The effect of the angiotensin II receptor, type 1 receptor antagonists, losartan and telmisartan, on thioacetamide-induced liver fibrosis in rats.

It has been reported previously that the density of angiotensin II receptors is increased in the rat liver in experimentally-induced fibrosis. We hypothesized that pharmacological blockade of angiotensin receptors may produce beneficial effects in models of liver fibrosis. In this study, we used the widely used thioacetamide (TAA)-induced model of liver fibrosis (300 mg/L TAA ad libitum for 12 weeks). Rats received daily injections (i.p), lasting 4 weeks of the angiotensin II type 1 receptor antagonists, losartan 30 mg/kg (TAA + L) or telmisartan 10 mg/kg (TAA + T) and were compared to rat that received TAA alone. Chronic treatment with losartan and telmisartan was associated with a significant reduction in the activity of alkaline phosphatase, and decreased concentrations of tumor necrosis factor-alpha and transforming growth factor beta-1 compared to controls. We also found a significant reduction interleukin-6 in rats receiving telmisartan (P < 0.05) but not losartan. Both treatments increased the concentration of liver glutathione along with a concomitant decrease of GSSG compared to controls. In addition, increased paraoxonase 1 activity was observed in the serum of rats receiving telmisartan group compared to the TAA alone controls. Finally, histological evaluation of liver sections revealed losartan and telmisartan treatment was associated with reduced inflammation and liver fibrosis. Taken together, these results indicate that both telmisartan and losartan have anti-inflammatory and anti-oxidative properties in the TAA model of liver fibrosis. These finding add support to a growing body of literature indicating a potentially important role for the angiotensin system in liver fibrosis and indicate angiotensin antagonists may be useful agents for fibrosis treatment.

Effects of renin-angiotensin system inhibitors on fibrosis in patients with alcoholic chronic pancreatitis.

Chronic pancreatitis (CP) results in impairment of exocrine as well as endocrine functions and progressive fibrosis. Previous studies, have demonstrated the presence of renin-angiotensin system receptors within different pancreatic cells. The aim of the present study was to assess the effects of renin-angiotensin system (RAS) inhibitors on serum levels of fibrosis biomarkers (matrix metalloproteinase 2 and 9 (MMP-2, MMP-9), tissue inhibitor of MMP (TIMP- 1, TIMP-2), hyaluronic acid (HA)) and fasting glucose levels in patients with alcoholic CP. Seventy seven outpatients (mean age 43 years, 62 males) with diagnosed alcoholic CP were randomly enrolled into 5 study groups depending on the RAS inhibitors administered and their doses (2.5 or 5 mg and 12.5 or 25 mg for ramipril or losartan, respectively). Venous blood was sampled monthly for a period of one year to monitor serum drug levels. MMP-2, -9, TIMP-1, TIMP-2 and HA were measured with ELISA method on the onset and at the end of the study. Only forty five patients regularly participated in follow-up visits and completed the study. The fluctuations in serum HA levels observed among patients from the remaining groups also did not reach statistical significance. Serum MMP-2 levels (P = 0.06) and MMP-2/TIMP-1 ratio (P = 0.06) showed increasing tendency in the losartan 25 mg group. High doses of ramipril and losartan statistically significantly reduced fasting glucose levels. High doses of losartan can increase the MMP-2 activity in serum of alcoholic CP patients, which potentially is likely to affect turnover of extracellular matrix proteins within the pancreas. Moreover, high doses of both RAS inhibitors decrease the fasting glucose level.

Comparison of anti-inflammatory properties of peroxisome proliferator-activated receptor gamma agonists rosiglitazone and troglitazone in prophylactic treatment of experimental colitis.

Non-specific inflammatory bowel disease (IBD), including ulcerative colitis and Crohn`s disease, is a chronic noninfectious inflammatory disease whose incidence is increasingly high, especially in the developed countries. Effective methods of its treatment and prevention of recurrences are still under investigation. Amongst the options to control effectively the inflammatory processes of the gastrointestinal tract are thiazolidinediones - peroxisome proliferator-activated receptors gamma (PPAR-γ) agonists, whose beneficial effects on macroscopic and histopathological features of colitis have been confirmed in numerous studies. In the present study, possible effects of PPAR-γ agonists rosiglitazone and troglitazone enhancing the resistance of colonic tissues to the damaging factor were examined and compared. Rats received the food with 0.01% rosiglitazone or troglitazone for 4 weeks; during the final 2 weeks, colitis-inducing 1.5% DSS (dextran sodium sulfate) was additionally administered in the drinking water. The large intestine specimens were microscopically evaluated and the levels of Th1- (IL-2, INF) and Th2-dependent (IL-4, IL-10) cytokines were determined in the serum and intestinal homogenates. Prophylactic treatment with rosiglitazone and troglitazone ameliorated colitis substantially down-regulating the microscopic inflammatory parameters. Rosiglitazone and troglitazone administered before the induction of colitis exerted comparable effects on colitis. Both substances significantly reduced the levels of pro-inflammatory cytokines and increased the levels of inflammation-limiting cytokines. We conclude that thiazolidinedione drugs are likely to be successfully used for therapy and prevention of non-specific bowel diseases.

Comparison of the anti-inflammatory and therapeutic actions of PPAR-gamma agonists rosiglitazone and troglitazone in experimental colitis.

Non-specific inflammatory bowel diseases, including ulcerative colitis and Crohn`s disease, are chronic non-infectious diseases that showed an increase in prevalence in recent years, particularly in the developed countries. The effective methods of their treatment and prevention of recurrences are currently under investigation. One type of therapy that can prevent the inflammatory recurrence in the gastrointestinal tract is the PPAR-γ agonists thiazolidinediones. Numerous studies available in literature have confirmed the beneficial effects of thiazolidinediones (glitazones), namely rosiglitazone and troglitazone in the gut. The objective of the present study was to compare the possible effects of rosiglitazone 10 mg/kg b.w. or 30 mg/kg b.w. and troglitazone 30 mg/kg b.w. on experimental colitis induced by administration of 1.5% dextran sodium sulphate (DSS) administered in drinking water to rats. Specimens collected from the large intestine were microscopically evaluated, and concentrations of Th1- dependent (IL-2, INF) and Th2-dependent (IL-4, IL-10) cytokines were determined in the serum and intestinal homogenates. Both rosiglitazone and troglitazone have demonstrated significant anti-inflammatory properties. This observation was confirmed by histopathological and immunoenzymatic tests. The therapeutic efficacy of rosiglitazone was dose-dependent. Troglitazone resulted in significantly stronger enhancement of anti-inflammatory cytokine expression than rosiglitazone and comparable downregulation of pro-inflammatory cytokine expression compared to rosiglitazone used in a higher dose.

Can we expect progress in the treatment of fibrosis in the course of chronic pancreatitis?

Chronic pancreatitis (CP) is a necroinflammatory process characterized by loss of both exocrine and endocrine function. To date, the disease has been treated symptomatically. Real advances in CP management can be expected once the pathophysiology of the disease is elucidated and individual stages of its development are properly managed. A key role in the CP pathogenesis is played by activation of pancreatic stellate cells (PSCs) that cooperate with the remaining pancreatic cells. All these cells produce cytokines, growth factors, angiotensin and other substances, which paracrinally or autocrinally induce further, persistent activation of PSCs. The activated PSCs are capable of producing and modifying the extracellular matrix. An optimal therapeutic preparation should exert beneficial effects on all the above-mentioned phenomena observed in CP. The most promising treatment modalities include blocking of the renin-angiotensin system (RAS), activation of peroxisome proliferator-activated receptors gamma (PPAR-γ), influence on the remaining PSC signaling pathways, blocking of substances produced by activated PSCs, and antioxidants. The findings of many recent experimental studies are highly encouraging; however, their efficacy should be confirmed in well-designed clinical trials.

Effects of peroxisome proliferator-activated receptors-gamma ligands on dextran sodium sulphate-induced colitis in rats.

Recent studies indicate the involvement of peroxisone proliferator-activated receptor-γ (PPAR-γ) in the inflammatory reaction. The exact mechanism of PPAR-γ action has not been elucidated. It is supposed that PPAR-γ regulates transcription of genes responsible for encoding cytokines involved in the inflammatory response. The latest studies, carried out to explain the pathogenesis of non-specific colitis, confirm beneficial effects of PPAR-γ agonists on attenuation of colon inflammation. The aim of the present study was to assess the effects of nuclear PPAR-γ activity on the course of experimental acute colitis induced by intragastric administration of dextran sodium sulphate (DSS) using the PPAR-γ agonist rosiglitazone and the antagonist BADGE in rats. Colitis in Wistar rats was induced by 1.5% DSS administered in drinking water for 8 days. Animals with induced colitis received rosiglitazone, bisphenol A diglycidyl ether (BADGE) or both substances. After decapitation, colons were macroscopically and histopathologically evaluated. Levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α) and myeloperoxidase (MPO) were determined in serum and colon homogenates using ELISA. In rats with experimentally induced colitis receiving rosiglitazone, the inflammatory reaction was found to be markedly limited; ulceration, oedema and infiltration activity were reduced. The activated PPAR-γ inhibit the expression of proinflammatory factors, such as IL-6, TNF-α, and neutrophil chemotaxis, which was evidenced by MPO reduction in serum and colon homogenates mediated by rosiglitazone. The positive effects of rosiglitazone on expression of IL-10 were also demonstrated. During the short period of observation, BADGE did not increase histopathological inflammatory markers.

Influence of the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, rosiglitazone and antagonist, biphenol-A-diglicydyl ether (BADGE) on the course of inflammation in the experimental model of colitis in rats.

PPAR-γ plays a role in the development of immune response, particularly in inflammation. The inflammatory reaction may be stimulated or suppressed by the presence of PPAR ligands. Some researchers suggest positive influence of the PPAR-γ agonist on suppression of the intestinal inflammatory process, yet there has not been much evidence showing that the antagonist of PPAR-γ can affect the inflammatory process. The aim of the present study was to define the mechanism by which PPAR-γ ligands affect the course of experimentally induced colitis in rats. Colitis was induced in rats by rectal administration of TNBS (trinitrobenzene sulfonate). Rosiglitazone was administrated to animals at the dose of 8 mg/kg four times via an intra-gastric probe. Biphenol-A-diglicydyl ether (BADGE) was administrated intraperitoneally at the dose of 120 mg/kg, three times every second day. One group of animals received rosiglitazone together with BADGE before the induction of inflammation. Histological and ELISA examinations of large intestine samples were performed. Levels of IL-1ß, IL-6, TNF-α cytokines were determined in serum and homogenates. Rats exposed to rosiglitazone had higher body weight yet lower large intestine weight. Histological findings showed less ulceration, lower expression of crypts' loss and smaller oedema. Animals, which did not receive rosiglitazone, and those receiving it together with BADGE, developed more severe inflammatory changes. Rosiglitazone decreased the expression of inflammatory cytokines, such as IL-6 and TNF-α, both in serum and in intestinal homogenates. BADGE used with TNBS did not increase the expression of inflammatory cytokines; however, applied together with rosiglitazone, it caused inflammation similar to that observed among rats with experimentally induced colitis. Rosiglitazone reduces inflammation by decreasing the expression of IL-6 and TNF-α. BADGE administered with rosiglitazone blocks the activity of PPAR-γ and abolishes the protective effects of PPAR-γ agonist.

Non-variceal upper gastrointestinal bleeding--guidelines on management.

In gastroenterology non-variceal upper gastrointestinal bleeding is health hazard. Frequency of occurrence accounts for 40-150 cases per 100000 inhabitants with death rate of 7-14%. Researches which goal is to improve treatment effectiveness as well as to establish standardized procedures for managing patients with symptoms of non-variceal upper gastrointestinal bleeding; have been conducted since many years. At the moment of admission, designed standards enable appropriate elaboration of patients' health state, referral to the right clinic and implementation of the most accurate treatment methods. Increase of suppression of primary bleeding as well as prevention of recurrence is associated with dynamic development of endoscopic treatment methods as well as with optimization of pharmacological treatment. In significant percentage, efficiency of non - variceal bleedings treatment depends on clinic's character (availability of equipment, experience of personnel) and on cooperation between several specialists (including gastroenterologist, surgeon, anesthetist, operative radiologist). Aim of the work is to present the latest evaluation of the mentioned subject, based on accessible literature. This work includes the basic principles for determination of bleeding intensity and risk of its recurrence as well as directions referring to fluids resuscitation and to monitoring of patients. Information on currently applied endoscopic methods for inhibition of non variceal upper gastrointestinal bleeding (injection, mechanical and thermo-coagulation techniques), comparison of their efficiency and possibility of application is provided in the work. The paper work also presents the newest directives for pharmacological treatment and guidelines for possible surgical treatment.

RAS inhibitors decrease apoptosis of acinar cells and increase elimination of pancreatic stellate cells after in the course of experimental chronic pancreatitis induced by dibutyltin dichloride.

Chronic pancreatitis (CP) is a progressive disease, in which the exocrine function of the gland is gradually lost and fibrosis develops due to repeated episodes of acute pancreatitis. The aim of the study was to investigate the effects of RAS inhibitors on the apoptosis of acinar cells and pancreatic stellate cells (PSCs) elimination in experimental CP induced by dibutyltin dichloride (DBTC). CP was induced by administration of DBTC to the femoral vein. Simultaneously captopril, losartan, enalapril and lisinopril were administered intraperitoneally. The rats were decapitated after 60 days and tissue of pancreas was collected. In rats treated by DBTC the features of inflammatory infiltration, ductal lumen dilatation, fibrosis were found. Strong reactivity with caspase2(L) and clusterin-beta antibodies was observed in areas of fibrosis. In animals treated with RAS inhibitors inflammatory changes and fibrosis were less severe. In groups of rats treated with DBTC and RAS inhibitors immunoreactivity of caspase(2L) and clusterin-beta was weak. Positive immunostaining against smooth muscle actine and desmin was observed in the elongated cells (PSC-s). This reaction was weak in groups of rat treated with DBTC and RAS inhibitors. Treatment of CP rats with RAS inhibitors alleviate apoptosis of pancreatic acinar cells and induces PSCs elimination.

The role of adenosine A2a receptors in experimental acute pancreatitis.

PURPOSE: The role of adenosine and its receptors in acute pancreatitis remains unelucidated. The aim was to evaluate the effects of the adenosine A2a receptor agonist and antagonist in the severe, taurocholate-induced experimental acute pancreatitis (EAP). MATERIAL AND METHODS: The experiments were performed on 80 male Wistar rats, subdivided into 4 groups: C--the control rats, I--the EAP group, IIA--EAP group treated with the A2a adenosine receptor agonist CGS 21680, IIB--EAP group treated with the A2a adenosine receptor antagonist ZM 241385. The blood for alpha-amylase and lipase and tissues samples for the morphological examinations and immunohistochemistry for A2a receptors were collected in 2, 6, 24 hours of the experiment. RESULTS: The serum alpha-amylase tended to decrease in the group IIA as compared to EAP untreated after 6 and 24 h. No significant effect of both treatments on serum lipase was noted. The administration of CGS 21680 resulted in favorable decrease of the inflammatory cell infiltration, hemorrhagic changes, necrosis and vacuolization of acinar cells, without an evident effect on the edema of the interstitial tissue. The administration of ZM 241385 did not affect the scores of necro-hemorrhagic changes and inflammatory infiltration, whereas it decreased the scores of vacuolization and edema. In all groups the expression of A2a receptors was similar. CONCLUSIONS: Our findings suggest, that A2a adenosine receptors are involved in the course of sodium taurocholate EAP. It is probable that the modulation of some subgroups of adenosine receptors could alleviate the course of severe experimental AP.