Sarah Navina

Protease-activated receptor-2 protects against pancreatitis by stimulating exocrine secretion

Background: Protease-activated receptor-2 (PAR-2) is present in the pancreas, where it has been shown to play a protective role during pancreatitis. However, the mechanism by which it protects against pancreatitis still remains to be elucidated. Acute pancreatitis is associated with premature zymogen activation and a blockage in digestive enzyme secretion. Aim: To examine the effects of PAR-2 activation on the severity of pancreatitis, and to determine whether its protective effects are mediated by affecting either premature activation or secretory blockage, or both. Results: The results confirmed that PAR-2 −/− mice have more severe pancreatitis than wild-type mice. Interestingly, intrapancreatic trypsin levels in the PAR-2 knockouts remained high after 6 h of pancreatitis, whereas they reverted to normal in the wild types. During pancreatitis, PAR-2 mRNA levels were upregulated in wild-type mice in response to supramaximal caerulein administration. Further, after a single injection of supramaximal caerulein, PAR-2 mRNA levels were also elevated, reaching a peak at 3 h. Stimulating PAR-2 with trypsin or the PAR-2-activating peptide, serine-leucine-isoleucine-glycine-arginine-leucine (SLIGRL), induced significantly more secretion from the acini of these caerulein-sensitised mice compared with the controls. PAR-2 activation also reversed the inhibition of secretion observed in both the caerulein and arginine models. Conclusions: Trypsin released during the early stages of pancreatitis activates PAR-2 receptors on the acinar cells and stimulates secretion from these cells. Thus, PAR-2 activation may decrease pancreatic injury and limit the severity of pancreatitis by allowing extracellular trypsin to act as a secretagogue.

Role of pancreatic fat in the outcomes of pancreatitis.

The role of obesity in relation to various disease processes is being increasingly studied, with reports over the last several years increasingly mentioning its association with worse outcomes in acute disease. Obesity has also gained recognition as a risk factor for severe acute pancreatitis (SAP).The mortality in SAP may be as high as 30% and is usually attributable to multi system organ failure (MSOF) earlier in the disease, and complications of necrotizing pancreatitis later [9-11]. To date there is no specific treatment for acute pancreatitis (AP) and the management is largely expectant and supportive. Obesity in general has also been associated with poor outcomes in sepsis and other pathological states including trauma and burns. With the role of unsaturated fatty acids (UFA) as propagators in SAP having recently come to light and with the recognition of acute lipotoxicity, there is now an opportunity to explore different strategies to reduce the mortality and morbidity in SAP and potentially other disease states associated with such a pathophysiology. In this review we will discuss the role of fat and implications of the consequent acute lipotoxicity on the outcomes of acute pancreatitis in lean and obese states and during acute on chronic pancreatitis.

Nelfinavir/ritonavir reduces acinar injury but not inflammation during mouse caerulein pancreatitis

There is no clinical treatment that reduces acinar injury during pancreatitis. Human immunodeficiency virus (HIV) protease inhibitors (PI), including nelfinavir (NFV) and ritonavir (RTV), may reduce the rate of pancreatitis in HIV-infected patients. Since permeability transition pore (PTPC)-mediated mitochondrial dysfunction occurs during pancreatitis, and we have shown that PI prevents PTPC opening, we studied its effects in a model of pancreatitis. The effect of NFV plus RTV (NFV/RTV) or vehicle on caerulein-induced pancreatitis in mice was compared by measuring changes in mitochondrial membrane potential in vitro and cytochrome c leakage in vivo. Histological and inflammatory makers were also compared. NFV/RTV improved DiOC6 retention in acini exposed to caerulein in vitro. In vivo NFV prevented cytosolic leakage of cytochrome c and reduced pancreatic acinar injury, active caspase-3 staining, TUNEL-positive acinar cells, and serum amylase (P < 0.05). Conversely, trypsin activity, serum cytokine levels, and pancreatic and lung inflammation were unaffected. NFV/RTV reduces pancreatic injury and acinar cell death in experimental mouse caerulein-induced pancreatitis but does not impact inflammation.

226 Fibrosis Reduces Severity of Acute Attacks in Chronic Pancreatitis (CP) by Preventing Peri-Fat Acinar Necrosis (PFAN) Around Fat Necrosis (FN)

Background: The diagnosis of chronic pancreatitis in patients with characteristic symptoms but normal pancreatic imaging is challenging. Assessment of pancreatic function through collection of duodenal fluid following secretin stimulation testing (SST) has been advocated in this setting. The diagnostic accuracy of SST in detecting early chronic pancreatitis is not fully known. Aim: To determine if subjects with suspected chronic pancreatitis and abnormal SST subsequently develop histologic or radiographic changes of chronic pancreatitis compared with those with normal SST. Methods: We performed a retrospective review of subjects who received SST at our institution between January 1995 and December 2007 for suspected chronic pancreatitis. All had normal cross sectional and endoscopic imaging of the pancreas prior to SST. A positive test was defined as a peak bicarbonate level of <75mEq/L in duodenal fluid collected over 1 hr following administration of IV secretin. For all subjects, medical records were reviewed for evidence of subsequent development of chronic pancreatitis by imaging and/or pathology from surgical specimens. Subjects were contacted by phone if there was insufficient follow-up by medical records. Patients were then categorized as a ‘true positive, or a ‘true negative for chronic pancreatitis based on follow-up evidence, allowing for the calculation of sensitivities, specificities, negative predictive value (NPV) and positive predictive value (PPV). Results: 87 subjects with suspected early chronic pancreatitis who underwent SST were reviewed. 60 tested negative and 27 tested positive. Of the 27 patients who tested positive (76% female, average age of 46.6 years), 4 were lost to follow-up. Of the remaining 23 SST positive subjects, 11(48%) developed radiologic or histologic evidence of chronic pancreatitis after a median of 3 years (1-9 years). There was no difference in average or median peak bicarbonate levels (60 mEq/L and 65 mEq/L, respectively) between the group of subjects that developed imaging or histologic evidence of chronic pancreatitis and the group that did not. Of the 60 subjects who tested negative (67% female, average age of 45 years), 13 were lost to follow-up. Of the remaining 47, only one subject was eventually diagnosed with chronic pancreatitis based on subsequent imaging (p<0.001) after a median follow-up period of 6 years (3-11 years). The sensitivity of the SST in diagnosing chronic pancreatitis was 92% with a specificity of 79%; PPV of chronic pancreatitis was 47.8% with a NPV of 97.8%. Conclusions: In imaging-negative patients with suspected chronic pancreatitis, SST is a sensitive predictor of early chronic pancreatitis as well as a highly accurate test for ruling out early chronic pancreatitis with a NPV of 97.8%.

Primary (Obesity Associated) Intrapancreatic Fat is Quantitatively, Morphologically, Pathogenically and Clinically Distinct From Secondary (Chronic Pancreatitis Associated) Intrapancreatic Fat

matched controls (GSP) were selected for each HIP case. Hospital course was then compared between the two groups, based on local/systemic complications of acute pancreatitis, management and length of stay. Statistics: Fischers exact t-test was used and a two sided p-value was calculated; p-value of less than 0.05 was considered statistically significant. Results: There were 292 patients admitted during the study period. Etiologies were GSP (41.8%), alcoholic pancreatitis (23.3%), others (autoimmune, drugs, ERCP, idiopathic) (30.1%) and HIP (4.8%). There were 14 HIP cases (64% men)and 42 GSP controls (60% men). Mean age was 43.8 (range 24-64) and 44 (range 17-71) for cases and controls, respectively. Mean admission lipase levels were lower in HIP(638 mg/dl) than in GSP(2399 mg/dl). BISAP score on admission in all HIP cases was less than 2. As shown in the table, there was a significant difference between the two groups in the following variables: 2 or more abdominal CT scans, systemic complications (such as pleural effusions, ARDS, renal failure), transfer to the ICU (for renal failure,candidemia and respiratory distress) and use of TPN. There were no deaths in either group. Conclusions: Based on our data, HIP appears to follow a more aggressive course with greater resource utilization than GSP. Furthermore, a low BISAP score in HIP may not be predictive of in-hospital morbidity. These findings need to be confirmed in a prospective study with a larger sample size. Statistical comparison of various variables during the hospital course between cases (HIP) and controls (GSP)