Abdominal surgery induced gastric ileus and activation of M1-like macrophages in the gastric myenteric plexus: prevention by central vagal activation in rats.

Inflammation plays a role in abdominal surgery (AS)-induced intestinal ileus that is alleviated by electrical vagal stimulation. Intracisternal injection of RX-77368, the stable thyrotropin-releasing hormone agonist, activates dorsal motor nucleus neurons and gastric vagal efferent discharges. We investigated the gastric inflammation induced by AS and the modulation by intracisternal RX-77368 in rats. RX-77368 (50 ng/rat) or saline was injected followed, 1 h later, by laparotomy and small intestinal/cecal manipulation. The sham group had anesthesia alone. After 6 h, gastric emptying (GE) and the inflammation in gastric corpus were determined. AS inhibited GE by 72% vs. control and doubled the number of M1-like macrophage immunoreactive for major histocompatibility complex class II (MHCII; M1 marker) but not for cluster of differentiation 206 (CD206; M2 marker) (MHCII+/CD206-) while there was no change in M2-like macrophages (MHCII-/CD206+). AS increased mRNA levels of interleukin-1ß (IL-1ß) and tumor necrosis factor α (TNF-α) by 1.7- and 1.5-fold, respectively, in the gastric submucosa plus muscle layers and the infiltration of neutrophils labeled by myeloperoxidase by 9.5-fold in the muscularis externa. RX-77368 inhibited AS-related gastric changes while not altering these parameters in the sham group. There was a significant negative correlation between GE and IL-1ß (r = -0.46), TNF-α (r = -0.44), M1 macrophage (r = -0.82), and neutrophils (r = -0.91). The M2-like macrophages and IL-10 expression were unchanged by AS with intracisternal saline or RX-77368. These data indicate that AS activates gastric M1 macrophages and increases proinflammatory cytokines expression, which are prevented by central vagal activation and may contribute to the correlated dampening of postoperative gastric ileus.NEW & NOTEWORTHY MHCII+/CD206- (M1) and MHCII-/CD206+ (M2) constitute two distinct populations of macrophages that are in close apposition to the cholinergic neurons in the rat gastric myenteric plexus (MP). Abdominal surgery (6 h) activates M1 macrophage leading to inflammation in the gastric MP correlated with the delayed gastric emptying, which was abolished by central vagal stimulation via intracisternal injection of RX-77368. Vagal stimulation linked with the cephalic phase may have potential beneficial effects to curtail postoperative gastric ileus.

Autoantibodies to calcium channels in type 1 diabetes mediate autonomic dysfunction by different mechanisms in colon and bladder and are neutralized by antiidiotypic antibodies.

Autoantibodies (Abs) directed against L-type voltage-gated calcium channels (VGCCs) have been shown to contribute to autonomic dysfunction of the gastrointestinal tract and bladder in patients with Type 1 diabetes mellitus (T1D). We used a passive transfer model to determine whether the functional activity of the Ab requires crosslinking of channels in colon and bladder and can be neutralized by intravenous immunoglobulin (IVIg). Mice were injected with mono- and divalent F(ab) fragments of patient IgG with anti-VGCC activity and tested for gut and bladder function using a colonic migrating motor complex (MMC) assay and bladder-filling cystometry. The ability of IVIg to neutralize anti-VGCC IgG-mediated autonomic dysfunction was investigated by injection of mice with an equimolar concentration of IVIg prior to T1D IgG injection, or by injection with T1D IgG passed over a sepharose 4B column coupled with F(ab')(2) from IVIg. Passive transfer of T1D IgG and its F(ab')(2) or F(ab) fragments reduced the amplitude of spontaneous colonic motility. In contrast, intact IgG and F(ab')(2,) but not F(ab), produced the urodynamics features of an overactive bladder. T1D IgG-mediated colonic and bladder dysfunction was neutralized in vivo by prior injection of animals with equimolar IVIg. Moreover, anti-VGCC activity was depleted by preabsorption of patient IgG on a IVIg F(ab')(2) column. The activity of anti-VGCC IgG is mediated by the antigen-binding site consistent with a true functional Ab. The pathogenic effect on the bladder requires crosslinking of the channel, whereas monovalent binding of Ab is sufficient for disruption of colon motility. The anti-VGCC Abs are neutralized by antiidiotypic antibodies present in IVIg that may prevent the emergence of these Abs in healthy individuals.

The influence of rejection on graft motility after intestinal transplantation in swine: the possibility of using this method for the real-time monitoring of acute cellular rejection.

BACKGROUND: We have previously reported that rejected allografts show dysmotility, which can be detected by real-time monitoring in swine. We examined the correlation between the motility and the mucosal histology to detect rejection at an early stage by real-time monitoring. METHODS: Intestinal transplantation was performed orthotopically using FK506. The distal segment of the allograft measuring about 20 cm was isolated and exteriorized as "Thiry-Vella" stoma for biopsies. Strain-gage force transducers were attached on a graft for the real-time monitoring of graft motility. The pigs without intestinal transplantation were used as controls (C). The rejection was classified into 4 groups based on the histologic findings: nonrejection, mild rejection, moderate rejection, and severe rejection. Migrating motor complex (MMC) phase 3 was estimated by the following parameters: duration, amplitude, interval, motility index, velocity, and frequency of the propagation. RESULTS: In the nonrejection group, all parameters were almost the same as in C group. In contrast, in the moderate rejection and severe rejection groups, most of the parameters were significantly lower than those in the C group. In the mild rejection group, the contractility of the MMC was not significantly altered, but the frequency of the propagation decreased significantly. CONCLUSIONS: The graft motility detected by the real-time strain-gage method correlated closely to the grade of mucosal histology. This method is therefore considered to be useful for detecting rejection at an early stage by examining the frequency of MMC propagation.

Gastric IgA in cystic fibrosis in relation to the migrating motor complex.

BACKGROUND: Gastrointestinal symptoms in cystic fibrosis are frequent, but little is known about the underlying pathophysiology. Mucosal secretion of IgA is important for the immunologic function in the human gastrointestinal tract but has not been studied in cystic fibrosis. The aim of this study was to quantify the release of IgA by the gastric mucosa in relation to interdigestive motor activity in patients with cystic fibrosis with different genotypes. METHODS: The study included 7 healthy adult volunteers and 10 adult patients with cystic fibrosis, all Helicobacter pylori-negative. All patients had pathological sweat tests and clinical symptoms and signs of cystic fibrosis. All but one were colonized with Pseudomonas aeruginosa. Three patients were pancreatic sufficient. The investigation was performed using intragastric perfusion and gastroduodenal manometry. RESULTS: During the investigation, 8 of 10 patients with cystic fibrosis showed the characteristic pattern of interdigestive motility. The patients had significantly lower levels of gastric IgA compared to healthy subjects during phases II and III of migrating motor complex, median (range) 120 (67-442) and 36 (6-299) microg/5 min. 382 (40-1176) and 56 (4-398) (P = 0.03 and P = 0.04), respectively. Only one patient with genotype R668C/unknown showed IgA levels within the normal range. There was no correlation to gastric presence of duodenogastric reflux markers. CONCLUSION: The interdigestive motility pattern was normal in most patients with cystic fibrosis. The low levels of IgA released from the gastric mucosa in the patients might indicate a defective gastric transmucosal IgA transport in cystic fibrosis.

Myenteric neuronal antibodies in scleroderma: passive transfer evokes alterations in intestinal myoelectric activity in a rat model.

Although the mechanism for neuropathic gastrointestinal motility disturbances in scleroderma is unknown, we have previously described anti-myenteric antibodies in some patients with scleroderma. The aim of this study was to screen patients with scleroderma who had gastrointestinal symptoms for the presence of anti-myenteric neuronal antibodies and then purify the immunoglobulin G (IgG) fraction from serum samples for passive immunization into a rat model and observe for intestinal motility effects. Patients with scleroderma were screened, a serum sample from a patient with high titer anti-myenteric neuronal antibodies was obtained, and IgG was purified. Using a rat model with chronic indwelling intestinal electrodes to measure intestinal myoelectric activity, we passively transferred the IgG from either control subjects or this patient with scleroderma. We immunosuppressed the rats and intraperitoneally injected IgG from control subjects and this patient with scleroderma daily for 7 days. Recordings of myoelectric activity in control injected rats revealed no difference from baseline, but a prolongation in the activity front duration and interval and a disruption were seen after scleroderma IgG injections. IgG from a patient with scleroderma with antimyenteric neuronal antibodies, when passively immunized into a rat model, evokes intestinal myoelectric activity alterations. We hypothesize that these antibodies could account for the gastrointestinal neuropathic motility disturbances seen in scleroderma.