Short-chain fatty acid enemas fail to decrease colonic hypersensitivity and inflammation in TNBS-induced colonic inflammation in rats

BACKGROUND AND AIMS: Short-chain fatty acid (SCFA) (especially butyrate) enemas are widely used to reduce symptoms associated with human inflammatory bowel disease. The purpose of this study was to evaluate their real effect on colonic sensitivity in rats. METHODS: The effects of saline and SCFA enemas (acetate, propionate and particularly butyrate) were studied on visceral pain thresholds following colonic distension in control rats and in rats with colitis (instilled with trinitrobenzene sulfonic acid (TNBS)). RESULTS: Butyrate enemas (40 mM twice daily for 14 days) decreased colonic pain thresholds in control rats; they did not reduce the TNBS-induced hypersensitivity, but on the contrary increased its duration (without modifying the inflammation score). This pronociceptive effect was confirmed in control rats receiving twice daily enemas of 80 mM for 3 days and two enemas of 240 mM of a butyrate solution. The other SCFA enemas did not modify the hypersensitivity of rats with colitis and induced proinflammatory effects. CONCLUSIONS: The beneficial effect of SCFA (especially butyrate) enemas on hypersensitivity and inflammation in inflammatory bowel disease is questionable and needs to be thoroughly investigated in humans.     

Pressure is proinflammatory in lung venular capillaries

Endothelial responses may contribute importantly to the pathology of high vascular pressure. In lung venular capillaries, we determined endothelial [Ca(2+)](i) by the fura-2 ratioing method and fusion pore formation by quantifying the fluorescence of FM1-43. Pressure elevation increased endothelial [Ca(2+)](i). Concomitantly evoked exocytotic events were evident in a novel spatial-temporal pattern of fusion pore formation. Fusion pores formed predominantly at vascular branch points and colocalized with the expression of P-selectin. Blockade of mechanogated Ca(2+) channels inhibited these responses, identifying entry of external Ca(2+) as the critical triggering mechanism. These endothelial responses point to a proinflammatory effect of high vascular pressure that may be relevant in the pathogenesis of pressure-induced lung disease.     

The endogenous cannabinoid system protects against colonic inflammation

Excessive inflammatory responses can emerge as a potential danger for organisms' health. Physiological balance between pro- and anti-inflammatory processes constitutes an important feature of responses against harmful events. Here, we show that cannabinoid receptors type 1 (CB1) mediate intrinsic protective signals that counteract proinflammatory responses. Both intrarectal infusion of 2,4-dinitrobenzene sulfonic acid (DNBS) and oral administration of dextrane sulfate sodium induced stronger inflammation in CB1-deficient mice (CB1(-/-)) than in wild-type littermates (CB1(+/+)). Treatment of wild-type mice with the specific CB1 antagonist N-(piperidino-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide (SR141716A) mimicked the phenotype of CB1(-/-) mice, showing an acute requirement of CB1 receptors for protection from inflammation. Consistently, treatment with the cannabinoid receptor agonist R(-)-7-hydroxy-Delta(6)-tetra-hydrocannabinol-dimethylheptyl (HU210) or genetic ablation of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) resulted in protection against DNBS-induced colitis. Electrophysiological recordings from circular smooth muscle cells, performed 8 hours after DNBS treatment, revealed spontaneous oscillatory action potentials in CB1(-/-) but not in CB1(+/+) colons, indicating an early CB1-mediated control of inflammation-induced irritation of smooth muscle cells. DNBS treatment increased the percentage of myenteric neurons expressing CB1 receptors, suggesting an enhancement of cannabinoid signaling during colitis. Our results indicate that the endogenous cannabinoid system represents a promising therapeutic target for the treatment of intestinal disease conditions characterized by excessive inflammatory responses.     

Kupffer-cell depletion attenuates colonic and extracolonic granulomatous inflammation in chronic colitis

Intramural injection of peptidoglycan-polysaccharide polymers into the distal colon in rats induces granulomatous colitis associated with extracolonic manifestations. We sought to clarify the effects of Kupffer-cell depletion induced by the intravenous administration of gadolinium on colonic and extracolonic inflammation in this model. The effects of Kupffer-cell depletion on acute and chronic inflammation were evaluated 3 days and 3 weeks after injection of peptidoglycan-polysaccharide, respectively. We assessed the effects of gadolinium on colonic cytokine levels in vivo and the viability of elicited peritoneal macrophages and peptidoglycan-polysaccharide-induced production of nitrite, an indirect index of nitric oxide production, by these cells in vitro. A single injection of gadolinium caused a marked decrease in the number of Kupffer cells stained with antibodies within 3 days. Gadolinium treatment did not alter acute inflammation at 3 days. Repeated treatment with gadolinium dramatically attenuated grossly observed chronic inflammation, including thickening of colon wall, hepatic and splenic nodules, and swelling of foot joints; and significantly reduced the proportional areas occupied by granulomas in the colon, liver, and spleen at 3 weeks. These protective effects were reflected in significant reduction in colon and liver weights; gross scores; colonic myeloperoxidase activity, an indirect quantitative index of granulocyte infiltration; colonic interleukin-1beta levels; plasma nitrite and nitrate levels; and decreased tendency toward arthritis. Although gadolinium did not cause injury in elicited peritoneal macrophages in vitro, the compound dose-dependently attenuated peptidoglycan-polysaccharide-induced production of nitrite by these cells. Chronic Kupffer-cell depletion attenuates peptidoglycan-polysaccharide-induced granulomatous inflammation in the colon, liver, and spleen and reduces the incidence of arthritis, possibly by suppressing the production of interleukin-1beta and nitric oxide.     

The effect of antioxidant therapy on colonic inflammation in the rat

Under normal physiological conditions, chemical and antioxidant defenses protect tissues from the damaging effects of reactive oxygen metabolites (ROM). It has been proposed that ROMs are involved in the development of tissue injury in many inflammatory diseases and also in patients with colitis. In the present study we aimed to investigate the effects of antioxidant therapy on the extent of colonic inflammation and ROM levels in the injured tissues in a trinitrobenzene sulfonic acid-induced colitis model in the rat. Sprague-Dawley rats were pretreated with the antioxidants superoxide dismutase (30,000 U/kg s.c.) or catalase (400,000 U/kg s.c.) prior to induction of colitis and they were decapitated 24 h (acute group) or 6 days (chronic group) after the induction of colitis (each group consists of eight to ten rats). Pretreatment with the antioxidants reduced the macroscopic damage score significantly in both acute and chronic groups compared with untreated colitis groups, whereas they reduced the microscopic damage score and colonic wet weight only in the chronic group. The chemiluminescence assay - a technique to assess the presence of reactive oxygen species in the tissues - values of the groups pretreated with the antioxidants showed a tendency to decrease compared with the untreated colitis group, but they were not statistically significant. Based on these findings, pretreatment with the antioxidants superoxide dismutase or catalase has beneficial effects on the extent of colonic inflammation, particularly in the chronic period, and this may support the importance of antioxidant therapy to reduce the severity of inflammatory bowel disease in humans.     

Long term follow-up of appendiceal and distal right-sided colonic inflammation

The aim of this study was to investigate the possibility of appendiceal orifice inflammation (AOI) as a preceding lesion in the development of ulcerative colitis. A total of 20 patients were identified (mean age 41.2 years; 11 males) who had ulcerative colitis-like inflammatory lesions at the appendiceal orifice without concomitant typical features of ulcerative colitis, such as rectal involvement. A total of 19 patients were followed up endoscopically for a mean duration of 18.4 months (range 2?-?84 months). Typical ulcerative colitis developed in five patients (25?%; four proctitis, one pancolitis) in a mean time of 18.4 months (range 2?-?36 months). Negative conversion of all inflammatory lesions occurred in seven patients (35?%) after a mean follow-up of 20 months (range 3?-?84 months). In the remaining seven patients (35?%), initial lesions did not progress to ulcerative colitis and did not go into remission during a mean follow-up of 16.9 months (range 2?-?42 months). These results suggest that, at least in some cases, AOI precedes development of ulcerative colitis.     

Deep tissue inflammation upregulates neuropeptides and evokes nociceptive behaviors which are modulated by a neuropeptide antagonist

Promising recent developments in the therapeutic value of neuropeptide antagonists have generated renewed importance in understanding the functional role of neuropeptides in nociception and inflammation. To explore this relationship we examined behavioral changes and primary afferent neuronal plasticity following deep tissue inflammation. One hour following craniofacial muscle inflammation ipsilateral as well as contralateral head withdrawal thresholds and ipsi- and contralateral hindpaw withdrawal thresholds were lowered and remained reduced for 28 days. Elevated levels of calcitonin gene-related peptide (CGRP) within the trigeminal ganglion temporally correlated with this mechanical allodynia. Inflammation also induced an increase in the number of CGRP and substance P (SP)-immunopositive trigeminal ganglion neurons innervating inflamed muscle but did not evoke a shift in the size distribution of peptidergic muscle afferent neurons. Trigeminal proprioceptive muscle afferent neurons situated within the brainstem in the mesencephalic trigeminal nucleus did not express CGRP or SP prior to or following inflammation. Intravenous administration of CGRP receptor antagonist (8-37) two minutes prior to adjuvant injection blocked plasma extravasation and abolished both head and hindlimb mechanical allodynia. Local injection of CGRP antagonist directly into the masseter muscle prior to CFA produced similar, but less pronounced, effects. These findings indicate that unilateral craniofacial muscle inflammation produces mechanical allodynia at distant sites and upregulates CGRP and SP in primary afferent neurons innervating deep tissues. These data further implicate CGRP and SP in deep tissue nociceptive mechanisms and suggest that peptide antagonists may have therapeutic potential for musculoskeletal pain.     

The neuropeptide neuromedin U promotes inflammation by direct activation of mast cells

Neuromedin U (NMU) is a neuropeptide that is expressed in the gastrointestinal tract and central nervous system. NMU interacts with two G protein-coupled receptors, NMU-R1 and NMU-R2. Whereas NMU-R2 localizes predominantly to nerve cells, NMU-R1 is expressed in peripheral tissues including lymphocytes and monocytes, suggesting a role of NMU in immunoregulation. However, the functions of NMU in peripheral tissues have not been clarified. In this study, using NMU-deficient mice, we first demonstrated that NMU plays an important role in mast cell-mediated inflammation. Complete Freund's adjuvant-induced mast cell degranulation as well as edema and neutrophil infiltration, which occurred weakly in mast cell-deficient WBB6F(1)-W/W(v) mice, did not occur in NMU-deficient mice. Moreover, intraplantar injection of NMU into paws induced early inflammatory responses such as mast cell degranulation, vasodilation, and plasma extravasation in WT mice but not in WBB6F(1)-W/W(v) mice. NMU-R1 was highly expressed in primary mast cells, and NMU induced Ca(2+) mobilization and degranulation in peritoneal mast cells. These data indicate that NMU promotes mast cell-mediated inflammation; therefore, NMU receptor antagonists could be a novel target for pharmacological inhibition of mast cell-mediated inflammatory diseases.     

Detection of colonic inflammation with Fourier transform infrared spectroscopy using a flexible silver halide fiber

Persistent colonic inflammation increases risk for cancer, but mucosal appearance on conventional endoscopy correlates poorly with histology. Here we demonstrate the use of a flexible silver halide fiber to collect mid-infrared absorption spectra and an interval model to distinguish colitis from normal mucosa in dextran sulfate sodium treated mice. The spectral regime between 950 and 1800 cm(-1) was collected from excised colonic specimens and compared with histology. Our model identified 3 sub-ranges that optimize the classification results, and the performance for detecting inflammation resulted in a sensitivity, specificity, accuracy, and positive predictive value of 92%, 88%, 90%, and 88%, respectively.     

Mitomycin C-induced colitis in rats: a new animal model of acute colonic inflammation implicating reactive oxygen species.

The mechanism of the tissue damage induced by colonic inflammation in ulcerative colitis is not established. We therefore developed and characterized a simple new rat model of acute colonic inflammation induced by a single systemic injection of mitomycin C. After an intraperitoneal injection of mitomycin-C, colon histologic examination revealed transient (3 to 14 days) diffuse, colonic inflammation and injury that, like human ulcerative colitis, was limited to the mucosal layer. The rest of the gastrointestinal tract was spared. Gut permeability, as measured by urinary excretion of orally administered lactulose and mannitol, was unchanged 3 days after injection, when inflammation was already present; permeability was increased at 7 days, when inflammation was maximal. Mitomycin C did not produce inflammation in experimentally bypassed segments of small bowel despite the presence of colonic-type bacteria, suggesting that lack of intraluminal bacteria was not responsible for the absence of inflammation in the small intestine. Chemiluminescence, a means of estimating levels of reactive oxygen species, was greater in the intact, inflamed colon of mitomycin C-treated rats than in bypassed segments. Moreover, inflamed mucosal scrapings produced more in vitro luminol-enhanced chemiluminescence. Furthermore, the reactive oxygen species scavengers allopurinol, catalase, and WR-2721 decreased inflammation severity. We therefore conclude: (1) the mitomycin C-treated rat is a novel, easy to prepare animal model of acute inflammation of colonic mucosa, with morphologic similarities to the acute phase of ulcerative colitis in human beings; (2) increased gut permeability in mitomycin C-treated rats is the result, not the cause, of the inflammation; and (3) reactive oxygen species play an important role in colonic inflammation and tissue injury in this model, and possibly in human ulcerative colitis.     

Antihyperalgesic effects of intrathecal neuropeptide Y during inflammation are mediated by Y1 receptors

Inflammation induces an up-regulation of neuropeptide tyrosine (NPY) and its receptors in the dorsal horn, suggesting an important role in nociceptive transmission. Our initial studies revealed that NPY dose-dependently increased hotplate response latency, and to a lesser degree, thermal paw withdrawal latency (PWL); these effects occurred at doses that affect neither motor coordination (as assessed by the rotarod test) nor paw skin temperature. We next evaluated the behavioral effects of intrathecal administration of NPY and NPY antagonists with the aim of assessing the contribution of NPY to correlates of persistent nociception associated with the unilateral plantar injection of carrageenan or complete Freund's adjuvant (CFA). NPY robustly and dose-dependently increased PWL on the side ipsilateral to carrageenan injection, with only a small effect on the contralateral side. Similarly, NPY (30 microg) produced a large and long-lasting increase in PWL on the side ipsilateral to CFA injection (140% change), with only a small effect on the contralateral side (25% change). The ipsilateral effect of NPY was completely inhibited with the potent Y1 antagonist, BIBO 3304 (3 microg), but not the Y2 antagonist, BIIE 0246. When administered alone, BIBO 3304 (but not BIIE 0246) slightly decreased thermal PWL on the side ipsilateral (25% change), but not contralateral, to CFA injection; this suggests that inflammation strengthens inhibitory NPY tone. We conclude that spinal Y1 receptors contribute to the inhibitory effects of NPY on thermal hypersensitivity in the awake rat. Further studies are necessary to determine whether enhanced release of NPY and Y1-mediated inhibition of spinal nociceptive transmission ultimately results in a compensatory, adaptive inhibition of thermal hypersensitivity in the setting of inflammation.     

Regulation of proliferation of human colonic subepithelial myofibroblasts by mediators important in intestinal inflammation.

An increase in myofibroblast number may be necessary for wound healing but may also lead to postinflammatory scarring. We have, therefore, studied the role of mediators important in inflammatory bowel disease in regulating proliferation of human colonic myofibroblasts. Using primary cultures of these cells, we have shown increases in [3H]thymidine incorporation in response to platelet-derived growth factor (EC50 = 14 ng/ml), basic fibroblast growth factor (EC50 = 2.2 ng/ml), and epidermal growth factor (EC50 = 1.1 ng/ml). Coulter counting of cell suspensions demonstrated increases in cell number with these growth factors along with insulin-like growth factor-I and -II. In addition the proinflammatory cytokines IL-1beta and TNF-alpha produced increases in [3H]thymidine incorporation. IL-1beta and platelet-derived growth factor together produced an increase in [3H]thymidine greater than either agonist alone; this effect was not, however, seen when we examined changes in cell numbers. Finally, we demonstrate a mechanism whereby these responses may be downregulated: vasoactive intestinal peptide (1 microM) elevates cyclic AwMP in these cells 4. 2-fold over control and produces a dose-related inhibition of platelet-derived growth factor-driven proliferation with a maximum inhibition of 33% at 1 microM.     

Peripheral anti-nociceptive effect of nociceptin/orphanin FQ in inflammation and stress-induced colonic hyperalgesia in rats

Nociceptin/orphanin FQ (N/OFQ) and its NOP receptors are present in the central nervous system and in the periphery playing important roles in the modulation of gastrointestinal functions and pain. The aim of this study was to investigate the role of central and peripheral N/OFQ–NOP receptor system in the nociceptive response to colorectal distension (CRD) in basal condition and in two models of gut hypersensitivity triggered by both inflammation and stress. Male Wistar rats were tested in basal and in post-inflammatory conditions, i.e., 5 days after IC TNBS instillation (80 mg/Kg) and received N/OFQ (2 nmol/Kg IP), UFP-101 (a selective NOP receptor antagonist, 10 nmol/Kg IP), N/OFQ+UFP-101, N/OFQ (0.5 nmol/rat ICV) or vehicle. Female rats were tested in basal and after partial restraint stress receiving the same pharmacological treatment. CRD was performed using barostat and abdominal contractions were recorded by electromyography. In basal condition, N/OFQ, ICV and IP injected, did not modify basal visceral sensitivity. Both in TNBS and stress-induced hyperalgesia, IP but not ICV injection of N/OFQ significantly decreased the number of abdominal contractions. Peripheral injection of UFP-101 antagonized N/OFQ effect. Moreover, in post-inflammatory colitis, UFP-101, injected alone, exacerbated visceral hyperalgesia to CRD compared with vehicle. These findings indicate that in rats, N/OFQ, only peripherally injected, reduces visceral hypersensitivity triggered by inflammation or stress without affecting basal sensitivity. N/OFQ visceral anti-hyperalgesic effect involves peripheral NOP receptors. In a post-inflammatory, but not in an acute stress colitis model, N/OFQergic system is endogenously activated.     

Cluster headache is not associated with signs of a systemic inflammation

OBJECTIVE: To investigate whether there is clinical or biochemical evidence for a transient systemic inflammation during active periods of cluster headache. METHODS: Twenty-seven male and female consecutively selected patients with episodic cluster headache filled in questionnaires aiming at detecting any concurrent systemic vasculitic or rheumatoid disease. They were physically examined by both a neurologist and a rheumatologist independent of each other. Blood and urine samples were taken one to three times during an active cluster period and once in remission. The following analyses were performed: hemoglobin, erythrocyte sedimentation rate, C-reactive protein, complete blood counts including differential counts, creatinine, albumin, creatine kinase, electrophoreses of serum (with haptoglobin, orosomucoid, IgG, IgM), von Willebrand's factor, antinuclear antibodies, rheumatoid factor, cytoplasmic antineutrophil cytoplasmic autoantibodies, perinuclear antineutrophil cytoplasmic autoantibodies, and routine urinary tests. An age- and sex-matched control group of 99 consecutive patients attending the Outpatient Department of Neurology for symptoms/diseases other than severe headache completed the same questionnaire as the patient group. RESULTS: Only one patient with cluster headache showed clinical signs (livedo reticularis) that could have been due to an ongoing systemic vasculitis. Most symptoms were equally or even more prevalent in the control group than among the patients with cluster headache. However, cold feet were about twice as prevalent among female patients with cluster headache than in the control group. This was considered due to their smoking habits. Laboratory tests showed no statistically significant differences between the active cluster periods and remission. There were some slightly abnormal values in single laboratory tests, some of which were probably due to concurrent upper respiratory infections. The findings of laboratory tests for one patient could have been due to nephritis. All patients were negative for cytoplasmic antineutrophil cytoplasmic autoantibodies and perinuclear antineutrophil cytoplasmic autoantibodies. CONCLUSIONS: These results were taken as evidence that no systemic inflammation is present during the active cluster headache period. However, whether a local retro-orbital inflammation underlies the pathophysiology of cluster headache remains obscure.     

Formylpeptide receptor-2 contributes to colonic epithelial homeostasis,inflammation, and tumorigenesis

Commensal bacteria and their products provide beneficial effects to the mammalian gut by stimulating epithelial cell turnover and enhancing wound healing, without activating overt inflammation. We hypothesized that N-formylpeptide receptors, which bind bacterial N-formylpeptides and are expressed by intestinal epithelial cells, may contribute to these processes. Here we report that formylpeptide receptor-2 (FPR2), which we show is expressed on the apical and lateral membranes of colonic crypt epithelial cells, mediates N-formylpeptide–dependent epithelial cell proliferation and renewal. Colonic epithelial cells in FPR2-deficient mice displayed defects in commensal bacterium–dependent homeostasis as shown by the absence of responses to N-formylpeptide stimulation, shortened colonic crypts, reduced acute inflammatory responses to dextran sulfate sodium (DSS) challenge, delayed mucosal restoration after injury, and increased azoxymethane-induced tumorigenesis. These results indicate that FPR2 is critical in mediating homeostasis, inflammation, and epithelial repair processes in the colon.     

Neurotensin activation of the NTR1 on spinally-projecting serotonergic neurons in the rostral ventromedial medulla is antinociceptive

Microinjection of neurotensin (NT) in the rostral ventromedial medulla (RVM) produces dose-dependent antinociception. The NTR1 (Neurotensin Receptor Subtype 1) may mediate part of this response, however definitive evidence is lacking, and the spinal mediators of NTR1-induced antinociception are unknown. In the present study, we used immunohistochemical techniques to show that the NTR1, but not the NTR2 is expressed by spinally projecting serotonergic neurons of the RVM. We also show that microinjection of NT or the NTR1-selective agonist PD149163 in the RVM both produce dose-dependent antinociception in the tail-flick test that is blocked by the NTR1-selective antagonist SR48692. The antinociception produced by NT or PD149163 is also blocked by intrathecal administration of the non-selective serotonergic receptor antagonist methysergide. The results of these experiments provide anatomical and behavioral evidence that activation of NTR1-expressing spinally projecting neurons in the RVM produces antinociception through release of serotonin in the spinal dorsal horn. These results support the conclusion that the NTR1 plays an important role in the central modulation of nociception.     

Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice

Transgenic sickle mice expressing betaS hemoglobin have activated vascular endothelium that exhibits enhanced expression of NF-kappaB and adhesion molecules that promote vascular stasis in sickle, but not in normal, mice in response to hypoxia/reoxygenation. Sickle mice hemolyze rbcs in vivo as demonstrated by increased reticulocyte counts, plasma hemoglobin and bilirubin, and reduced plasma haptoglobin. The heme content is elevated in sickle organs, which promotes vascular inflammation and heme oxygenase-1 expression. Treatment of sickle mice with hemin further increases heme oxygenase-1 expression and inhibits hypoxia/reoxygenation-induced stasis, leukocyte-endothelium interactions, and NF-kappaB, VCAM-1, and ICAM-1 expression. Heme oxygenase inhibition by tin protoporphyrin exacerbates stasis in sickle mice. Furthermore, treatment of sickle mice with the heme oxygenase enzymatic product carbon monoxide or biliverdin inhibits stasis and NF-kappaB, VCAM-1, and ICAM-1 expression. Local administration of heme oxygenase-1 adenovirus to subcutaneous skin increases heme oxygenase-1 and inhibits hypoxia/reoxygenation-induced stasis in the skin of sickle mice. Heme oxygenase-1 plays a vital role in the inhibition of vaso-occlusion in transgenic sickle mice.     

Bioglass attenuates a proinflammatory response in mouse peritoneal endotoxicosis

Bioglass is a bioactive, resorbable ceramic particle that was developed to assure binding to living tissues. Bioglass is currently employed to fill osseus defects in oral surgery, and it possesses both unique anti-inflammatory and antimicrobial properties. In an effort to determine whether Bioglass may be useful as an adjunct anti-inflammatory device in local inflammatory processes, we examined whether exposure of the peritoneal cavity to Bioglass would induce a pro- or anti-inflammatory response, and then modulate a subsequent proinflammatory response to endotoxin. Three- to fifty-milligram doses of 5 pm Bioglass were administered intraperitoneally in C57BL/6 mice. Total leukocyte, myeloperoxidase, and cytokine levels in the peritoneal wash fluid were determined. In addition, the peritoneal cavity was preexposed to Bioglass, and was then subjected to a subsequent endotoxin administration. All doses of Bioglass were found to induce a significant peritoneal IL-6 response; however, Bioglass did not induce a TNF-alpha, IL-1alpha, IL-10, or a white cell recruitment into the peritoneal lavage fluid. Pretreatment of the peritoneal cavity with Bioglass produced a transient reduction in the proinflammatory response to endotoxin. We conclude that exposure to Bioglass produces an IL-6 response without concurrent expression of TNF-alpha or IL-1alpha. Bioglass appears to transiently suppress the inflammatory response to endotoxin, possibly through the early induction of IL-6. These findings suggest that Bioglass may offer a unique approach in modifying the inflammatory response in local tissue compartments.