteration of active electrolyte transport in rat distal colon

1983 ◽  
Vol 245 (5) ◽  
pp. G668-G675 ◽  
Author(s):  
E. S. Foster ◽  
T. W. Zimmerman ◽  
J. P. Hayslett ◽  
H. J. Binder
Keyword(s):  
Colonic Mucosa ◽  
Short Circuit ◽  
Short Circuit Current ◽  
Distal Colon ◽  
Transport Processes ◽  
Electrolyte Transport ◽  
Sodium Absorption ◽  
Rat Distal Colon ◽  
Potassium Absorption ◽  
Potassium Secretion

To determine the effect of corticosteroids on active transport processes, unidirectional fluxes of 22Na, 36Cl, and 42K were measured under short-circuit conditions across isolated stripped distal colonic mucosa of the rat in control, secondary hyperaldosterone, and dexamethasone-treated animals. In controls net sodium and chloride fluxes (JNanet and JClnet) and short-circuit current (Isc) were 6.6 +/- 2.2, 7.6 +/- 1.6, and 1.3 +/- 0.2 mu eq X h-1 X cm-2, respectively. Although aldosterone increased Isc to 7.3 +/- 0.5 mu eq X h-1 X cm-2, JNanet (6.9 +/- 0.7 mu eq X h-1 X cm-2) was not altered and JClnet was reduced to 0 compared with controls. Dexamethasone also stimulated Isc but did not inhibit JClnet. In Cl-free Ringer both aldosterone and dexamethasone produced significant and equal increases in JNanet and Isc. Theophylline abolished JNanet in control animals but not in the aldosterone group. Aldosterone reversed net potassium absorption (0.58 +/- 0.11 mu eq X h-1 X cm-2) to net potassium secretion (-0.94 +/- 0.08 mu eq X h-1 X cm-2). Dexamethasone reduced net potassium movement to 0 (-0.04 +/- 0.12 mu eq X h-1 X cm-2). These studies demonstrate that 1) corticosteroids stimulate electrogenic sodium absorption and 2) aldosterone, but not dexamethasone, inhibits neutral NaCl absorption and stimulates active potassium secretion. The effects of mineralocorticoids and glucocorticoids on electrolyte transport are not identical and may be mediated by separate and distinct mechanisms.

Eicosanoid interactions in the canine proximal colon

1989 ◽  
Vol 256 (4) ◽  
pp. G673-G679 ◽  
Author(s):  
C. M. Keenan ◽  
P. K. Rangachari
Keyword(s):  
Arachidonic Acid ◽  
Prostaglandin E2 ◽  
Metabolic Pathway ◽  
Colonic Mucosa ◽  
Short Circuit ◽  
Leukotriene B4 ◽  
Proximal Colon ◽  
Cyclooxygenase Inhibitors ◽  
Lipoxygenase Product ◽  
Short Circuit Currents

Effects of eicosanoids on the canine proximal colonic mucosa were examined. Both arachidonic acid (AA) and prostaglandin E2 (PGE2) increased short-circuit currents. Tetrodotoxin did not affect these responses, suggesting that functioning nerves are not required. Indomethacin abolished responses to AA, indicating that the cyclooxygenase pathway is the primary metabolic pathway. Indomethacin significantly potentiated responses to PGE2, suggesting that in the presence of cyclooxygenase inhibition either 1) a normally inhibitory cyclooxygenase product is not present or 2) a potentiating lipoxygenase product is being produced in greater amounts. PGE2 is produced in significant quantities, whereas leukotriene B4 (LTB4) is produced in smaller amounts. Cyclooxygenase inhibitors significantly decreased PGE2 production but had no effect on LTB4. This suggests that an inhibitory PG may be opposing the response to PGE2. Therefore, we tested the effects of several cyclooxygenase products on PGE2 responsiveness. PGD2 alone significantly reduced responses to PGE2. In the canine proximal colon the response to AA is apparently the algebraic sum of the opposing responses of PGE2 and PGD2.

Effects of platelet-activating factor on ion transport in isolated rat jejunum

1989 ◽  
Vol 257 (5) ◽  
pp. G845-G850 ◽  
Author(s):  
A. C. Hanglow ◽  
J. Bienenstock ◽  
M. H. Perdue
Keyword(s):  
Ion Transport ◽  
Early Phase ◽  
Short Circuit ◽  
Late Phase ◽  
Platelet Activating Factor ◽  
Short Circuit Current ◽  
Cyclooxygenase Inhibitors ◽  
Base Line ◽  
Intermediate Cell ◽  
Rat Jejunum

In isolated normal rat jejunum, platelet-activating factor (PAF) induced a dose-dependent increase in short-circuit current (Isc) that was reduced in chloride-free buffer and inhibited by the Cl- channel blocker, diphenylamine-2-carboxylate. An immediate rise in Isc (early phase) occurred that fell to a new elevated base line by 15 min (late phase). These responses to PAF occurred only when experiments were conducted at or before approximately 9 A.M. Early phase responses were blocked by the specific PAF antagonists, BN52021 and WEB2086, and were inhibited by the neurotoxin, tetrodotoxin. Early and late phases were also reduced by cyclooxygenase inhibitors and by doxantrazole, a mast cell stabilizing drug. However, histamine and serotonin antagonists were ineffective. We conclude that PAF causes changes in ion transport that include Cl- secretion and acts on the epithelium possibly via an intermediate cell and enteric nerves. In addition, known PAF receptors are involved in one component of the response that appears to follow a circadian rhythm.

Effect of the thiol-oxidizing agent diamide on NH2Cl-induced rat colonic electrolyte secretion

1993 ◽  
Vol 265 (1) ◽  
pp. C166-C170 ◽  
Author(s):  
H. Tamai ◽  
J. F. Kachur ◽  
M. B. Grisham ◽  
M. W. Musch ◽  
E. B. Chang ◽  
...  
Keyword(s):  
Colonic Mucosa ◽  
Short Circuit ◽  
Chloride Ion ◽  
Short Circuit Current ◽  
Rat Colon ◽  
Maximal Effect ◽  
Oxidizing Agent ◽  
Maximal Increase ◽  
Ussing Chambers ◽  
Electrolyte Secretion

The granulocyte-derived oxidant, monochloramine (NH2Cl), is known to stimulate chloride ion secretion in rat distal colonic mucosa mounted in Ussing chambers, through mechanisms that are sensitive and insensitive to tetrodotoxin (TTX). The possible role of intracellular thiols, in the mechanism of action of NH2Cl as a secretagogue, was evaluated with the thiol-oxidizing agent diamide and by measuring tissue sulfhydryl levels in response to NH2Cl. Serosal exposure to the antioxidant glutathione (0.25 mM), 5 min before NH2Cl (50 microM) addition, decreased the maximal effect of 50 microM NH2Cl on short-circuit current (Isc). The NH2Cl-stimulated increase in Isc was not affected by mucosal amiloride (5 microM). Pretreatment with 0.1 mM diamide shortened the lag period before the increase in Isc in response to NH2Cl, but it did not affect the maximal increase in Isc. Although TTX (0.5 microM) increased the lag time for achievement of the maximal Isc response to NH2Cl, the neurotoxin did not inhibit the effect of diamide, suggesting that diamide acts primarily on the nonneural component of NH2Cl-stimulated secretion. Incubation of colonic mucosa with NH2Cl, with or without diamide, decreased cellular acid-soluble sulfhydryl concentrations. Taken together, the results support a role for epithelial cell thiols in NH2Cl-stimulated electrolyte secretion by the rat colon.

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