Production of IL-1β, hydrogen peroxide, and nitric oxide by colonic mucosa decreases sigmoid smooth muscle contractility in ulcerative colitis

2005 ◽  
Vol 289 (6) ◽  
pp. C1408-C1416 ◽  
Author(s):  
Weibiao Cao ◽  
Claudio Fiocchi ◽  
Victor E. Pricolo
Keyword(s):  
Nitric Oxide ◽  
Ulcerative Colitis ◽  
Circular Muscle ◽  
Muscle Cells ◽  
Muscle Layer ◽  
Normal Mucosa ◽  
Neurokinin A ◽  
Muscle Contractility ◽  
Smooth Muscle Contractility

We have previously shown that sigmoid circular muscle cells from patients with ulcerative colitis (UC) exhibit reduced contraction and Ca2+ signaling in response to the neurotransmitter neurokinin A (NKA) and that IL-1β and H2O2 may contribute to these reduced responses in UC. In addition, we have found that nitric oxide (NO) levels were significantly increased in UC circular muscle. To establish the site of origin for IL-1β, H2O2, and NO, we assembled an in vitro system in which normal or UC mucosa were sealed between two chambers filled with oxygenated Krebs solution. Because the mucosa consists of full-thickness mucosa and submucosa, it is expected that whatever is released into the undernatant from the submucosal side may diffuse to the circular muscle layer in the intact colon. Treatment of normal sigmoid circular muscle cells for 2 h with undernatants collected from the UC submucosal side (UCS) significantly decreased contraction induced by NKA and thapsigargin and the NKA- and caffeine-induced Ca2+ signal in Ca2+-free medium. In addition, UC mucosa released into the undernatant on its submucosal side significantly more H2O2, IL-1β, and NO than normal mucosa. The reduction in contraction and Ca2+ signal induced by UCS was partially reversed by pretreatment with an IL-1β antibody or with catalase. The NO scavenger hemoglobin partially prevented UCS-induced reduction in contraction and Ca2+ signaling in response to NKA but not the reduced response to thapsigargin or caffeine. Sodium nitroprusside inhibited NKA but not the caffeine-induced Ca2+ signal. We conclude that in UC the mucosa releases IL-1β, H2O2, and NO, which may contribute to the impaired Ca2+ release and altered sigmoid muscle contractility.

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.

In vitro model of acute esophagitis in the cat

2005 ◽  
Vol 289 (5) ◽  
pp. G860-G869 ◽  
Author(s):  
Ling Cheng ◽  
Weibiao Cao ◽  
Claudio Fiocchi ◽  
Jose Behar ◽  
Piero Biancani ◽  
...  
Keyword(s):  
In Vitro Model ◽  
Circular Muscle ◽  
Muscle Layer ◽  
Normal Mucosa ◽  
Esophageal Mucosa ◽  
Acute Esophagitis ◽  
Vitro Model ◽  
Esophageal Contraction

We have shown that IL-1β and IL-6, possibly originating from the mucosa in response to injury, inhibit neurally mediated contraction of esophageal circular muscle but do not affect ACh-induced contraction, reproducing the effect of experimental esophagitis on esophageal contraction. To examine the interaction of mucosa and circular muscle in inflammation, we examined the effect of HCl on in vitro esophageal mucosa and circular muscle. Circular muscle strips, when directly exposed to HCl, contracted normally. However, when circular muscle strips were exposed to supernatants of mucosa incubated in HCl (2–3 h, pH 5.8), contraction decreased, and the inhibition was partially reversed by an IL-6 antibody. Supernatants from the mucosa of animals with in vivo-induced acute esophagitis (AE) similarly reduced contraction. IL-6 levels were higher in mucosal tissue from AE animals than in control mucosa and in AE mucosa supernatants than in normal mucosa supernatants. IL-6 levels increased significantly in normal mucosa and supernatants in response to HCl, suggesting increased production and release of IL-6 by the mucosa. IL-6 increased H2O2 levels in the circular muscle layer but not in mucosa. Exposure of the mucosa to HCl caused IL-1β to increase only in the mucosa and not in the supernatant. These data suggest that HCl-induced damage occurs first in the mucosa, leading to the production of IL-1β and IL-6 but not H2O2. IL-1β appears to remain in the mucosa. In contrast, IL-6 is produced and released by the mucosa, eventually resulting in the production of H2O2 by the circular muscle, with this affecting circular muscle contraction.

Enhanced nitric oxide production associated with airway hyporesponsiveness in the absence of IL-10

2005 ◽  
Vol 288 (5) ◽  
pp. L868-L873 ◽  
Author(s):  
Bill T. Ameredes ◽  
Jigme M. Sethi ◽  
He-Liang Liu ◽  
Augustine M. K. Choi ◽  
William J. Calhoun
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Tracheal Ring ◽  
No Production ◽  
Muscle Contractility ◽  
Smooth Muscle Contractility ◽  
Nos Inhibitors

Interleukin (IL)-10 is an anti-inflammatory cytokine implicated in the regulation of airway inflammation in asthma. Among other activities, IL-10 suppresses production of nitric oxide (NO); consequently, its absence may permit increased NO production, which can affect airway smooth muscle contractility. Therefore, we investigated airway reactivity (AR) in response to methacholine (MCh) in IL-10 knockout (−/−) mice compared with wild-type C57BL/6 (C57) mice, in which airway NO production was measured as exhaled NO (ENO), and NO production was altered with administration of either NO synthase (NOS)-specific inhibitors or recombinant murine (rm)IL-10. AR, measured as enhanced pause in vivo, and tracheal ring tension in vitro were lower in IL-10−/− mice by 25–50%, which was associated with elevated ENO levels (13 vs. 7 ppb). Administration of NOS inhibitors NG-nitro-l-arginine methyl ester (8 mg/kg ip) or l- N6-(1-iminoethyl)-lysine (3 mg/kg ip) to IL-10−/− mice decreased ENO by an average of 50%, which was associated with increased AR, to levels similar to C57 mice. ENO in IL-10−/− mice decreased in a dose-dependent fashion in response to administered rmIL-10, to levels similar to C57 mice (7 ppb), which was associated with a 30% increment in AR. Thus increased NO production in the absence of IL-10, decreased AR, which was reversed with inhibition of NO, either by inhibition of NOS, or with reconstitution of IL-10. These findings suggest that airway NO production can modulate airway smooth muscle contractility, resulting in airway hyporesponsiveness when IL-10 is absent.

Toxic dilatation of colon in a rat model of colitis is linked to an inducible form of nitric oxide synthase

1996 ◽  
Vol 270 (3) ◽  
pp. G425-G430 ◽  
Author(s):  
M. Mourelle ◽  
J. Vilaseca ◽  
F. Guarner ◽  
A. Salas ◽  
J. R. Malagelada
Keyword(s):  
Nitric Oxide ◽  
Selective Inhibition ◽  
No Synthase ◽  
Muscle Contractility ◽  
Smooth Muscle Contractility ◽  
Toxic Dilatation ◽  
Inducible No Synthase ◽  
And Control

The contribution of nitric oxide (NO) to the altered colonic contractility of acute colitis was investigated in the 2,4,6-trinitroben-zenesulfonic acid model. NO synthase was measured in colonic tissue; the effects of NO synthase inhibition on colonic contractility were studied in vitro and in vivo. Inducible NO synthase was not detected in normal colons, whereas inflamed colons showed high activity. Acute inflammation was associated with enlarged colonic perimeter. NO synthase inhibitors or selective inhibitors of the inducible enzyme prevented colonic dilatation. In vitro, contractile responses to KCl were lower in muscle from colitic than control rats. After NO synthase inhibition, however, no difference was observed between colitic and control muscle contractility. In vivo, intracolonic pressure was lower in colitic than in control rats. Selective inhibition of inducible NO synthase increased intracolonic pressure in colitic but not in control rats. In conclusion, NO generation by inducible enzymes impairs smooth muscle contractility in colitis and may be involved in the pathogenesis of toxic dilatation of the colon.

Hydrogen peroxide contributes to motor dysfunction in ulcerative colitis

2004 ◽  
Vol 286 (5) ◽  
pp. G833-G843 ◽  
Author(s):  
Weibiao Cao ◽  
Matthew D. Vrees ◽  
Michael T. Kirber ◽  
Claudio Fiocchi ◽  
Victor E. Pricolo
Keyword(s):  
Ulcerative Colitis ◽  
Hydrogen Peroxide ◽  
Circular Muscle ◽  
Muscle Cells ◽  
Motor Dysfunction ◽  
Induced Response ◽  
Neurokinin A ◽  
Normal Cells ◽  
Colonic Motor ◽  
Intracellular Ca

Ulcerative colitis (UC) affects colonic motor function, but the mechanism responsible for this motor dysfunction is not well understood. We have shown that neurokinin A (NKA) may be an endogenous neurotransmitter mediating contraction of human sigmoid colonic circular muscle (HSCCM). To elucidate factors responsible for UC motor dysfunction, we examined the role of hydrogen peroxide (H2O2) in the decrease of NKA-induced response of HSCCM. As previously demonstrated, NKA-induced contraction or Ca2+ increase of normal muscle cells is mediated by release of Ca2+ from intracellular stores, because it was not affected by incubation in Ca2+-free medium (CFM) containing 200 μM BAPTA. In UC, however, CFM reduced both cell contraction and NKA-induced Ca2+ increase, suggesting reduced Ca2+ release from intracellular stores. In normal Ca2+ medium, NKA and KCl caused normal Ca2+ signal in UC cells but reduced cell shortening. The decreased Ca2+ signal and contraction in response to NKA or thapsigargin were partly recovered in the presence of H2O2 scavenger catalase, suggesting involvement of H2O2 in UC-induced dysmotility. H2O2 levels were higher in UC than in normal HSCCM, and enzymatically isolated UC muscle cells contained much higher levels of H2O2 than normal cells, which were significantly reduced by catalase. H2O2 treatment of normal cells in CFM reproduced the reduction of NKA-induced Ca2+ release observed in UC cells. In addition, H2O2 caused a measurable, direct release of Ca2+ from intracellular stores. We conclude that H2O2 may contribute to reduction of NKA-induced Ca2+ release from intracellular Ca2+ stores in UC and contribute to the observed colonic motor dysfunction.

Circumferential, not longitudinal, colonic stretch increases synaptic input to mouse prevertebral ganglion neurons

2003 ◽  
Vol 285 (6) ◽  
pp. G1129-G1138 ◽  
Author(s):  
Steven M. Miller ◽  
J. H. Szurszewski
Keyword(s):  
Synaptic Input ◽  
Muscle Tension ◽  
Circular Muscle ◽  
Longitudinal Axis ◽  
Muscle Layer ◽  
Intraluminal Pressure ◽  
Colon Wall ◽  
Mesenteric Ganglion ◽  
Ganglion Neurons

The relationship between longitudinal and circular muscle tension in the mouse colon and mechanosensory excitatory synaptic input to neurons in the superior mesenteric ganglion (SMG) was investigated in vitro. Electrical activity was recorded intracellularly from SMG neurons, and muscle tension was simultaneously monitored in the longitudinal, circumferential, or both axes. Colonic intraluminal pressure and volume changes were also monitored simultaneously with muscle tension changes. The results showed that the frequency of fast excitatory postsynaptic potentials (fEPSPs) in SMG neurons increased when colonic muscle tension decreased, when the colon relaxed and refilled with fluid after contraction, and during receptive relaxation preceding spontaneous colonic contractions. In contrast, fEPSP frequency decreased when colonic muscle tension increased during spontaneous colonic contraction and emptying. Manual stretch of the colon wall to 10-15% beyond resting length in the circumferential axis of flat sheet preparations increased fEPSP frequency in SMG neurons, but stretch in the longitudinal axis to 15% beyond resting length in the same preparations did not. There was no increase in synaptic input when tubular colon segments were stretched in their long axes up to 20% beyond their resting length. The circumferential stretch-sensitive increase in the frequency of synaptic input to SMG neurons persisted when the colonic muscles were relaxed pharmacologically by nifedipine (2 μM) or nicardipine (3 μM). These results suggest that colonic mechanosensory afferent nerves projecting to the SMG function as length or stretch detectors in parallel to the circular muscle layer.

Functional difference between SP and NKA: relaxation of gastric muscle by SP is mediated by VIP and NO

1993 ◽  
Vol 264 (4) ◽  
pp. G678-G685
Author(s):  
J. G. Jin ◽  
S. Misra ◽  
J. R. Grider ◽  
G. M. Makhlouf
Keyword(s):  
Nitric Oxide ◽  
Circular Muscle ◽  
No Synthase ◽  
No Production ◽  
Neurokinin A ◽  
Functional Difference ◽  
Receptor Agonists ◽  
Gastric Muscle ◽  
Guinea Pig Stomach ◽  
Synthase Inhibitor

The mechanism of action of endogenous tachykinins [substance P (SP) and neurokinin A and B (NKA and NKB)] and of receptor-specific tachykinin analogues (SP methyl ester (SPME), [beta-Ala8]NKA-(4-10), and senktide) was examined in circular muscle of guinea pig stomach. Cross-desensitization studies confirmed that SPME and SP interacted with NK-1 receptors, [beta-Ala8]NKA-(4-10) and NKA with NK-2 receptors, and senktide and NKB with NK-3 receptors. NK-1 and NK-3-receptor agonists induced relaxation and stimulated vasoactive intestinal peptide (VIP) release and nitric oxide (NO) production: tetrodotoxin abolished VIP release, NO production, and relaxation, converting the response to NK-1-receptor agonists to contraction; the NO synthase inhibitor NG-nitro-L-arginine (L-NNA) abolished NO production, partly inhibited VIP release (56-64%, P < 0.01), and abolished relaxation; the VIP antagonist VIP-(10-28) partly inhibited NO production (73-74%, P < 0.001) and relaxation (56-58%, P < 0.01); and atropine augmented relaxation by 28-35% (P < 0.01). The pattern of inhibition implied that: 1) relaxation was mediated by VIP and NO; 2) VIP release was partly dependent on NO production, since it was strongly inhibited by L-NNA; and 3) NO was largely produced by the action of VIP on muscle cells, since it was strongly inhibited by VIP-(10-28). NK-2-receptor agonists elicited only contraction that was not affected by tetrodotoxin; these agonists also inhibited VIP release, NO production, and relaxation induced by NK-1- and NK-3-receptor agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

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