misoprostol and Colitis

Some studies have shown a somatic nociceptive response due to the activation of transient receptor potential A1 channels (TRPA1), which is modulated by the TRPA1 antagonist HC-030031. However, a few studies report the role of TRPA1 in visceral pain. Therefore, we investigated the participation of TRPA1 in visceral nociception and the involvement of nitric oxide, the opioid system and resident cells in the modulation of these channels.. Mice were treated with vehicle or HC-030031 (18.75-300 mg/kg) before ifosfamide (400 mg/kg), 0.75% mustard oil (50 μL/colon), acetic acid 0.6% (10 mL/kg), zymosan (1 mg/cavity) or misoprostol (1 μg/cavity) injection. Visceral nociception was assessed through the electronic von Frey test or the writhing response. Ifosfamide-administered mice were euthanized for bladder analysis. The involvement of nitric oxide and the opioid system were investigated in mice injected with ifosfamide and mustard oil, respectively. The participation of resident peritoneal cells in acetic acid-, zymosan- or misoprostol-induced nociception was also evaluated.. HC-030031 failed to protect animals against ifosfamide-induced bladder injury (p > 0.05). However, a marked antinociceptive effect against ifosfamide, mustard oil, acetic acid, zymosan and misoprostol was observed (p < 0.05). Neither L-arginine (600 mg/kg) nor naloxone (2 mg/kg) could reverse the antinociceptive effect of HC-030031. The reduction of the peritoneal cell population inhibited the acetic acid and zymosan-related writhes without interfering with the misoprostol effect.. Our findings suggest that the blockade of TRPA1 attenuates visceral nociception by a mechanism independent of the modulation of resident cells, nitric oxide and opioid pathways.

Topics: Abdomen; Acetanilides; Animals; Antineoplastic Agents, Alkylating; Cell Count; Colitis; Cystitis; Dinoprostone; Endorphins; Ifosfamide; Inflammation; Male; Mice; Misoprostol; Motor Activity; Mustard Plant; Nitric Oxide; Nociception; Pain; Peritoneal Lavage; Physical Stimulation; Plant Oils; Purines; Transient Receptor Potential Channels; TRPA1 Cation Channel

Although Crohn's disease has been traditionally considered to be Th1-mediated, the newly identified Th17 cells emerged recently as crucial participants. Th1/Th17 differentiation is controlled primarily by the IL-12 family of cytokines secreted by activated dendritic cells (DCs) and macrophages. IL-23 and IL-12/IL-27 have opposite effects, supporting the Th17 and Th1 phenotypes, respectively. We found that PGE(2), a major lipid mediator released in inflammatory conditions, shifts the IL-12/IL-23 balance in DCs in favor of IL-23, and propose that high levels of PGE(2) exacerbate the inflammatory process in inflammatory bowel disease through the IL-23-->IL-17 axis. We assessed the effects of PGE(2) on IL-12, IL-27, and IL-23 and found that PGE(2) promotes IL-23, inhibits IL-12 and IL-27 expression and release from stimulated DCs, and subsequently induces IL-17 production in activated T cells. The effects of PGE(2) are mediated through the EP2/EP4 receptors on DCs. In vivo, we assessed the effects of PGE analogs in an experimental model for inflammatory bowel disease and found that the exacerbation of clinical symptoms and histopathology correlated with an increase in IL-23 and IL-17, a decrease in IL-12p35 expression in colon and mesenteric lymph nodes, and a substantial increase in the number of infiltrating neutrophils and of CD4(+)IL-17(+) T cells in the colonic tissue. These studies suggest that high levels of PGE(2) exacerbate the inflammatory process through the preferential expression and release of DC-derived IL-23 and the subsequent support of the autoreactive/inflammatory Th17 phenotype.

Topics: Animals; Anti-Ulcer Agents; Colitis; Colon; Cytokines; Dendritic Cells; Dinoprostone; Disease Models, Animal; Inflammatory Bowel Diseases; Interleukin-12; Interleukin-17; Interleukin-23; Interleukins; Intestinal Mucosa; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Misoprostol; Neutrophils; T-Lymphocytes, Helper-Inducer; Trinitrobenzenesulfonic Acid

Topics: Anti-Inflammatory Agents, Non-Steroidal; Colitis; Humans; Misoprostol; Tumor Necrosis Factor-alpha

Intestinal epithelial permeability can be modulated by the immune system and can be greatly increased by transepithelial migration of neutrophils. Since immunosuppressants have been reported to inhibit the ability of neutrophils to migrate, we assessed the effects of two immunosuppressants on epithelial permeability and granulocyte infiltration in a model of acute colitis. Epithelial permeability was measured at 3 and 6 h after induction of colitis in the rabbit by intracolonic administration of trinitrobenzene sulfonic acid. At these times, blood-to-lumen leakage of 51Cr-EDTA was elevated by approximately 8- and 18-fold, respectively, above levels observed in healthy controls. Pretreatment with either of the immunosuppressants (cyclosporin A and L-683,590) significantly reduced the changes in 51Cr-EDTA leakage observed at the latter time point. These drugs also significantly attenuated granulocyte infiltration of the colon after induction of colitis, as measured by tissue myeloperoxidase activity. Unlike the immunosuppressants, misoprostol, a prostaglandin analogue, attenuated the increases in colonic permeability but had no effect on granulocyte infiltration in this model. These results demonstrate that two structurally unrelated immunosuppressants are capable of markedly reducing neutrophil infiltration and the colonic permeability changes observed in an experimental model of acute colitis, although the mechanisms through which these effects are produced remain unclear.

Topics: Animals; Colitis; Colon; Cyclosporine; Disease Models, Animal; Epithelium; Immunosuppressive Agents; Male; Misoprostol; Neutrophils; Permeability; Peroxidase; Rabbits; Tacrolimus; Trinitrobenzenesulfonic Acid

The ability of nonsteroidal anti-inflammatory drugs to exacerbate experimental colitis, and the possible contributions of the "shunting" of arachidonate via the 5-lipoxygenase pathway, were investigated using a rat model in which colitis was induced by intracolonic administration of trinitrobenzene sulfonic acid in a vehicle of 50% ethanol. Twice daily treatment with indomethacin (0.1-1 mg/kg SC) during the first week after trinitrobenzene sulfonic acid/ethanol administration resulted in dose-dependent increases in the severity of colitis and in the incidence of mortality. Mortality was not observed in vehicle-treated colitic rats or in normal rats treated with indomethacin. Similar exacerbation of colitis was observed in rats treated with naproxen (5 mg/kg). Whereas treatment with a 5-lipoxygenase inhibitor, PF-5901 (100 mg/kg PO), resulted in a significant reduction of the severity of colitis, concomitant administration of PF-5901 and indomethacin (0.5 mg/kg SC) did not inhibit the exacerbative effects of the indomethacin in this model. In separate studies, administration of indomethacin was found to significantly increase colonic myeloperoxidase activity (a measure of tissue granulocyte numbers) and suppress colonic prostaglandin E2 synthesis, while not significantly affecting colonic leukotriene B4 synthesis. The effect on myeloperoxidase activity was seen during the period 21-24 hours after trinitrobenzene sulfonic acid ethanol administration, but not during the period 45-48 hours after induction of colitis. In in vitro studies using samples of inflamed colon and in vivo studies in which colonic eicosanoid production was measured by colonic dialysis, inhibition of prostaglandin E2 synthesis was not accompanied by significant changes in leukotriene B4 synthesis. These results suggest that inhibitors of colonic prostaglandin synthesis can markedly exacerbate colitis, and that this effect is unrelated to alterations in colonic leukotriene B4 synthesis. Endogenous prostaglandins may exert anti-inflammatory effects during the acute stages of colitis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Colon; Dinoprostone; Drug Combinations; Indomethacin; Leukotriene B4; Male; Misoprostol; Naproxen; Peroxidase; Quinolines; Rats; Rats, Inbred Strains

The implication of leukotrienes as mediators of inflammation and recent evidence that prostaglandin analogues provide a beneficial effect during experimental colitis led to the speculation that (i) leukotrienes may be injurious and (ii) prostaglandins may be protective to colonic mucosa. Using a 2% acetic acid induced rat colitis model, we administered specific cyclooxygenase (indomethacin) and leukotriene biosynthesis inhibitors (MK-886) to examine the effect of endogenous prostaglandins and leukotrienes on colonic macroscopic injury, mucosal inflammation as measured by myeloperoxidase activity, net in vivo intestinal fluid absorption, and colonic PGE2 and LTB4 levels as measured by in vivo rectal dialysis. Indomethacin treatment prior to induction of colitis reduced endogenous mucosal PGE2 levels and exacerbated macroscopic ulceration and net fluid absorption. Addition of the exogenous PGE1 analogue misoprostol to the indomethacin-exacerbated colitis completely healed colonic macroscopic ulceration and inflammation but only partially improved fluid absorptive injury. The specific leukotriene biosynthesis inhibitor MK-886 administered prior to induction of colitis healed macroscopic ulceration and inflammation but not fluid absorptive injury. This mucosal reparative effect of MK-886 occurred at a dose that reduced colonic LTB4 synthesis while concomitantly enhancing PGE2 levels. Combining MK-886 with misoprostol treatment improved not only macroscopic ulceration and inflammation but also provided a synergistic effect that maintained net colonic fluid absorption at noncolitic control levels. These studies suggest that, during the induction of experimental colitis, endogenous prostaglandins play a pivotal role in providing a mucosal healing effect, and that leukotriene biosynthesis inhibitor may manifest part of its beneficial effect by shifting arachidonic acid metabolism towards production of prostaglandins.

Topics: Acetates; Animals; Body Fluids; Colitis; Dialysis; Dinoprostone; Indoles; Indomethacin; Intestinal Mucosa; Leukotriene Antagonists; Leukotriene B4; Male; Misoprostol; Peroxidase; Rats; Rats, Sprague-Dawley

Prostaglandins have been demonstrated to have a mucosal protective effect when administered prior to the experimental induction of colitis in animals. We here determined whether prostaglandins would have a beneficial therapeutic effect when administered after colitis had been established. Diffuse, chronic, trinitrobenzene sulfonic acid-induced colitis was established in rats, and misoprostol was administered daily for up to 10 days following the induction of colitis. The effects of misoprostol therapy were compared to those obtained by treatment with 5-aminosalicylic acid and betamethasone. Misoprostol therapy following trinitrobenzene sulfonic acid-induced colitis accelerated colonic healing, as measured in terms of macroscopic ulceration area and fluid absorption, whereas 5-aminosalicylic acid and betamethasone therapy did not. Ileal fluid absorption impairment was repaired by betamethasone but not by misoprostol or 5-aminosalicylic acid therapy.

Topics: Aminosalicylic Acids; Animals; Betamethasone; Colitis; Intestinal Absorption; Intestinal Mucosa; Male; Mesalamine; Misoprostol; Rats; Rats, Inbred Strains; Trinitrobenzenesulfonic Acid

The objectives of this study were 1) to quantify the effects of misoprostol (Miso; prostaglandin E1 analogue) on acetic acid-induced increases in mucosal permeability and inflammation; 2) to determine what effect acetic acid, Miso, or the combination of Miso plus acetic acid has on colonic blood flow; and 3) to assess whether the protective effect of Miso may be attributable to its vasodilatory properties. We found that intrarectal administration of acetic acid produced a 6.4-fold increase in colonic myeloperoxidase activity (an index of granulocyte infiltration), an 8.2-fold increase in mucosal permeability, a 1.6-fold increase in colonic weight, and a 6.8% decrease in body weight 48 h after enema. Miso pretreatment significantly attenuated the increases in colonic myeloperoxidase activity, mucosal permeability, and colon weight as well as prevented the loss of body weight. In a different series of experiments, we found that blood flow in the descending, transverse, and ascending colon increased 2.5- to 3.5-fold immediately after the acetic acid enema; however, it returned to control values at 1 and 4 h after enema. Miso pretreatment, followed by acetic acid, resulted in a further increase (2.5-fold) in blood flow in the descending colon 1 h after enema compared with acetic acid alone. This Miso-induced increase in blood flow at 1 h could not account for its protective effect inasmuch as colonic mucosal permeability (i.e., injury) in Miso-pretreated animals was not significantly different from values obtained in animals pretreated with vehicle and then given the enema.

Topics: Acetates; Acetic Acid; Administration, Rectal; Alprostadil; Animals; Anti-Ulcer Agents; Colitis; Colon; Intestinal Mucosa; Male; Misoprostol; Permeability; Rats; Rats, Inbred Strains; Regional Blood Flow