Marcin Dembiński

Dual, time-dependent deleterious and protective effect of anandamide on the course of cerulein-induced acute pancreatitis. Role of sensory nerves

Some recent studies indicate that cannabis may induce acute pancreatitis in humans and administration of anandamide increases the severity of acute pancreatitis; whereas another study exhibits some therapeutic effects in acute pancreatitis. Aim of the present study was to discover what is the reason for these opposite confusing results and to determine the role of sensory nerves in this effect. Acute pancreatitis was induced in rats by cerulein. Anandamide, an endogenous cannabinoid, was administered i.p. (1.5 micromol/kg) before or 2 h after cerulein administration. Stimulation of sensory nerves was performed by capsaicin (0.5 mg/kg s.c.). In rats treated with combination of anandamide plus capsaicin, capsaicin was given 10 min after each dose of anandamide. After the last injection of cerulein or 4 h later, the study was terminated. In our study we observed that stimulation of sensory nerves by capsaicin, before administration of cerulein, reduced the severity of acute pancreatitis. Anandamide, administered alone before cerulein, increased pancreatic damage in acute pancreatitis. Anandamide administered in combination with capsaicin, before cerulein, abolished the capsaicin-induced protective effect on the pancreas. Opposite effects were observed when capsaicin and anandamide were administered after injection of cerulein. Capsaicin increased the severity of acute pancreatitis, whereas anandamide reduced pancreatic damage and reversed the deleterious effect of capsaicin. We conclude that the effect of anandamide on the severity of acute pancreatitis depends on the phase of this disease. Administration of anandamide, before induction of pancreatitis, aggravates pancreatic damage; whereas anandamide administered after induction of pancreatitis, reduces the severity of acute pancreatitis. Sensory nerves are involved in the mechanism of this biphasic effect of anandamide.

Ischemic preconditioning reduces the severity of ischemia/reperfusion-induced pancreatitis.

In various organs, including heart, kidneys, brain, liver and stomach, preconditioning by brief exposure to ischemia protects the organ against damage evoked by subsequent severe ischemia. This study has been undertaken to check whether two brief ischemic periods protect the pancreas against severe ischemia/reperfusion-induced pancreatitis and, if so, what is the role of sensory and vagal nerves in this phenomenon. In male Wistar rats, the ischemic preconditioning of the pancreas was performed by clamping of celiac artery (2 x 5 min with 5 min interval). Thirty minutes after preconditioning or sham operation, the ischemia/reperfusion-induced pancreatitis was evoked by clamping of inferior splenic artery for 30 min using microvascular clips, followed by 1 h reperfusion. Sensory nerves ablation was induced 10 days before final experiments by capsaicin. Truncal vagotomy was performed 1 week before the experiment. Exposure to regular 30-min pancreatic ischemia followed by 1 h reperfusion led to the development of acute hemorrhagic pancreatitis. Ischemic preconditioning, applied prior to induction of pancreatitis, caused the reduction in plasma lipase, plasma interleukin-1beta and histological signs of pancreatic damage, as well as attenuated the reduction in pancreatic blood flow and DNA synthesis. Ablation of sensory nerves by capsaicin caused an aggravation of ischemia/reperfusion-induced pancreatic damage and attenuated a protective effect of ischemic preconditioning. Noxious effect of sensory nerves ablation on the pancreas was accompanied by the reduction in pancreatic blood flow and an increase in plasma interleukin-1beta. Similar but less pronounced deleterious effect on the pancreas was observed after vagotomy. We conclude that: (1) pancreatic ischemic preconditioning reduces the severity of ischemia/reperfusion-induced pancreatitis; (2) this effect seems to be related, at least in part, to the improvement of pancreatic blood flow and the reduction in the release of proinflammatory interleukin-1beta; (3) sensory and vagal nerves are involved in protective effect of ischemic preconditioning against pancreatic damage.

Ghrelin accelerates the healing of cysteamine-induced duodenal ulcers in rats

Summary Background Previous studies have shown that administration of ghrelin exhibits protective and therapeutic effects in the gut. The aim of the present investigation was to examine the influence of ghrelin administration on the course of cysteamine-induced duodenal ulcers, as well as effects on mucosal production of oxygen free radicals and duodenal antioxidant defense. Material/Methods Duodenal ulcers were induced in male Wistar rats by cysteamine administered intragastrically at the dose of 200 mg/kg in 1 ml of saline, 3 times at 4-h intervals. Starting 24 h after the first dose of cysteamine, rats were treated intraperitoneally twice a day with saline or ghrelin given at the dose of 4, 8 or 16 nmol/kg/dose. Seven days after administration of the first dose of cysteamine, the study was terminated. Results Induction of ulcers by cysteamine was accompanied by a reduction in duodenal blood flow, mucosal DNA synthesis and mucosal activity of superoxide dismutase (SOD); whereas mucosal concentration of interleukin-1β and malonyldialdehyde (MDA – an index of lipid peroxidation) were increased. Treatment with ghrelin increased healing rate of duodenal ulcers and enhanced duodenal blood flow, mucosal DNA synthesis and mucosal activity of SOD, and reduced mucosal concentration of interleukin-1β and MDA. Conclusions Treatment with ghrelin increases the healing rate of duodenal ulcers and this effect is related, at least in part, to improvement of duodenal mucosal blood flow, mucosal cell proliferation and antioxidant defense, as well as being related to reduction in mucosal oxidative stress and inflammatory response.

Administration of obestatin accelerates the healing of chronic gastric ulcers in rats

Summary Background Previous studies have shown that administration of obestatin exhibits a protective effect in the pancreas, attenuating the development of acute pancreatitis. The aim of the present study was to investigate the influence of obestatin administration on the healing of chronic gastric ulcers. Material/Methods Chronic gastric ulcers were induced in rats by 100% acetic acid applied to the serosal surface of the gastric wall. Obestatin was given twice a day intraperitoneally at the dose of 4, 8 or 16 nmol/kg/dose for 6 days. Six days after induction of ulcers, rats were anesthetized and the stomach was exposed for measurement of gastric blood flow and ulcer area. Biopsy samples from the gastric mucosa were taken for determination of mucosal DNA synthesis and for measurement of gastric expression of mRNA for interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Results Induction of gastric ulcers alone increased mucosal blood flow and tissue expression of mRNA for TNF-α and IL-1β, whereas gastric mucosal DNA synthesis was reduced. In rats with gastric ulcers, administration of obestatin increased gastric mucosal blood flow, accelerated the healing rate of these ulcers and partly reversed the gastric ulcer-induced reduction in gastric mucosal DNA synthesis. These results were associated with a reduction in gastric mucosal expression of pro-inflammatory IL-1β and TNF-α. Conclusions Treatment with obestatin increases gastric mucosal blood flow and cell proliferation, leading to acceleration of healing of gastric ulcers. These effects are associated with a reduction in mucosal expression of pro-inflammatory IL-1β and TNF-α.

Protective Effect of Pretreatment with Acenocoumarol in Cerulein-Induced Acute Pancreatitis

Coagulation is recognized as a key player in inflammatory and autoimmune diseases. The aim of the current research was to examine the effect of pretreatment with acenocoumarol on the development of acute pancreatitis (AP) evoked by cerulein. Methods: AP was induced in rats by cerulein administered intraperitoneally. Acenocoumarol (50, 100 or 150 µg/kg/dose/day) or saline were given once daily for seven days before AP induction. Results: In rats with AP, pretreatment with acenocoumarol administered at the dose of 50 or 100 µg/kg/dose/day improved pancreatic histology, reducing the degree of edema and inflammatory infiltration, and vacuolization of acinar cells. Moreover, pretreatment with acenocoumarol given at the dose of 50 or 100 µg/kg/dose/day reduced the AP-evoked increase in pancreatic weight, serum activity of amylase and lipase, and serum concentration of pro-inflammatory interleukin-1β, as well as ameliorated pancreatic DNA synthesis and pancreatic blood flow. In contrast, acenocoumarol given at the dose of 150 μg/kg/dose did not exhibit any protective effect against cerulein-induced pancreatitis. Conclusion: Low doses of acenocoumarol, given before induction of AP by cerulein, inhibit the development of that inflammation.

Therapeutic Effect of Low Doses of Acenocoumarol in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats

Intravascular activation of coagulation is observed in acute pancreatitis and is related to the severity of this inflammation. The aim of our study was to evaluate the impact of acenocoumarol therapy on the course of acute pancreatitis induced in male rats by pancreatic ischemia followed by reperfusion. Acenocoumarol at a dose of 50, 100, or 150 µg/kg/dose was administered intragastrically once a day, starting the first dose 24 h after the initiation of pancreatic reperfusion. Results: Histological examination showed that treatment with acenocoumarol reduces pancreatic edema, necrosis, and hemorrhages in rats with pancreatitis. Moreover, the administration of acenocoumarol decreased pancreatic inflammatory infiltration and vacuolization of pancreatic acinar cells. These findings were accompanied with a reduction in the serum activity of lipase and amylase, concentration of interleukin-1β, and plasma d-Dimer concentration. Moreover, the administration of acenocoumarol improved pancreatic blood flow and pancreatic DNA synthesis. Acenocoumarol given at a dose of 150 µg/kg/dose was the most effective in the treatment of early phase acute pancreatitis. However later, acenocoumarol given at the highest dose failed to exhibit any therapeutic effect; whereas lower doses of acenocoumarol were still effective in the treatment of acute pancreatitis. Conclusion: Treatment with acenocoumarol accelerates the recovery of ischemia/reperfusion-induced acute pancreatitis in rats.

Synergic Interaction of Rifaximin and Mutaflor (Escherichia coli Nissle 1917) in the Treatment of Acetic Acid-Induced Colitis in Rats

Background. Inflammatory bowel disease results from the dysregulation of immune response to environmental and microbial agents in genetically susceptible individuals. The aim of the present study was to examine the effect of rifaximin and/or Mutaflor (Escherichia coli Nissle 1917, EcN) administration on the healing of acetic acid-induced colitis. Methods. Colitis was induced in male Wistar rats by rectal enema with 3.5% acetic acid solution. Rifaximin (50 mg/kg/dose) and/or Mutaflor (109 CFU/dose) were given intragastrically once a day. The severity of colitis was assessed at the 8th day after induction of inflammation. Results. Treatment with rifaximin significantly accelerated the healing of colonic damage. This effect was associated with significant reversion of the acetic acid-evoked decrease in mucosal blood flow and DNA synthesis. Moreover, administration of rifaximin significantly reduced concentration of proinflammatory TNF-α and activity of myeloperoxidase in colonic mucosa. Mutaflor given alone was without significant effect on activity of colitis. In contrast, Mutaflor given in combination with rifaximin significantly enhanced therapeutic effect of rifaximin. Moreover, Mutaflor led to settle of the colon by EcN and this effect was augmented by pretreatment with rifaximin. Conclusion. Rifaximin and Mutaflor exhibit synergic anti-inflammatory and therapeutic effect in acetic acid-induced colitis in rats.

More stapler firings increase the risk of perioperative morbidity after laparoscopic sleeve gastrectomy

Introduction Staple-line bleeding and leakage are the most common serious complications of laparoscopic sleeve gastrectomy. The relationship between multiple stapler firings and higher risk of postoperative complications is well defined in colorectal surgery but has not been addressed in bariatric procedures so far. Identification of new factors such as “the numbers of stapler firings used during laparoscopic sleeve gastrectomy (LSG)” as a predictor for complications can lead to optimization of the patient care at bariatric centers. Aim To determine the association between perioperative morbidity and the number of stapler firings during laparoscopic sleeve gastrectomy. Material and methods This observational study was based on retrospective analysis of prospectively collected data in patients operated on for morbid obesity in a teaching hospital/tertiary referral center for general surgery. The patients who underwent LSG were analyzed in terms of the number of stapler firings used as a new potential risk predictor for postoperative complications after surgery, adjusting for other patient- and treatment-related factors. The study included 333 patients (209 women, 124 men, mean age: 40 ±11). Results During the first 30 days after surgery, complications were observed in 18 (5.41%) patients. Multivariate analysis showed that prolonging operative time increased morbidity (every minute, OR = 1.01; 95% CI: 1.00–1.02) and the complication rate increased with the number of stapler firings (every firing, OR = 1.91; 95% CI: 1.09–3.33; p = 0.023). Conclusions Additional stapler firings above the usual number and a prolonged operation should alert a surgeon and the whole team about increased risk of postoperative complications.

Are we ready for the ERAS protocol in colorectal surgery

Introduction Modern perioperative care principles in elective colorectal surgery have already been established by international surgical authorities. Nevertheless, barriers to the introduction of routine evidence-based clinical care and changing dogmas still exist. One of the factors is the surgeon. Aim To assess perioperative care trends in elective colorectal surgery among general surgery consultants in surgical departments in Malopolska Voivodeship, Poland. Material and methods An anonymous standardized 20-question questionnaire was developed based on ERAS principles and sent out to Malopolska Voivodeship general surgery departments. Answers of general surgery consultants showed the level of acceptance of elements of perioperative care. Results The overall response rate was 66%. Several elements (antibiotic and antithrombotic prophylaxis, postoperative oxygen therapy, no nasogastric tubes) had quite a high acceptance rate. On the other hand, most crucial surgical perioperative elements (lack of mechanical bowel preparation, preoperative oral carbohydrate loading, use of laparoscopy and lack of drains, early fluid and oral diet intake, early mobilization) were not followed according to evidence-based ERAS protocol recommendations. Surgeons were not willing to change their practice, but were supportive of changes in anesthesiologist-dependent elements of perioperative care, such as restrictive fluid therapy, use of transversus abdominis plane blocks, etc. Conclusions Many elements of perioperative care in elective colorectal surgery in Malopolska Voivodeship are still dictated by dogma and are not evidence-based. The level of acceptance of many important ERAS protocol elements is low. Surgeons are ready to accept only changes that do not interfere with their practice.

Laparoscopic transperitoneal adrenalectomy in morbidly obese patients is not associated with worse short-term outcomes

To evaluate the impact of obesity and morbid obesity on short‐term outcomes after laparoscopic adrenalectomy.