Fasting prevents acute pancreatitis induced by cerulein in rats

We examined the effect of fasting on the course of experimental acute pancreatitis induced in rats by four subcutaneous injections of 20 g/kg body weight of cerulein at hourly intervals. Rats were either fasted from 24 hr before to 9 hr after the first cerulein injection or fed ad libitumthroughout the experiment. Twenty-four hours of fasting reduced cerulein-induced increases in serum levels of amylase and anionic trypsin(ogen) to 50 and 70% of those in fed rats, respectively. Increases in pancreatic wet weight after cerulein injections were also less in fasted rats than in fed rats. Pancreatic content of trypsin was significantly decreased after a 24-hr fast, and no further changes were induced by cerulein injections. The histological signs of acute pancreatitis were greatly alleviated by fasting. However, 24 hr of fasting did not alter the sensitivity and responsiveness of the exocrine pancreas to cerulein in both in vivoand in vitro.Plasma CCK bioactivity and immunoreactive secretin concentration in 24-hr-fasted rats were significantly lower than those in fed rats. Administration of CCK receptor antagonist, loxiglumide, 12 hr prior to the induction of acute pancreatitis reduced the increase in serum amylase activity in fed rats to nearly the same levels as that in fasted rats and alleviated histological signs of pancreatitis to some extent. These present observations suggest that fasting lessens the severity of cerulein-induced acute pancreatitis by reducing endogenous CCK release.This work was supported in part by a grant from the Japanese Ministry of Health and Welfare and Grant-in-Aid for Scientific Research (C).     

Low dose cabergoline induced interstitial pneumonitis.

Certain dopaminergic anti-Parkinson drugs (ergolines) have repeatedly been identified as a cause of pleuropulmonary disease with a focus on serosal cell damage. Recently, a pathogenetic link between ergolines and prior asbestos exposure was suggested, as regards the development of pleural pathology. This report describes a patient with idiopathic Parkinson's disease, who was on a multiple drug regimen including low dose cabergoline. The patient developed a febrile illness with widespread bilateral lung infiltrations nonresponsive to beta-lactam and macrolide antibiotics. Bronchoalveolar lavage and transbronchial lung biopsy showed a "hypersensitivity-like" interstitial lung disease, which cleared almost completely within 2 months after simple drug withdrawal. Circumstantial evidence suggests a so far undescribed adverse lung reaction to cabergoline, devoid of the more usual pleural changes.     

Studies on oxygen-derived free radicals in acute pancreatic damage in rats--pancreatic damage experimentally induced by diethyldithiocarbamate

In order to investigate the role of the oxygen-derived free radicals in the pathogenesis of acute pancreatitis, an experimentally induced pancreatic damage was prepared in rats by the injection of diethyldithiocarbamate (DDC), which was known to be an inhibitor of Cu, Zn-superoxide dismutase (SOD). Male Wistar rats weighing 200-250 g received a single subcutaneous injection of DDC at a dose of 1000 mg/kg. Serum activities of amylase were significantly increased at 3 and 5 hours after the injection of DDC. Thiobarbituric acid reactants (TBA reactants) concentrations in the pancreatic tissue were increased at 30 minutes after the injection of DDC. At 7 hours after the injections of DDC, focal necrosis and degeneration of pancreatic acinar cells were observed. Peroral administration of allopurinol, an inhibitor of xanthine oxidase, before the injection of DDC suppressed the increase of TBA reactants concentration in the pancreatic tissue, but did not suppress the increase of serum activities of amylase. These results indicate that oxygen-derived free radicals may play an important role in the pathogenesis of acute pancreatic damage. However, since allopurinol did not suppress the increase of serum activities of amylase, further examination is needed to analyze the mechanism of DDC-induced pancreatic damage.     

Tumor necrosis factor α antibody prevents brain damage of rats with acute necrotizing pancreatitis

AIM: To study the protective effects of tumor necrosis factor á (TNFα) antibody on pancreatic encephalopathy in rats.METHODS:One hundred and twenty SD rats were randomly divided into normal control group,acute necrotizing pancreatitis group and TNFα antibody treated group.Acute hemorrhage necrotizing pancreatitis model in rats was induced by retrograde injection of 50 g/L sodium taurocholate into the pancreatobiliary duct.Serum TNFα was detected and animals were killed 12 h after drug administration.Changes in content of brain water,MDA and SOD as well as leucocyte adhesion of brain microvessels were measured.RESULTS:In TNFα antibody treated group,serum TNFálevel was decreased.Content of brain water,MDA and SOD as well as leucocyte adhesion were decreased significantly in comparison with those of acute necrotizing pancreatitis group (P＜0.05).CONCLUSION:TNFα antibody can alleviate the brain damage of rats with acute hemorrhage necrotizing pancreatitis.     

Microalbuminuria is related to marked end organ damage in previously untreated,elderly hypertensive patients

We wondered whether, in an elderly hypertensive population in a primary prevention setting, free from diabetes mellitus and clinical atherosclerosis, differences between end organ damage and microalbuminuria (MA) could be found using a lower level of urinary albumin excretion than that of classically defined MA. From a population survey of 173 previously untreated hypertensive patients (4x blood pressure systolic > or = 160 and < or = 220 mmHg, and/or diastolic > or = 95 and < or = 115 mmHg), mean age 67 +/- 4 years, were screened for MA (defined as albumin excretion between 20 and 300 mg/24 h). End organ damage was determined by B-mode ultrasound scanning of carotid and femoral arteries and echocardiography. Out of 173 hypertensives, 14 showed MA (8%). These hypertensives had a significantly higher intima media thickness (IMT; 1.01 +/- 0.21 vs 0.88 +/- 0.6 mm, p < 0.05) and increased left ventricular mass index (118 +/- 31 vs 103 +/- 22 g/m2, p < 0.05) than hypertensives without MA. Linear regression analysis showed that MA, age, male gender and diastolic blood pressure were independently related to IMT, while systolic blood pressure, male gender and body mass index were independently related to left ventricular mass. Even using lower levels of urinary albumin excretion rate, patients with MA had significantly higher IMT and increased left ventricular mass. Moreover, MA was independently related to IMT in these elderly hypertensives. These results suggest that the threshold value for MA should be reconsidered in hypertension.     

Tumor necrosis factor α antibody prevents brain damage of rats with acute necrotizing pancreatitis

AIM: To study the protective effects of tumor necrosis factor α (TNFα) antibody on pancreatic encephalopathy in rats.METHODS: One hundred and twenty SD rats were randomly divided into normal control group, acute necrotizing pancreatitis group and TNFα antibody treated group. Acute hemorrhage necrotizing pancreatitis model in rats was induced by retrograde injection of 50 g/L sodium taurocholate into the pancreatobiliary duct. Serum TNFα was detected and animals were killed 12 h after drug administration. Changes in content of brain water, MDA and SOD as well as leucocyte adhesion of brain microvessels were measured.RESULTS: In TNFα antibody treated group, serum TNFα level was decreased. Content of brain water, MDA and SOD as well as leucocyte adhesion were decreased significantly in comparison with those of acute necrotizing pancreatitis group (P&lt;0.05).CONCLUSION: TNFα antibody can alleviate the brain damage of rats with acute hemorrhage necrotizing pancreatitis.     

Taurocholic acid prevents biliary damage induced by hepatic artery ligation in cholestatic rats

Background

Ischemic injury by hepatic artery ligation (HAL) during obstructive cholestasis induced by bile duct ligation (BDL) results in bile duct damage, which can be prevented by administration of VEGF-A. The potential regulation of VEGF and VEGF receptor expression and secretion by bile acids in BDL with HAL is unknown.

Aims

We evaluated whether taurocholic acid (TC) can prevent HAL-induced cholangiocyte damage via the alteration of VEGFR-2 and/or VEGF-A expression.

Methods

Utilizing BDL, BDL + TC, BDL + HAL, BDL + HAL + TC, and BDL + HAL + wortmannin + TC treated rats, we evaluated cholangiocyte apoptosis, proliferation, and secretion as well VEGF-A and VEGFR-2 expression by immunohistochemistry. In vitro, we evaluated the effects of TC on cholangiocyte secretion of VEGF-A and the dependence of TC-induced proliferation on the activity of VEGFR-2.

Results

In BDL rats with HAL, chronic feeding of TC prevented HAL-induced loss of bile ducts and HAL-induced decreased cholangiocyte secretion. TC also prevented HAL-inhibited VEGF-A and VEGFR-2 expression in liver sections and HAL-induced circulating VEGF-A levels, which were blocked by wortmannin administration. In vitro, TC stimulated increased VEGF-A secretion by cholangiocytes, which was blocked by wortmannin and stimulated cholangiocyte proliferation that was blocked by VEGFR-2 kinase inhibitor.

Conclusion

TC prevented HAL-induced biliary damage by upregulation of VEGF-A expression.     

Nitric oxide synthase inhibition reduces albumin induced lung damage in acute pancreatitis

Background/objectivesColloid resuscitation in acute pancreatitis (AP) is a matter of controversy due to the possible deleterious effect on lung function. A previous study demonstrates that albumin administration increases lung damage in burns and this effect can be reversed by inducible nitric oxide synthase (iNOS) inhibition. This study evaluates the effects of S-methylisothiourea (SMT), a specific iNOS inhibitor, on lungs and pancreas of rats with AP receiving intravenous albumin.MethodsAP was induced in Wistar rats by intraductal 5% taurocholate injection. To evaluate the effect of albumin on lung damage, animals received IV saline or human albumin immediately after AP (Groups: Saline and Albumin). To evaluate the effect of iNOS inhibition on lung damage, SMT was given immediately after AP (Group Saline+SMT, and Group Albumin+SMT). At 12 h after AP induction, serum amylase activity, lung vascular permeability and myeloperoxidase (MPO) activity were evaluated. Lung and pancreas histological analysis were performed.ResultsSerum amylase activity, pancreatic edema, lung vascular permeability, MPO activity, and inflammatory infiltration were significantly increased after AP. Albumin administration increased lung vascular permeability, inflammatory infiltration, and pancreatic edema compared to saline administration (p < 0.05). Albumin administration with SMT reduced lung vascular permeability, MPO activity, and inflammatory infiltration compared to albumin administration alone (p < 0.05).ConclusionLung and pancreatic damage induced by albumin administration for restoration of plasma volume in AP are reduced by iNOS inhibition. Awareness of this fact may be useful in high-risk patients who need to receive albumin for volume replacement.     

Inflammation is involved in the organ damage induced by sinoaortic denervation in rats

OBJECTIVE: The present study was designed to test the hypothesis that inflammation is involved in the end-organ damage (EOD) induced by sinoaortic denervation (SAD) in rats. METHOD: SAD was performed in male Sprague-Dawley rats at the age of 10 weeks. Under anaesthesia, aortic nerves were cut and the sinus region of the carotid artery was stripped and painted with 10% phenol. Pathological evaluation of EOD and the determination of plasma or tissue levels of the factors related to inflammation, including thromboxane B2 (TXB2) interleukin-1 (IL-1), tumour necrosis factor alpha (TNF-alpha) and reactive oxygen species (ROS) were performed at 16 weeks after SAD. Pathological evaluation of EOD included heart weight ratio, myocardial and blood vessel hydroxyproline and collagen volume fraction, glomerular injury score and number of infiltrating inflammatory cells. Indomethacin (20 mg/kg per day, orally) or vitamin E (100 mg/kg per day, orally) was administered for 12 weeks, beginning from 4 weeks after SAD, to observe their effects on SAD-induced EOD. RESULTS: There were significant fibrosis and inflammatory infiltration in the myocardium and blood vessels, represented by higher hydroxyproline and collagen volume fraction, and a large amount of inflammatory cells in the tissues of SAD rats. Heart weight and kidney glomerular injury score were significantly higher in SAD than in sham-operated rats. Plasma TXB2, TNF-alpha, IL-1 and tissue ROS increased significantly after SAD. Indomethacin and vitamin E significantly decreased the contents of some factors related to inflammation in SAD rats. Both drugs also alleviated myocardial and vessel fibrosis, inflammatory infiltration and kidney damage. CONCLUSION: Inflammation is involved in the organ damage induced by SAD in rats.     

Possible role of dopamine in changes in LH and prolactin concentrations after experimentally induced hyperprolactinaemia in rats

Nine-month-old female rats bearing an ectopic pituitary gland (from a litter-mate) under the right kidney capsule since day 30 of life and their sham-operated controls, were treated with a dopamine agonist (lysuride) or antagonist (metoclopramide). Plasma prolactin and LH levels were measured by double-antibody radioimmunoassays. Vaginal smears were taken before and during the treatment periods. Eight months after the operation, a significant (P less than 0.01) increase in basal prolactin levels together with a significant (P less than 0.05) reduction in LH values and permanent dioestrus occurred in the grafted animals when compared with controls. Lysuride treatment resulted in a marked reduction in plasma prolactin levels both in control and grafted rats over the whole 12 days of treatment, together with a partial restoration of plasma LH levels on day 1. From day 7 onwards a depression in LH values was again observed. Oestrous cycles were partially restored at the beginning of the treatment, but after 7 days dioestrus returned. Metoclopramide administration induced a significant (P less than 0.001) increase in basal prolactin levels in both grafted and control rats. Basal plasma LH values were unaffected in controls when compared with vehicle-treated animals. An increase could be seen in hyperprolactinaemic rats after 7 or 12 days of treatment however. The LH response to the administration of LH releasing hormone (LHRH) was greater in the experimental and control metoclopramide-treated rats when compared with vehicle-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Honey prevents hepatic damage induced by obstruction of the common bile duct

AIM： To examine the possible effects of honey supplementation on hepatic damage due to obstruction of the common bile duct in an experimental rat model. METHODS： The study was performed with 30 male rats divided into three groups： a sham group, an obstructive jaundice group, and an obstructive jaundice plus honey group. At the end of the study period, the animals were sacrificed, and levels of nitric oxide （NO）, and NO synthase （NOS） activities were measured in liver tissues, and levels of adenosine deaminase （ADA） and alanine transaminase （ALT） activities were measured in serum.
RESULTS： Blood ALT and ADA activities were significantly elevated in the jaundice group as compared to those of the sham group. In the obstructive jaundice plus honey group, blood ALT and ADA activities were significantly decreased as compared to those of the jaundice group. In erythrocytes and liver tissues, NO levels were found to be significantly higher in the obstructive jaundice plus honey group compared to those of the sham group. Additionally, NO levels were found to be significantly higher in liver tissues from the animals in the obstructive jaundice plus honey group than those of the jaundice group.
CONCLUSION： Honey was found to be beneficial in the prevention of hepatic damage due to obstruction of the common bile duct.     

Melatonin ameliorates oxidative organ damage induced by acute intra-abdominal compartment syndrome in rats

Acutely increased intra-abdominal pressure (IAP) can lead to multiple organ failure. As blood flow to intra-abdominal organs is reduced by high venous resistance, ischemia-reperfusion (I/R) injury plays an important role in the pathogenesis of abdominal compartment syndrome (ACS) following IAP. Melatonin, a secretory product of the pineal gland, is known to have free radical scavenging and antioxidative properties in several oxidative processes. The objective of this study was to examine the potential protective properties of melatonin on the oxidative organ damage in a rat model of ACS. Under ketamine anesthesia, an arterial catheter was inserted intraperioneally (i.p.) and using an aneroid manometer connected to the catheter, IAP was kept at 20 mmHg (ischemia group; I) for 1 hr. In the ischemia/reperfusion (I/R) group, pressure applied for an hour was decompressed and a 1-hr reperfusion period was allowed. In another IR group, melatonin was administered (10 mg/kg, i.p.) immediately before the decompression of IAP. The results demonstrate that tissue levels of malondialdehyde (MDA) and myeloperoxidase activity (MPO; index of tissue neutrophil infiltration) were elevated, while glutathione (GSH; a key to antioxidant) levels were reduced in both I and I/R groups (P < 0.05-0.001). Melatonin treatment in I/R rats reversed these changes (P < 0.01-0.001). Moreover, melatonin given to the I/R group reduced the elevations in serum aspartate aminotransferase, alanine aminotransferase and blood urea nitrogen levels and abolished the increase in serum creatinine levels. Our results indicate that melatonin, because of antioxidant and free radical scavenging properties, ameliorates reperfusion-induced oxidative organ damage. In conclusion, the results of the present study suggest that the therapeutic value of melatonin as a 'reperfusion injury-limiting' agent must be considered in ACS.     

Etidronate prevents high dose glucocorticoid induced bone loss in premenopausal individuals with systemic autoimmune diseases

OBJECTIVE: To assess the efficacy of etidronate and alfacalcidol in preventing glucocorticoid induced bone loss in premenopausal women and men starting high dose glucocorticoid therapy. METHODS: Premenopausal women (n = 16) and men (n = 5) who had just developed autoimmune diseases, and who agreed to use high dose glucocorticoid therapy for the first time, were randomized to receive alfacalcidol (1 micro g/day) alone (alfacalcidol group, n = 11); or alfacalcidol (1 micro g/day) and intermittent cyclical etidronate (200 mg/day for 14 days), given for 4 cycles (combined group, n = 10). They were treated with these medications as well as high dose glucocorticoids for 12 months. RESULTS: In the alfacalcidol group the percentage changes in bone mineral density (BMD) of the lumbar spine after 6 and 12 mo of therapy were -9.6 +/- 0.6% and -10.3 +/- 1.0%, respectively. However, in the combined group the percentage changes in lumbar spine BMD after 6 and 12 mo were -3.8 +/- 1.3% and -4.5 +/- 2.1%. The percentage lumbar spine bone loss rate in the combined group was significantly lower than in the alfacalcidol group at both 6 and 12 mo. After 12 mo the percentage change in femoral neck BMD was increased 2.3 +/- 1.5% in the combined group and was decreased 2.5 +/- 2.4% in the alfacalcidol group; this difference was also statistically significant. There were no significant differences in metabolic bone markers between the groups during the study. CONCLUSION: The results suggest that etidronate could prevent high dose glucocorticoid induced bone loss in premenopausal individuals with systemic autoimmune diseases.     

Angiopoietin-1 prevents hypertension and target organ damage through its interaction with endothelial Tie2 receptor

AIMS: The endothelium has emerged recently as a therapeutic target in the treatment of hypertension because endothelial dysfunction and subsequent vascular rarefaction cause target organ damage and further elevate blood pressure (BP). It led us to hypothesize that one of the endothelial survival factors, a potent derivative of angiopoietin-1 (cartilage oligomeric matrix protein, COMP-Ang-1), could be a novel class of antihypertensive agents that maintain endothelial integrity and function, thereby preventing the development of hypertension and target organ damage. METHODS AND RESULTS: To study the role of COMP-Ang-1 in preventing hypertension and target organ damage, a COMP-Ang-1 plasmid was electroporated into adductor muscles of 6 weeks old, pre-hypertensive, spontaneously hypertensive rats (SHRs), and the secretion of its expressed protein into the bloodstream was confirmed by western blotting. In comparison with sham and reporter gene transfer, COMP-Ang-1 gene transfer significantly prevented increases in systolic BP and reduced microvascular rarefaction and tissue damage in the heart and kidney. However, overexpression of soluble Tie2 receptor completely abolished these beneficial effects of COMP-Ang-1 gene transfer on SHRs, indicating that expressed COMP-Ang-1 protein has antihypertensive effects in SHRs by binding Tie2 receptors on the vascular endothelium. In particular, COMP-Ang-1 gene-transferred SHRs had significantly higher plasma levels of nitrite than other controls, which was found to be due to that expressed COMP-Ang-1 protein promoted nitrite synthesis by activating endothelial nitric oxide synthase, one of the Tie2 downstream-signalling molecules. CONCLUSION: The present study suggests a new potential of endothelial survival factor, COMP-Ang-1, as an antihypertensive agent that effectively reduces the hypertension-associated cardiovascular and renal damage, as well as prevents the further elevation of BP.     

Bovine colostrum is a health food supplement which prevents NSAID induced gut damage

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are effective for arthritis but cause gastrointestinal injury. Bovine colostrum is a rich source of growth factors and is marketed as a health food supplement. AIMS: To examine whether spray dried, defatted colostrum or milk preparations could reduce gastrointestinal injury caused by indomethacin. METHODS: Effects of test solutions, administered orally, were examined using an indomethacin restraint rat model of gastric damage and an indomethacin mouse model of small intestinal injury. Effects on migration of the human colonic carcinoma cell line HT-29 and rat small intestinal cell line RIE-1 were assessed using a wounded monolayer assay system (used as an in vitro model of wound repair) and effects on proliferation determined using [3H]thymidine incorporation. RESULTS: Pretreatment with 0.5 or 1 ml colostral preparation reduced gastric injury by 30% and 60% respectively in rats. A milk preparation was much less efficacious. Recombinant transforming growth factor beta added at a dose similar to that found in the colostrum preparation (12.5 ng/rat), reduced injury by about 60%. Addition of colostrum to drinking water (10% vol/vol) prevented villus shortening in the mouse model of small intestinal injury. Addition of milk preparation was ineffective. Colostrum increased proliferation and cell migration of RIE-1 and HT-29 cells. These effects were mainly due to constituents of the colostrum with molecular weights greater than 30 kDa. CONCLUSIONS: Bovine colostrum could provide a novel, inexpensive approach for the prevention and treatment of the injurious effects of NSAIDs on the gut and may also be of value for the treatment of other ulcerative conditions of the bowel.