Laia Bonjoch

IL17 Functions through the Novel REG3β–JAK2–STAT3 Inflammatory Pathway to Promote the Transition from Chronic Pancreatitis to Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) offers an optimal model for discovering druggable molecular pathways that participate in inflammation-associated cancer development. Chronic pancreatitis, a common prolonged inflammatory disease, behaves as a well-known premalignant condition that contributes to PDAC development. Although the mechanisms underlying the pancreatitis-to-cancer transition remain to be fully elucidated, emerging evidence supports the hypothesis that the actions of proinflammatory mediators on cells harboring Kras mutations promote neoplastic transformation. Recent elegant studies demonstrated that the IL17 pathway mediates this phenomenon and can be targeted with antibodies, but the downstream mechanisms by which IL17 functions during this transition are currently unclear. In this study, we demonstrate that IL17 induces the expression of REG3β, a well-known mediator of pancreatitis, during acinar-to-ductal metaplasia and in early pancreatic intraepithelial neoplasia (PanIN) lesions. Furthermore, we found that REG3β promotes cell growth and decreases sensitivity to cell death through activation of the gp130-JAK2-STAT3-dependent pathway. Genetic inactivation of REG3β in the context of oncogenic Kras-driven PDAC resulted in reduced PanIN formation, an effect that could be rescued by administration of exogenous REG3β. Taken together, our findings provide mechanistic insight into the pathways underlying inflammation-associated pancreatic cancer, revealing a dual and contextual pathophysiologic role for REG3β during pancreatitis and PDAC initiation.

Differences in the Inflammatory Response Induced by Acute Pancreatitis in Different White Adipose Tissue Sites in the Rat

Background There is increasing evidence of the role of adipose tissue on the systemic effects of acute pancreatitis. Patients with higher body mass index have increased risk of local and systemic complications and patients with android fat distribution and higher waist circumference are at greater risk for developing the severe form of the disease. Here we evaluated the changes on different areas of adipose tissue and its involvement on the inflammatory response in an experimental model of acute pancreatitis. Methods Pancreatitis was induced in male Wistar rats by intraductal administration of sodium taurocholate. Orlistat was administered to inhibit lipase activity. Activation of peritoneal macrophages was evaluated by measuring IL1β and TNFα expression. Inflammation was evaluated by measuring myeloperoxidase activity in mesenteric, epididymal and retroperitoneal areas of adipose tissue. Changes in the expression of inflammatory mediator in these areas of adipose tissue were also evaluated by RT-PCR. Results Pancreatitis induces the activation of peritoneal macrophages and a strong inflammatory response in mesenteric and epididymal sites of adipose tissue. By contrast, no changes were found in retroperitoneal adipose tissue. Inhibition of lipase prevented the activation of macrophages and the local inflammation in adipose tissue. Conclusions Our results confirm the involvement of adipose tissue on the progression of systemic inflammatory response during acute pancreatitis. However, there is a considerable diversity in different adipose tissue sites. These differences need to be taken into account in order to understand the progression from local pancreatic damage to systemic inflammation during acute pancreatitis.

Fluid resuscitation with lactated Ringer’s solution vs normal saline in acute pancreatitis: A triple-blind, randomized, controlled trial:

Background Little is known regarding the optimal type of fluid resuscitation in acute pancreatitis (AP). Objective The objective of this article was to compare the effect of lactated Ringer’s solution (LR) vs normal saline (NS) in the inflammatory response in AP. Methods We conducted a triple-blind, randomized, controlled trial. Patientsu2009≥u200918 admitted with AP were eligible. Patients were randomized to receive LR or NS. Primary outcome variables were number of systemic inflammatory response syndrome (SIRS) criteria at 24 hours, 48 hours and 72 hours and blood C-reactive protein (CRP) levels at 48 hours and 72 hours. In vitro complementary experiments were performed to further explore the interaction between pH, lactate and inflammation. Results Nineteen patients receiving LR and 21 receiving NS were analyzed. The median (p25–p75) number of SIRS criteria at 48 hours were 1 (1–2) for NS vs 1 (0–1) for LR, pu2009=u20090.060. CRP levels (mg/l) were as follows: at 48 hours NS 166 (78–281) vs LR 28 (3–124), pu2009=u20090.037; at 72 hours NS 217 (59–323) vs LR 25 (3–169), pu2009=u20090.043. In vitro, LR inhibited the induction of inflammatory phenotype of macrophages and NF-κB activation. This effect was not observed when using Ringer’s solution without lactate, suggesting a direct anti-inflammatory effect of lactate. Conclusions Lactated Ringer’s is associated with an anti-inflammatory effect in patients with acute pancreatitis.

REG3β modifies cell tumor function by impairing extracellular vesicle uptake

Extracellular vesicles (EVs), including exosomes and microvesicles, are nano-sized membrane vesicles containing proteins and nucleic acids, which act as intercellular messengers. They play an important role in a variety of physiological processes, as well as in pathological situations such as inflammation or cancer. Here, we show that in the case of pancreatic ductal adenocarcinoma (PDAC), the healthy pancreatic tissue surrounding the tumor releases REG3β, a lectin that binds to the glycoproteins present in the surface of EVs, thus interfering with their uptake and internalization by target cells. In vitro, the disruption of the signaling mediated by EVs due to the presence of REG3β, prevents the EV-induced phenotypic switch in macrophages, inhibits the increased cell migration of cancer cells and reverses a number of metabolomic changes promoted by EVs. In vivo, the uptake of REG3β+ EVs by tumor cells is significantly impaired. Furthermore, it results in an increase of circulating REG3β+ EVs in blood of pancreatic cancer patients. Our findings highlight the effect of a lectin released by the healthy pancreatic tissue surrounding the tumor in modulating the EV-mediated interactions between different cell types in PDAC.

New Roles for Corticosteroid Binding Globulin and Opposite Expression Profiles in Lung and Liver

Corticosteroid-binding globulin (CBG) is the specific plasma transport glycoprotein for glucocorticoids. Circulating CBG is mainly synthesized in liver but, its synthesis has been located also in other organs as placenta, kidney and adipose tissue with unknown role. Using an experimental model of acute pancreatitis in cbg-/- mice we investigated whether changes in CBG affect the progression of the disease as well as the metabolism of glucocorticoids in the lung. Lack of CBG does not modify the progression of inflammation associated to pancreatitis but resulted in the loss of gender differences in corticosterone serum levels. In the lung, CBG expression and protein level were detected, and it is noteworthy that these showed a sexual dimorphism opposite to the liver, i.e. with higher levels in males. Reduced expression of 11β-HSD2, the enzyme involved in the deactivation of corticosterone, was also observed. Our results indicate that, in addition to glucocorticoids transporter, CBG is involved in the gender differences observed in corticosteroids circulating levels and plays a role in the local regulation of corticosteroids availability in organs like lung.

Oleic acid chlorohydrin, a new early biomarker for the prediction of acute pancreatitis severity in humans

BackgroundThe early prediction of the severity of acute pancreatitis still represents a challenge for clinicians. Experimental studies have revealed the generation of specific halogenated lipids, in particular oleic acid chlorohydrin, in the early stages of acute pancreatitis. We hypothesized that the levels of circulating oleic acid chlorohydrin might be a useful early prognostic biomarker in acute pancreatitis in humans.MethodsIn a prospective, multicenter cohort study, plasma samples collected within 24xa0h after presentation in the emergency room from 59 patients with acute pancreatitis and from 9 healthy subjects were assessed for oleic acid chlorohydrin levels.ResultsPancreatitis was mild in 30 patients, moderately severe in 16 and severe in 13. Oleic acid chlorohydrin levels within 24xa0h after presentation were significantly higher in patients that later progressed to moderate and severe acute pancreatitis. Using 7.49xa0nM as the cutoff point, oleic acid chlorohydrin distinguished mild from moderately severe-to-severe pancreatitis with high sensitivity/specificity (96.6/90.0%) and positive/negative predictive values (90.3/96.4%). Using 32.40xa0nM as the cutoff value sensitivity, specificity, positive and negative predictive values were all 100% for severe acute pancreatitis. It was found to be a better prognostic marker than BISAP score, hematocrit at 48xa0h, SIRS at admission, persistent SIRS or C-reactive protein at 48xa0h.ConclusionsOleic acid chlorohydrin concentration in plasma is elevated in patients with acute pancreatitis on admission and correlates with a high degree with the final severity of the disease, indicating that it has potential to serve as an early prognostic marker for acute pancreatitis severity.

Involvement of exosomes in lung inflammation associated with experimental acute pancreatitis

A frequent complication of acute pancreatitis is the lung damage associated with the systemic inflammatory response. Although various pro‐inflammatory mediators generated at both local and systemic levels have been identified, the pathogenic mechanisms of the disease are still poorly understood. In recent years, exosomes have emerged as a new intercellular communication system able to transfer encapsulated proteins and small RNAs and protect them from degradation. Using an experimental model of taurocholate‐induced acute pancreatitis in rats, we aimed to evaluate the role of exosomes in the extent of the systemic inflammatory response. Induction of pancreatitis increased the concentration of circulating exosomes, which showed a different proteomic profile to those obtained from control animals. A series of tracking experiments using PKH26‐stained exosomes revealed that circulating exosomes effectively reached the alveolar compartment and were internalized by macrophages. In vitro experiments revealed that exosomes obtained under inflammatory conditions activate and polarize these alveolar macrophages towards a pro‐inflammatory phenotype. Interestingly, the proteomic analysis of circulating exosomes during acute pancreatitis suggested a multi‐organ origin with a relevant role for the liver as a source of these vesicles. Tracking experiments also revealed that the liver retains the majority of exosomes from the peritoneal cavity. We conclude that exosomes are involved in the lung damage associated with experimental acute pancreatitis and could be relevant mediators in the systemic effects of pancreatitis. Copyright

Lipids generated during acute pancreatitis increase inflammatory status of macrophages by interfering with their M2 polarization

BACKGROUNDnNecrosis of adipose tissue is a common complication of acute pancreatitis. The areas of steatonecrosis become a source of inflammatory mediators, including chemically modified fatty acids which could influence the progression of the systemic inflammation. In an experimental model of acute pancreatitis we analyzed the effects of lipids generated by two representative areas of adipose tissue on the switch to the M1 phenotype in macrophages.nnnMETHODSnPancreatitis was induced in rats by intraductal administration of 5% taurocholate and after 6xa0h, lipids from retroperitoneal, mesenteric or epididymal adipose tissues were collected. Lipid uptake, phenotype polarization and the activation of PPARγ and NFκB were evaluated in macrophages treated with these lipids.nnnRESULTSnAfter induction of pancreatitis, lipids from visceral adipose tissue promote the switch to an increased pro-inflammatory phenotype in macrophages. This effect is not related with a higher activation of NFκB but with an interfering effect on the activation of M2 phenotype.nnnCONCLUSIONSnDuring acute pancreatitis, lipids generated by some areas of adipose tissue interfere on the M2 polarization of macrophages, thus resulting in a more intense pro-inflammatory M1 response.

Minocycline inhibits peritoneal macrophages but activates alveolar macrophages in acute pancreatitis

Minocycline is a tetracycline antibiotic that, in addition to its antimicrobial function, has been reported to possess a relevant anti-inflammatory activity. Its effects have been extensively evaluated in inflammatory-related neurological diseases. Here, we evaluate its effect on the systemic inflammatory response in a model of experimental acute pancreatitis. Minocycline treatment significantly reduced the inflammation in pancreas and mesenterium, had no effect on the adipose tissue inflammation, and increased the inflammatory response in the lung. These differences seem to be related with different effects exerted on peritoneal and alveolar macrophages. In vitro, minocycline reduced the expression of IL-1β and inhibit the activation of nuclear factor kappa B (NF-κB) on peritoneal macrophages, while it had no effect on alveolar macrophages. Our data indicates that although minocycline may be useful as a tool to control some inflammatory processes, differences on its effects depending on the population of macrophages involved in the process can be expected. In the particular case of acute pancreatitis, it could promote or potentiate inflammation in the lung so that its use does not appear to be recommended.

Rare germline copy number variants in colorectal cancer predisposition characterized by exome sequencing analysis

Sebastià Franch-Expósito, Clara Esteban-Jurado, Pilar Garre, Isabel Quintanilla, Saray Duran-Sanchon, Marcos Díaz-Gay, Laia Bonjoch, Miriam Cuatrecasas, Esther Samper, Jenifer Muñoz, Teresa Ocaña, Sabela Carballal, María López-Cerón, Antoni Castells, Maria Vila Casadesús, Sophia Derdak, Steven Laurie, Sergi Beltran, Jaime Carvajal, Luis Bujanda, Clara Ruiz-Ponte, Jordi Camps, Meritxell Gironella, Juan José Lozano, Francesc Balaguer, Joaquín Cubiella, Trinidad Caldés, Sergi Castellví-Bel