In vitro, but not in vivo, reversibility of peritoneal macrophages activation during experimental acute pancreatitis

<p>Abstract</p> <p>Background</p> <p>Systemic inflammatory response syndrome is one of the major pathobiologic processes underlying severe acute pancreatitis and the degree of macrophage activation could be one of the factors that finally determine the severity of the disease. We evaluated the activation phenotype in peritoneal macrophages during the progression of an experimental model of acute pancreatitis induced in rats by intraductal administration of 5% sodium taurocholate and the effect of IL-4 and IL-13 to modulate this activation.</p> <p>Samples of pancreas, lung and adipose tissue as well as plasma were also obtained. In some animals IL4 and IL13 were injected 1 h after induction in order to modulate macrophage activation. The expressions of TNFα and Mannose Receptor, as indicators of classical and alternative macrophage activation, were evaluated. Levels of myeloperoxidase and plasma lipase were determined to evaluate the severity of the inflammatory process. The stability of IL-4 in ascitic fluid and plasma was evaluated.</p> <p>Results</p> <p>Peritoneal macrophages showed a classical M1 activation clearly induced 3 h after pancreatitis induction and maintained until 18 h. Treatment with IL-4 and IL-13 reversed the activation of macrophages from a classical M1 to alternative M2 <it>in vitro</it>, but failed to modulate the response of peritoneal macrophages <it>in vivo </it>despite a reduction in inflammation was observed in lung and adipose tissue. Finally, IL-4 shows a short half-live in ascitic fluid when compared with plasma.</p> <p>Conclusion</p> <p>Peritoneal macrophages adopt a pro-inflammatory activation early during acute pancreatitis. Treatment with M2 cytokines could revert <it>in vitro </it>the pancreatitis-induced activation of macrophages but fails to modulate its activation <it>in vivo</it>. This treatment has only a moderate effect in reducing the systemic inflammation associated to acute pancreatitis. Hydrolytic enzymes presents in ascitic fluid could be involved in the degradation of cytokines, strongly reducing its utility to modulate peritoneal macrophages in pancreatitis.</p

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 11â-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.Support was provided by: Fondo Investigación Sanitaria PI09/00505 to ME MG; Fondo Investigación Sanitaria PI13/00019 to DC SG-S; Predoctoral scholarship from the University of Barcelona to JG; European and Sardinian scholarship >Master and Back> to AL; Grant from Generalitat de Catalunya (AGAUR, Grant FI DGR 2013) to LB.Peer Reviewe

Differences in the inflammatory response induced by acute pancreatitis in different white adipose tissue sites in the rat

This is an open-access article distributed under the terms of the Creative Commons Attribution License.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. © 2012 Gea-Sorlí et al.This study was supported by the project SAF 2009-07605 and from Ministerio de Ciencia e Innovación.Peer Reviewe

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

© 2015, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved. Background Necrosis 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. Methods Pancreatitis was induced in rats by intraductal administration of 5% taurocholate and after 6 h, 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. Results After 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. Conclusions During 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.This work was supported by the projects SAF 2009-07605 from Ministerio de Ciencia e Innovación, and FIS PI13/00019 from Instituto de Salud Carlos III. L.Bonjoch is supported by a grant from Generalitat de Catalunya (AGAUR, Grant FI DGR 2013)Peer Reviewe

Role of macrophages in the progression of acute pancreatitis

In addition to pancreatic cells, other inflammatory cell populations contribute to the generation of inflammatory mediators during acute pancreatitis. In particular, macrophages could be activated by mediators released during pancreatitis by a damaged pancreas. It has been reported that peritoneal macrophages, alveolar macrophages and Kupffer cells become activated in different stages of severe acute pancreatitis. However, macrophages display remarkable plasticity and can change their physiology in response to environmental cues. Depending on their microenvironmental stimulation, macrophages could follow different activation pathways resulting in marked phenotypic heterogeneity. This ability has made these cells interesting therapeutical targets and several approaches have been assayed to modulate the progression of inflammatory response secondary to acute pancreatitis. However, despite the recent advances in the modulation of macrophage function in vivo, the therapeutical applications of these strategies require a better understanding of the regulation of gene expression in these cells

Modulación de la actividad de los macrófagos peritoneales durante la pancreatitis aguda experimental

Trabajo presentado a la XII Reunión del Club Español Pancreatico celebrada en Alicante del 13 al 15 de octubre de 2011.[Objetivos]: Durante la PA, los macrófagos (MФ) pueden seguir diferentes vías de activación. En este trabajo hemos evaluado el fenotipo de activación de los MФperitoneales. [Métodos]: En un modelo de pancreatitis por taurocolato en ratas se analizó la expresión de genes marcadores de las diferentes vías de activación que presentan los macrófagos. También hemos analizado el efecto de la IL4 y la IL13 para intentar revertir esta activación. [Resultados]: Los MФ peritoneales muestran una activación M1 ya al inicio de la PA. In vitro, el tratamiento con IL4 y IL13 revierte la activación de los macrófagos del fenotipo M1 al M2, pero in vivo falla modulando la respuesta de estas células. Finalmente observamos que la IL4 tiene una vida media más corta en líquido ascítico que en plasma. [Conclusiones]: Los MФ peritoneales adoptan una activación proinflamatoria al principio de la PA. Estos macrófagos pueden ser reprogramados in vitro hacia un fenotipo antiinflamatorio, aunque in vivo, este tratamiento no es suficiente para revertir el fenotipo. Esta falta de efecto parece estar relacionada con la degradación de las interleuquinas por las hidrolasas pancreáticas en la cavidad peritoneal.Peer Reviewe

Lipotoxicidad asociada a la pancreatitis aguda en diferentes zonas del tejido adiposo

Trabajo presentado en la XIII Reunión del Club Español Pancreático, celebrada en Alicante, España, del 19 al 21 de septiembre de 2013Peer Reviewe

Differential activation of peritoneal, alveolar and lung interstitial macrophages during acute pancreatitis

Trabajo presentado en la 42nd European Pancreatic Club (EPC) Meeting, celebrada en Estocolmo, Suecia, del 16 al 19 de junio de 2010Peer Reviewe

Release of inflammatory mediators by adipose tissue during acute pancreatitis

Obesity and lipid metabolism are associated with the severity of acute pancreatitis. Fat necrosis appears in the severe acute pancreatitis as a consequence of the release of lipolytic enzymes, but its potential role on the progression of the disease is unclear. In this study, we have examined the role of white adipose tissue as a source of inflammatory mediators that can promote systemic inflammation during experimental taurocholate-induced acute pancreatitis in rats. The inflammatory status and the expression of TNFα, iNOS, adiponectin and IL-10 were determined in necrotic and non-necrotic areas of adipose tissue. Samples of adipose tissue were also used to induce the activation of macrophages in vitro. Finally, the release of TNFα to mesenterial vessels surrounded by necrotic or non-necrotic fat was evaluated in ex vivo perfused mesenterium. A strong inflammatory infiltrate was observed in the border between necrotic and non-necrotic areas of adipose tissue. In these areas, high expression of TNFα and iNOS and a reduced expression of IL-10 were observed, while adiponectin showed only a moderate increase. Necrotic fat strongly activates peritoneal macrophages in vitro. Mesenterial areas with fat necrosis release to the vascular vessels significantly increased amounts of TNFα when compared to vessels without necrosis. Altogether, these results indicate that adipose tissue inflammation is a process secondary to acute pancreatitis but also contributes to the generation of mediators potentially involved in the induction of the systemic inflammatory response. In particular, the areas of fat necrosis are important sources of inflammatory mediators. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.This work was supported by Project No. SAF2006-08449 from Ministerio de Ciencia e Innovación.Peer Reviewe