Biomedical subjects

Masaru Odashima

Publications and source records attributed to Masaru Odashima.

27 records · Page 2Linked to original sources

PubMed2005

Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease.

BACKGROUND & AIMS: Adenosine has been implicated as an important regulator of the inflammatory response. Four subtypes of adenosine receptors (A 1 , A 2A , A 2B , and A 3 ) have been described, of which A 2A potentially inhibits inflammation. The aim of this study was to investigate the role of A 2A in mucosal inflammation by administering a selective A 2A agonist (ATL-146e) to experimental models of inflammatory bowel disease. METHODS: The anti-inflammatory effects of ATL-146e were studied in the acute and chronic rabbit formalin-immune complex models of colitis and the SAMP1/YitFc mouse model of spontaneous ileitis. RESULTS: ATL-146e significantly reduced the acute inflammatory index and tissue necrosis compared with vehicle ( P < .01) in the acute model of rabbit immune colitis. In the chronic rabbit immune colitis model, ATL-146e significantly suppressed inflammatory cell infiltration into the colonic mucosa ( P < .05) and prevented mortality. The administration of ATL-146e significantly decreased the chronic inflammatory index ( P < .01) and villus distortion index ( P < .01) in the ileum of SAMP1/YitFc mice, and ameliorated adoptively transferred ileitis in severe combined immunodeficient mice injected with CD4 + T cells from SAMP1/Yit mice ( P < .05). Tumor necrosis factor, interferon gamma, and interleukin 4 concentrations were significantly suppressed by ATL-146e treatment in supernatants from cultures of mesenteric lymph node cells of SAMP1/YitFc mice ( P < .05 vs vehicle-treated mice). CONCLUSIONS: A 2A adenosine receptor activation by ATL-146e significantly reduced inflammation in the intestinal mucosa. This effect was associated with decreased leukocyte infiltration and inhibition of proinflammatory cytokines. Activation of A 2A by selective agonism may therefore serve as a novel therapy for the treatment of inflammatory bowel disease.

Acute Disease↗

PubMed2005

Specific type IV phosphodiesterase inhibitor ameliorates thioacetamide-induced liver injury in rats.

BACKGROUND AND AIMS: Rolipram is a specific type IV phosphodiesterase inhibitor that suppresses the activity of immune cells and the production of pro-inflammatory cytokines. In this study, we assessed the effect of rolipram on acute liver injury using thioacetamide (TAA)-induced liver injury in rats as a model. METHODS: Rats were treated with rolipram (0.5-5 mg/kg, intraperitoneally) or vehicle and injected 30 min later with TAA (100 mg/kg, subcutaneously). Serum transaminase concentrations and tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta) and growth related oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1) levels were measured and livers were examined for microscopic changes. Dose-dependent protection against TAA liver injury was based on transaminase levels and inflammatory cytokine production, and was measured 9 h after TAA when the peak release of cytokines occurred. RESULT: Rolipram suppressed liver injury based on serum aspartate transaminase (AST), alanine transaminase (ALT) and histology and reduced TNF-alpha, IL-1beta and GRO/CINC-1 levels. Rolipram, at doses of 0.5-5 mg/kg, suppressed serum transaminase and TNF-alpha production in a dose-dependent manner, and these effects were significant at doses of 2.5 and 5 mg/kg. CONCLUSION: In our rodent model of acute liver injury, rolipram clearly reduced liver damage and inhibited pro-inflammatory cytokine production. These results suggest that specific type IV phosphodiesterase inhibitors, such as rolipram, have potent hepatoprotective effects that are associated with suppressing inflammatory cytokine production.

Animals↗

PubMed2005

Selective adenosine A receptor agonist, ATL-146e, attenuates stress-induced gastric lesions in rats.

BACKGROUND: Activation of adenosine A(2A) receptors reduces the production of various pro-inflammatory cytokines and suppresses neutrophil activation. Water-immersion restraint is well known to cause gastric mucosal lesions due to stress. The pathogenesis of stress-induced gastric mucosal lesions is characterized by activation of inflammatory cells and production of inflammatory cytokines. Agonists of adenosine A(2A) receptors are known to be anti-inflammatory, but the effects of these compounds on the development of gastric mucosal lesions has not been reported. In the present study, the effect of a potent and selective adenosine A(2A) receptor agonist, ATL-146e, on water-immersion stress-induced gastric mucosal lesions was studied. METHODS: Rats were subjected to water-immersion stress with or without pretreatment with a single intraperitoneal injection of a potent and selective agonist of the adenosine A(2A) receptor. The gastric concentrations of myeloperoxidase (MPO), as an index of neutrophil accumulation, and the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), were measured. RESULTS: The total length of gastric erosions (ulcer index) in control rats was 21.6 +/- 3.23 mm and was reduced by 86% to 3.1 +/- 0.83 mm by pretreatment with 5.0 microg/kg ATL146e (P < 0.001). The gastric content of MPO, TNF-alpha and IL-1beta were all increased after water-immersion stress and reduced to near normal levels by ATL-146e. CONCLUSION: A specific adenosine A(2A) agonist inhibits stress-induced gastric inflammation and damage. A(2A) agonist compounds may be useful for preventing ulcers and appear to act by blocking gastric inflammation.

Adenosine A2 Receptor Agonists↗

PubMed2004

Expression of a 72-kDa heat shock protein, and its cytoprotective function, in gastric mucosa in cirrhotic rats.

BACKGROUND: Portal hypertensive gastropathy (PHG) is a clinical entity that is observed frequently in patients with liver cirrhosis. In PHG, gastric mucosa is highly susceptible to mucosal injury caused by noxious agents. Many studies, including ours, have reported that a 72-kDa heat shock protein (HSP72) has a crucial cytoprotective function in gastric mucosa. In this study, we investigated the expression and cytoprotective effect of HSP72 on gastric mucosa in portal hypertensive rats. METHODS: PHG was produced by bile duct ligation (BDL) or carbon tetrachloride administration in male Sprague-Dawley rats. The expression of HSP72 in the gastric mucosa was evaluated by Western blotting. Induction of gastric mucosal HSP72 by 6-h water-immersion stress was compared between cirrhotic and control rats. Also, mucosal protective abilities against hydrochloric acid (HCl; 0.6 N) following pretreatment with water-immersion stress to induce HSP72 were studied in both groups. RESULTS: Portal venous pressure was significantly higher in cirrhotic rats compared with control rats ( P < 0.05). Baseline expression (before water-immersion stress) of mucosal HSP72 was significantly lower in cirrhotic rats compared with control rats. HCl-induced gastric mucosal lesions were significantly suppressed in control rats compared with cirrhotic rats, especially when HSP72 was preinduced by water-immersion stress. CONCLUSIONS: These findings suggest that HSP72 in the gastric mucosa plays a crucial role with respect to cytoprotection; the induction of HSP72 may provide therapeutic strategies for protection against mucosal injury in PHG.

Animals↗

PubMed2004

Induction of a 72-kDa heat shock protein and protection against lipopolysaccharide-induced liver injury in cirrhotic rats.

BACKGROUND AND AIM: A 70-kDa heat shock protein (stress-inducible HSP70, HSP72) has been reported to be a cytoprotectant in a variety of organs. It has been reported that HSP72 protected non-cirrhotic rats against endotoxemia. However, its cytoprotective effect against endotoxemia in cirrhotic rats has not yet been studied. In this study, we investigated the cytoprotective effect of HSP72 on lipopolysaccharide (LPS)-induced liver injury in carbon tetrachloride (CCl(4))-induced cirrhotic rats. METHODS: Liver cirrhosis was produced by an 8-week intraperitoneal injection of CCl(4) in male Sprague-Dawley rats. Expression of HSP72 was investigated using western blot analysis. Cirrhotic rats were given an intraperitoneal injection of LPS (10 mg/kg) with or without hyperthermia (42.5 degrees C, 15 min) preconditioning. Liver injury was assessed biochemically (aspartate transaminase, alanine transaminase, bilirubin, lactate dehydrogenase, creatinine) and histologically. The plasma tumor necrosis factor (TNF)-alpha level was determined. RESULTS: Hyperthermia preconditioning induced a 4-fold increase in HSP72 in the cirrhotic rat liver. Pre-induction of HSP72 prevented LPS-induced liver injury, as evaluated using serum biochemical parameters and histology with reduced TNF-alpha response. CONCLUSION: These findings suggest that pre-induction of HSP72 may provide therapeutic strategies for Gram-negative sepsis-induced liver injury in liver cirrhosis.

Animals↗

PubMed2004

[Rolipram, a specific type IV phosphodiesterase inhibitor, ameliorates indomethacin-induced gastric mucosal injury in rats].

Animals↗

PubMed2003

Rolipram, a specific type IV phosphodiesterase inhibitor, ameliorates indomethacin-induced gastric mucosal injury in rats.

Inhibition of type IV phosphodiesterase activity is beneficial in various inflammation mediated by its function to suppress the production of inflammatory cytokines in inflammatory cells. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin are well known to develop gastric mucosal lesion. As pathogenesis of indomethacin induced gastric mucosal lesion, activation of neutrophils and inflammatory cytokine production play critical roles. However, the effect of phosphodiesterase inhibitors on development of gastric mucosal lesion has not been reported. In the present study, we examined the effect of specific type IV phosphodiesterase inhibitor (rolipram) on NSAIDs-induced gastric mucosal lesion. Also, we examined the effect of rolipram on tissue prostaglandin E2 (PGE2) production. Indomethacin-induced gastric mucosal injury was produced by the intragastric administration of indomethacin (30 mg/kg). Rolipram was injected to the rats intraperitoneally 30 min before the indomethacin administration. Ulcer index and tissue myeloperoxidase (MPO) activity of the gastric mucosa was evaluated. The gastric concentration of PGE2 was determined by RIA. Gastric mucosal lesion induced by indomethacin was significantly inhibited with treatment of rolipram. Mucosal MPO activity was also suppressed by administration of rolipram. Gastric mucosal PGE2 concentration was not affected by intraperitoneal injection of rolipram. Based on these data, the beneficial effects of rolipram on indomethacin-induced gastric mucosal injury may be attributed to its anti-inflammatory properties.

Journal Article↗

PubMed2002

Down-regulation of intestinal lymphocyte activation and Th1 cytokine production by antibiotic therapy in a murine model of Crohn's disease.

Resident intestinal bacteria likely play an important role in the pathogenesis of Crohn's disease through their interaction with the gut immune system. SAMP1/YitFc mice spontaneously develop chronic, discontinuous, transmural ileitis with many features similar to Crohn's disease. The aim of this study was to determine the effects and elucidate the mechanisms of action of antibiotic treatment in the SAMP1/YitFc mouse model of ileitis. Mice were treated orally with ciprofloxacin and metronidazole before the development of ileitis (prevention protocol) or after ileitis was fully established (treatment protocol). Terminal ilea were harvested for histological scoring, and lamina propria and mesenteric lymph node cells were isolated for analysis of activation markers and cytokine production. Antibiotic therapy significantly decreased the severity of ileitis both in the prevention (40% reduction, p < 0.05) and the treatment (25% reduction, p < 0.01) protocols, compared with untreated, control mice. These effects were associated with a decreased percentage of CD4(+)/CD45RB(high) lymphocytes in mesenteric lymph nodes of antibiotic-treated mice, as well as decreased production of IFN-gamma (prevention: 0.53 +/- 0.21 vs 1.84 +/- 0.04 ng/ml, p < 0.05; treatment: 8.4 +/- 0.4 vs 12.4 +/- 0.7 ng/ml, p < 0.005) and TNF (prevention: 61.5 +/- 13 vs 134 +/- 19 pg/ml, p < 0.01; treatment: 333.5 +/- 11 vs 496 +/- 20 pg/ml, p < 0.001). The number of activated lamina propria lymphocytes was also reduced after antibiotic treatment. In conclusion, antibiotic therapy significantly ameliorates the severity of ileitis in SAMP1/YitFc mice by a mechanism involving down-regulation of activated gut lymphocytes and inhibition of intestinal Th1 cytokine production.

Administration, Oral↗

PubMed2002

Induction of a 72-kDa heat-shock protein in cultured rat gastric mucosal cells and rat gastric mucosa by zinc L-carnosine.

An antiulcer drug, zinc L-carnosine (polaprezinc), provides gastric mucosal protection against various irritants. In this study, we evaluated the effects of zinc L-carnosine on expression of 72-kDa heat shock protein (HSP72, stress inducible HSP70), which is known as an endogenous cytoprotectant in a wide variety of cells, including rat gastric mucosa in vitro and in vivo. Expression of HSP72 after exposure to zinc L-carnosine, zinc sulfate, or L-carnosine (1-300 microM) in rat gastric mucosal cells (RGM1) and intragastric administration of zinc L-carnosine, zinc sulfate (30 or 100 mg/kg) and L-carnosine (76 mg/kg) was investigated by western blotting and densitometric analysis. Exposure to zinc L-carnosine and zinc sulfate increased the expression of HSP72 significantly in RGM1 cells. Intragastric administration of zinc L-carnosine and zinc sulfate showed significant increment in HSP72 in rat gastric mucosa also in vivo. The ability to induce HSP72 is significantly higher in zinc L-carnosine compared with zinc sulfate based on molecular concentration in vivo. However, L-carnosine did not increase the expression of HSP72 in vitro and in vivo. Zinc derivatives, especially zinc L-carnosine, could be a strong HSP72 (chaperon) inducer, which has been known to enhance mucosal protective ability.

Animals↗