The role of cyclooxygenase inhibition in the effect of alpha-melanocyte-stimulating hormone on reactive oxygen species production by rat peritoneal neutrophils.

The effect of alpha-MSH on reactive oxygen species (ROS) production by rat peritoneal neutrophils and the effect of cyclooxygenase (COX) inhibition were investigated using the chemiluminescence (CL) technique. Cells were obtained by peritoneal lavage 4h after administration of oyster glycogen to rats and were stimulated with lipopolysaccharide (LPS) from Salmonella enderitidis and phorbol 12-myristate 13-acetate (PMA). The increasing concentrations of alpha-MSH (10(-12)-10(-6) M) were added to stimulated cells alone or along with the COX inhibitors indomethacin, ketorolac or nimesulide (10(-8)-10(-5) M). Luminol and lucigenin CL levels were significantly increased in cells stimulated with LPS and PMA compared to unstimulated ones. alpha-MSH significantly reduced lucigenin CL values and this effect was completely reversed in the presence of indomethacin (10(-8) and 10(-7) M). In conclusion, alpha-MSH inhibits the production of superoxide radicals by activated rat peritoneal neutrophils and COX contributes to this effect.

Modulation of the peripheral and central inflammatory responses by alpha-melanocyte stimulating hormone.

Inflammation, a localized response to tissue injury, and disorders characterized by inflammation are difficult problems in clinical medicine. This difficulty stems in large part from incomplete understanding of inflammatory processes and their regulation. Recent development of knowledge of the role of central nervous system and neuroendocrine system in host responses has provided a new view of the capacity of neuronal and soluble mediators in these systems to influence inflammation. One of these mediators is the endogenous neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH), which is an N-acetyl tridecapeptide derived from the cleavage of a larger precursor molecule, pro-opiomelanocortin (POMC). alpha-MSH is widely distributed in tissues of higher organisms; it has been identified in the pituitary, various brain regions, skin, circulation and other sites. The neuropeptide alpha-MSH is important to the natural limitation of fever, which is an early host response to endotoxin. In addition to its action within the brain to reduce fever, alpha-MSH has potent and broad anti-inflammatory effects in many forms of inflammation. This review will summarize the data on the actions of the peptide on various aspects of peripheral and central inflammation. On the basis of the data presented, we may think that the anti-inflammatory actions of the peptide via peripheral and / or central melanocortin receptors might put the peptide into practice therapeutically in near future.

Biliary decompression reduces the susceptibility to ethanol-induced ulcer in jaundiced rats.

We investigated the gastric response to an ulcerogenic irritant and the change in gastric functions in an experimental rat model of obstructive jaundice, with or without biliary drainage. After biliary obstruction for 14 days, rats with ligated bile duct (BDL) were randomly divided into three groups: BDL group without biliary drainage, BDL followed by choledochoduodenostomy (CD) or a choledochovesical fistula (CVF). The gastric functions were evaluated 2 weeks after the surgery. Gastric damage, induced by orogastric administration of ethanol, was evaluated 30 min later using a lesion index and microscopic scoring was then performed on fixed stomachs. Basal gastric acid secretion was measured by the pyloric ligation method. The lesion index and maximum lesion depth did not differ in the BDL and sham groups, while they were significantly reduced in the CD group. Gastric acid output and secretory volume were reduced in the BDL group compared to the sham group, while these reductions were abolished in the CD group. Afferent denervation with capsaicin further reduced the ulcer index in the later group. Our data suggest that gastric mucosal susceptibility to injury is dependent on the normal flow of bile into the duodenal lumen, which appears to be a requirement for adaptive gastric cytoprotection.

Beneficial effects of glycocholic acid (GCA) on gut mucosal damage in bile duct ligated rats.

In order to investigate the effect of bile acids on gastrointestinal inflammations, bile duct ligated rats (BDL) were treated with GCA (25 mM/ml, oral or colonic) or saline I h before ethanol challenge and twice daily for 3 days in the ileitis group, while GCA was given twice daily for 3 days in the colitis group. BDL reduced the macroscopic and microscopic damage scores in the ileitis group compared to sham operated group, while it had no significant effect on ulcer or colitis groups. However, GCA given in BDL group reduced the ulcer index and microscopic damage in colitis group compared to saline-treated groups, but had no effect in ileitis group. Both BDL and GCA administration in BDL group reduced ileitis- or colitis-induced elevations in MPO levels. GCA administration in BDL group inhibited gastric acid output and volume. Our results suggest that oral or colonic administration of primary bile acids may be useful for the treatment of gastrointestinal inflammations.

The effect of alpha-melanocyte stimulating hormone on endotoxin-induced intestinal injury.

We investigated the effect of alpha-melanocyte stimulating hormone (alpha-MSH) on endotoxin-induced intestinal inflammation and the role of nitric oxide and prostaglandins in this response. alpha-MSH treatment (25 microg/rat, intraperitoneally (i.p.); twice daily) reduced the severity of the lesions macroscopically and microscopically. This protective effect was found to be confined mainly to the distal ileum. These lesions were reversed by pretreatment with the non-selective COX inhibitor indomethacin (10 mg/kg, subcutaneously (s.c.)) but not by the selective COX-2 inhibitor nimesulide (3 mg/kg, s.c.), the NO donor sodium nitroprusside (4 mg/kg, i.v.) or the iNOS inhibitor dexamethasone (3 mg./kg, i.p.) at macroscopic level and reversed by Indo or Dex at microscopic level. Increased peroxidase activity -index of tissue neutrophil infiltration- in the distal ileum of LPS-treated rats was decreased by alpha-MSH and this effect was reversed by pretreatment with Indo. In conclusion, the neuropeptide alpha-MSH has a beneficial effect on endotoxin-induced distal intestinal lesions by a mechanism which probably involves nitric oxide and COX-1 derived prostaglandins.

The effect of alpha-melanocyte stimulating hormone on colonic inflammation in the rat.

The effect of alpha-melanocyte stimulating hormone (alpha-MSH) on colonic inflammation in the rat. In this study, we investigated the effects of alpha-MSH administration on trinitrobenzene sulfonic acid-induced colitis and the role of nitric oxide and prostaglandins in this response. alpha-MSH treatment (25 microg/rat, intraperitoneally; twice daily for 3 days) reduced the colonic macroscopic lesions compared to untreated ones in both acute and chronic colitis groups. This effect was reversed by pretreatment with the nitric oxide donor, sodium NP (4 mg/kg, intravenously) or cyclooxygenase-1 selective antagonist indomethacin (5 mg/kg, subcutaneously) in the acute group and with the cyclooxygenase-2 selective antagonist nimesulide (3 mg/kg, subcutaneously) in the chronic group. alpha-MSH had no effect on colonic wet weight and myeloperoxidase activity compared to the untreated colitis group. However, protein oxidation was markedly elevated in the alpha-MSH-treated group compared to untreated ones. Nitroprusside and indomethacin reversed the effect of alpha-MSH on macroscopic lesions in the acute groups, whereas nimesulide showed a similar effect in the chronic group. In conclusion, the results of our study show a protective role of alpha-MSH on colonic lesions which partially involves nitric oxide and prostaglandins.

Endothelin-1-induced PMN infiltration and mucosal dysfunction in the rat small intestine.

The objectives of this study were to characterize the effects of endothelin (ET)-1 on intestinal mucosal parameters and to assess the contribution of polymorphonuclear leukocytes (PMNs), intercellular adhesion molecule-1 (ICAM-1), and a platelet-activating factor (PAF) to the mucosal dysfunction induced by ET-1. Different concentrations of ET-1 (100, 200, and 400 pmol/kg) were infused into the superior mesenteric artery for 10 min, and tissue samples were obtained 30 min after terminating the infusion. ET-1 administration significantly elevated tissue myeloperoxidase activity, plasma carbonyl content, and tissue chemiluminescence intensity, indicating that ET-1 produces PMN infiltration and oxidant stress. Blood-to-lumen clearance of (51)Cr-EDTA significantly increased after ET-1 infusion (400 pmol/kg). Monoclonal antibodies against ICAM-1 (1A29, 2 mg/kg), antineutrophil serum, and PAF antagonist (WEB-2086, 10 mg/kg) attenuated the mucosal barrier dysfunction induced by ET-1. Overall, our data indicate that ET-1 causes PMN accumulation, oxidant stress, and mucosal dysfunction in the rat small intestine and that ET-1-induced mucosal dysfunction involves a mechanism that includes a role for PMNs, ICAM-1, and PAF.

Capsaicin-sensitive vagal fibres and 5-HT3-, gastrin releasing peptide- and cholecystokinin A-receptors are involved in distension-induced inhibition of gastric emptying in the rat.

The present study was undertaken to investigate how the activation of gastric mechanoreceptors by distension of the stomach in conscious gastric fistula rats influences gastric emptying; and the roles of capsaicin sensitive vagal afferent fibres and the 5-HT3, GRP and CCK-A receptors involved in mediating these responses. To activate mechanoreceptors by non-nutrient dependent pathways, methylcellulose in saline was used to distend the stomach (5 cm H2O) and the subsequent emptying of saline was examined immediately, and at 3, 5 and 10 min following distension. Prior distension delayed the subsequent emptying of saline instilled into the stomach compared with non-distended controls (2.28+/-0.09 ml/5 min; P < 0.001). Topical application of capsaicin, completely abolished the distension-induced inhibition of gastric emptying when compared with vehicle treated rats (2.82+/-0.09 vs. 2.38+/-0.04 ml/5 min; P < 0.001). Peripheral administration of a GRP antagonist (2258 U89UJ, 1 mg/kg), and a 5-HT3 antagonist (BRL4369UA, 50 microg/kg) significantly reversed (2.56+/-0.14 ml/5 min; P < 0.05 and 2.61+/-0.07 ml/5 min; P < 0.01; respectively) the delay in gastric emptying induced by distension. When the rats were treated with the CCK-A antagonist, gastric emptying of saline following distension was also significantly facilitated (2.56+/-0.07 ml/5 min; P < 0.001). In contrast, the CCK-B/gastrin receptor antagonist had no significant effect on the distension induced delay in gastric emptying (1.95+/-0.12 ml/5 min). The present results suggest that gastric distension in conscious gastric fistula rats delays gastric emptying by activating capsaicin-sensitive extrinsic afferent nerve fibres. Moreover, the results also indicate that distension-induced mechanisms involve GRP, 5-HT3 and CCK-A receptors, but not CCK-B receptors.