The present study has evaluated the healing effects of extract of dried fruit pulp of Terminalia chebula (TCE) on acetic acid (AA)-induced colitis in rats. TCE (600 mg/kg) showed healing effects against AA-induced colonic damage score and weight when administered orally daily for 14 days. TCE was further studied for its effects on various physical (mucus/blood in stool and stool frequency, food and water intake and body weight changes), histology, antibacterial activity and free radicals (NO and LPO), antioxidants (SOD, CAT and GSH) and myeloperoxidase in colonic tissue. Intra-colonic AA administration increased colonic mucosal damage and inflammation, mucus/bloody diarrhoea, stool frequency, but decreased body weight which were reversed by TCE and sulfasalazine (SS, positive control) treatments. TCE showed antibacterial activity and both TCE and SS enhanced the antioxidants, but decreased free radicals and myeloperoxidase activities affected in acetic acid-induced colitis. TCE indicated the presence of active principles with proven antioxidants, anti-inflammatory, immunomodulatory, and free radical scavenging and healing properties. Thus, TCE seemed to be safe and effective in healing experimental colitis.

Ulcerative colitis is characterized by elevated rates of epithelial cell apoptosis, and an up-regulation of pro-apoptotic cytokines including tumor necrosis factor alpha (TNF-alpha). Recently, angiotensin converting enzyme (ACE) has been shown to promote apoptosis. In addition, pharmacologic ACE inhibition (ACE-I) both prevents apoptosis and reduces TNF-alpha expression in vitro. We hypothesized that ACE-I, using enalaprilat, would decrease colonic epithelial cell apoptosis and reduce colitis severity in the dextran sulfate sodium (DSS)-induced colitis model in mice. We assessed the severity of colitis, and colonic epithelial cell apoptosis, after administration of DSS. Mice were given either daily ACE-I treatment or daily placebo. ACE-I treatment markedly improved clinical outcomes. In addition, ACE-I treatment significantly reduced the maximum histopathologic colitis grade. ACE-I also dramatically reduced the epithelial apoptotic rate. To investigate the mechanism by which ACE-I reduced apoptosis; we measured TNF-alpha, Bcl-2, and Bax expression. TNF-alpha mRNA was significantly lower with ACE-I treatment compared to placebo at every time point, as was the ratio of Bax to Bcl-2. We conclude that ACE-I reduces the severity of DSS-induced colitis and reduces epithelial cell apoptosis.

Inhibition of type IV phosphodiesterase (PDE4) activity is beneficial in various inflammations. However, the effect of phosphodiesterase inhibitors on the development of stress-induced gastric mucosal lesions has not been reported. In the present study, we examined the effect of a specific PDE4 inhibitor (rolipram) on stress-induced gastric mucosal lesions. Rats were exposed to water-immersion stress with or without pretreatment with rolipram. Ulcer index and myeloperoxidase activity of the gastric mucosa were evaluated. Gastric mucosal lesions and mucosal myeloperoxidase activity were suppressed by treatment with rolipram without acid suppression. The effect of intraperitoneal administration of 2.5 mg/kg rolipram on suppression of mucosal lesions was almost equal to that of treatment with 200 mg/kg cimetidine. We demonstrated that a specific PDE4 inhibitor has a potent anti-ulcer effect presumably mediated by an increment in intracellular cAMP in inflammatory cells, in which this enzyme is abundantly and specifically expressed.

Cilostazol, a specific type-III phosphodiesterase inhibitor, is widely used for the treatment of ischemic symptoms of peripheral vascular disease. Recent studies have reported that the mechanism of cilostazol is related to the suppression of pro-inflammatory cytokine production and improvement of local microcirculation disturbances. The pathogenesis of stress-induced gastric mucosal lesions is characterized by the activation of inflammatory cells and the production of inflammatory cytokines. The effects of cilostazol on the development of gastric mucosal lesions have not been reported. In the present study, we examined the effect of a cilostazol on water-immersion stress-induced gastric mucosal lesions.

Rats were subjected to water-immersion stress with or without pretreatment with a single intraperitoneal injection of the selective type-III phosphodiesterase inhibitor, cilostazol. We measured the gastric mucosal lesion and the concentrations of myeloperoxidase (MPO), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1), as an index of neutrophil accumulation and pro-inflammatory cytokine production.

Cilostazol ameliorated the gastric mucosal injury induced by water-immersion stress (P<0.001). The gastric contents of MPO, TNF-alpha, IL-1beta, and CRO/CINC-1 were all increased after water-immersion stress and were reduced to almost normal levels by cilostazol.

In this study, we demonstrated that a selective type-III phosphodiesterase inhibitor, cilostazol, inhibited stress-induced gastric inflammation and damage via suppressing the production of pro-inflammatory cytokines. Cilostazol may be useful for preventing gastric mucosal lesions.

Ulcerative colitis is associated with altered contractile activity and transit time of colon. On the other hand, cholecystokinin (CCK) has been shown to play an important role in regulation of gastrointestinal motor function including colonic contraction and transit. In the present study, an attempt was made to study the effect of proglumide, a CCK receptor antagonist on experimental colitis in rats. Experimental colitis was induced in male Sprague-Dawley rats by instilling 1 ml of 4% acetic acid followed by flushing with 0.5 ml air. The rats were kept in a head-down position for 30s. Finally, each rat received 1.5 ml colonic wash with 1.5 ml saline. Four groups of rats received proglumide orally (0, 250, 500 and 1000mg/kg). The first dose of proglumide was given 1 h before acetic acid challenge, whereas the second dose of proglumide was given 25 h after the first dose. Sham control rats received an equal volume of saline instead of acetic acid. Forty-eight hours after the acetic acid challenge, the colon was removed, weighed and split longitudinally and scored for injury. Part of the colon was used for histopathological study as well as analysis of myeloperoxidase (MPO) activity (as a marker of neutrophil activity). Acetic acid produced severe diarrhea and exfoliation of the colonic epithelium accompanied by extensive destruction of the mucosal interstitium. Proglumide dose dependently protected rats against acetic acid-induced increase in colon weight, diarrhea, MPO activity and colonic injury. Inhibition of CCK exerts a beneficial effect in experimental colitis. Further studies are warranted to determine the mechanism of protection and the therapeutic potential of CCK inhibitors.

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.

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.

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.

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.

Mild haemorrhage occasionally causes delayed death following failure of kidney or multiple organs, but the precise mechanisms have not yet been identified. We investigated the role of tumour necrosis factor-alpha (TNF-alpha), known as a major pro-inflammatory cytokine that leads to multiple organ failure, on the renal damage induced by mild haemorrhage. A mild haemorrhagic state was induced in male anaesthetized rats by bleeding via a common carotid catheter for 20 min at 16.7% of total body blood, 1.09 ml/100 g body weight, without fluid resuscitation. Mean arterial pressure and heart rate decreased soon after haemorrhaging but returned to baseline level up to 5 h after bleeding. TNF-alpha mRNA expression in the kidney and serum TNF-alpha levels were highest at 1 h after bleeding. Intraperitoneal pretreatment with FR167653, an inhibitory compound of TNF-alpha production, as well as of interleukin (IL)-1beta, significantly inhibited the increase in TNF-alpha. The inflammatory cell infiltration and tubular cell injury induced by haemorrhage were suppressed, and the renal dysfunction was dramatically improved by the FR167653 treatment. The morphological changes were also less in the treated group than in those that had not been treated. TNF-alpha has been reported to have striking effects on IL-1beta release and activation of neutrophils, and to play a pivotal role in the expression of the other pro-inflammatory cytokines. Our data show that endogenously-derived TNF-alpha does play a key role in the renal dysfunction during mild haemorrhage. These results should be useful to forensic pathologists to explain the pathogenesis of renal dysfunction induced by a mild haemorrhage and to identify the cause of death where there are no significant morphological changes after mild haemorrhage.

Obliterative bronchiolitis (OB) is the main cause of late mortality among long-term survivors of lung transplantation. Although p38 kinase is functional in multiple acute inflammatory injury models, its role in chronic lung rejection is undefined. p38 regulates the expression of the cytokines tumor necrosis (TNF)-alpha and interleukin (IL)-1beta, 2 mediators involved in the development of OB in a tracheal transplant model. These studies assessed whether specific inhibition of p38 with FR167653 (FR) protects against the development of OB in rat tracheal allografts.

Rat airways were heterotopically transplanted from Brown-Norway donors into Lewis recipients, and animals were sacrificed on day 14 (6 per group). Treated animals received 10 mg/kg daily of FR intraperitoneally beginning either immediately or at day 7 after transplant. Allografts were assessed by computerized morphometry, and tracheas were processed for TNF-alpha mRNA and protein expression by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry, respectively. Electrophoretic mobility shift assays evaluated nuclear factor kappa beta (NFkappaB) transactivation.

Control allografts averaged 61% occlusion and 98% loss of epithelium at 14 days, whereas FR administration reduced luminal occlusion to 28% (p < 0.001) and epithelial loss to 71% (p < 0.001). Delayed treatment beginning on day 7 slowed progression of disease, as tracheal occlusion averaged 44% and epithelial loss averaged 80%, both of which were significant (p < 0.05) improvements relative to 14-day controls. NFkappa transactivation (p < 0.004) and TNF-alpha mRNA and protein expression were reduced dramatically by FR at 14 days.

A specific p38 inhibitor, FR 167653, ameliorates obliterative airway disease in rat tracheal allografts via attenuated NFkappaB transactivation, which ultimately results in diminished TNF-alpha mRNA and protein expression.