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World J Gastrointest Pharmacol Ther. Oct 6, 2010; 1(5): 107-111
Published online Oct 6, 2010. doi: 10.4292/wjgpt.v1.i5.107
Role of macrophages in the progression of acute pancreatitis
Sabrina Gea-Sorlí, Daniel Closa, Department of Experimental Pathology, IIBB-CSIC-IDIBAPS-CIBEREHD, Barcelona 08036, Spain
Author contributions: Gea-Sorlí S wrote the sections on macrophages, macrophages and therapeutical target; Closa D wrote the sections on macrophage activation during acute pancreatitis, macrophage populations in pancreatitis, peritoneal macrophages, Kupffer cells and alveolar macrophages; Closa D and Gea-Sorlí S designed the figure.
Correspondence to: Dr. Daniel Closa, Department of Experimental Pathology, IIBB-CSIC, c/ Rosselló 161, 7°, Barcelona 08036, Spain.
Telephone: +34-93-3638307 Fax: +34-93-3638301
Received: February 26, 2010
Revised: July 30, 2010
Accepted: August 6, 2010
Published online: October 6, 2010


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.

Key Words: Pancreatitis, Macrophages, Inflammation, Systemic inflammatory response syndrome


Acute pancreatitis (AP) is an inflammatory process of the pancreatic gland that exhibits a broad clinical spectrum and its severity may vary from a mild, edematous to a severe, necrotizing disease with high morbidity and mortality. In the most severe forms, the process involves remote organ systems. In fact, systemic inflammatory response syndrome (SIRS) is one of the major pathobiological processes underlying severe acute pancreatitis. This is of major importance because half of deaths in the first week of the process are attributed to organ failure and, in particular, the acute respiratory distress syndrome associated with SIRS[1]. Despite advances in diagnosis and treatment of inflammatory pancreatic disease, to date, supportive care remains the only treatment for patients with pulmonary complications.

It is widely accepted that the premature activation of digestive enzymes (trypsin, elastase and lipase) within the pancreatic acinar cells is a critical initiating event that leads to autodigestion of the pancreas[2]. However, acute pancreatitis is also an inflammatory disorder which develops a complex cascade of immunological events which not only affect the pathogenesis but also the course of the disease. Although intra-acinar or interstitial activation of trypsinogen is most probably the trigger of acute pancreatitis[3], in recent years much emphasis has been put on the role of leukocytes[4]. In addition, a number of proinflammatory mediators have been identified to play a role in the progression of local pancreatic damage to systemic inflammation. This includes tumor necrosis factor α (TNFα), interleukin (IL)-1β, IL-6, MCP-1 and Platelet activating factor[5]. Some of these mediators are initially released by pancreatic acinar cells and results in the recruitment of neutrophils and monocytes. Numerous experimental and clinical data indicate that more pro-inflammatory mediators including cytokines, arachidonic acid derivatives, activated oxygen species and proteases are released locally by over activated neutrophils and monocytes/macrophages among other cells[6]. When released, these mediators gain access to the systemic circulation and play a central role in the progression of multisystem organ failure[7].


In addition to pancreatic cells, other cell populations contribute to the systemic generation of inflammatory mediators. In particular, it has been reported that peritoneal macrophages, alveolar macrophages and Kupffer cells become activated in different stages of severe acute pancreatitis[8-10].

Macrophages display remarkable plasticity and can change their physiology in response to environmental cues[11]. Depending on their microenvironmental stimulation, macrophages could follow different activation pathways resulting in marked phenotypic heterogeneity (Figure 1)[12]. These changes can give rise to different populations of cells with distinct functions.

Figure 1
Figure 1 Depending on the microenvironment, macrophages could follow different activation processes. Classical M1 activation is induced by bacterial products or pro-inflammatory cytokines as tumor necrosis factor α or IFNγ. Regulatory M2b activation is induced by glucocorticoids, prostaglandins or interleukin (IL)-10. Finally, reparative M2a activation depends mainly on IL-4 and IL-13. Since these phenotypes could be redirected, the modulation of macrophage phenotype could be a promising therapeutical approach for the treatment of the systemic effects of acute pancreatitis. TNFα: Tumor necrosis factor α.

During the initial stages of the inflammatory response, the presence of pro-inflammatory stimulus induces classically activated macrophages (M1 macrophages). Under this activation, M1 macrophages are characterized by the secretion of proinflammatory cytokines including TNFα, IL1β and IL6 and the induction of enzymes, such as iNOS or COX2, involved in the generation of other pro-inflammatory mediators as nitric oxide or arachidonic acid metabolites[11].

In addition to classical M1 activation, a second population of macrophages was identified in the presence of the Th2 cytokines IL4 and IL13. These macrophages are termed alternative, wound healing or M2a. Under this activation, these macrophages fail to produce NO and to present antigens to T cells but they up-regulate mannose receptor expression and arginase II[13,14]. These cells also contribute to the production of the extra-cellular matrix.

Finally, a third population of activated macrophages termed regulatory or M2b have been described in the later stages of immune responses. The primary role of these macrophages seems to be to limit the inflammatory response. The production of the regulatory cytokine TGFβ and IL10 can inhibit the production of proinflammatory mediators by the classical M1 macrophages[15]. These regulatory macrophages do not contribute to the production of the extracellular matrix but express high levels of co-stimulatory molecules (CD80 and CD86) and can present antigens to T cells[11].

Macrophages seem to retain their plasticity and respond to environmental signals[16]. Several in vitro studies indicate that the phenotype of a macrophage population can change in response to different stimuli[17]. On the other hand, in vivo there are some cases in which a phenotypic switch in the macrophage population occurs over time and is associated with pathology[18]. However, it is less clear whether these changes in the phenotype are the result of differentiation of the original macrophages or of the migration of a new population of macrophages into the tissue site where they replace the original cells[11].

Since macrophages orchestrate both the initiation and the resolution of inflammation, it is clear that the degree of macrophage activation could be one of the factors that finally determine the severity of the inflammatory process.


The fact that macrophages could generate both pro and anti-inflammatory mediators confers a pivotal role to these cells in the progression of acute pancreatitis. Several reports demonstrate that macrophages could be activated by mediators released during pancreatitis by a damaged pancreas. In particular, pancreatic enzymes such as trypsin, elastase, carboxypeptidase A and lipase induce the generation of TNFα in cultured peritoneal macrophages or in macrophage cell lines[19,20]. The fact that these effects are mediated by IκB degradation and NFκB activation indicates that these enzymes trigger macrophage activation through specific membrane-bound receptors[21].

In vitro activation of macrophages could also be observed by treating these cells with supernatants of pancreatic acinar cells cultures incubated with cerulein[22]. Similarly, ascitic fluid collected from rats after the induction of experimental models of pancreatitis activates macrophages in vitro[23,24]. This activation could also be blocked by treating the cells with NFκB inhibitors as pyrrolidine dithiocarbamate. Interestingly, lipids present in ascitic fluid also have an effect on the activation of macrophages. It has been observed that lipid fraction of ascitic fluid does not activate macrophages but interferes in the inhibitory activity of PPARγ nuclear receptor, thus resulting in an increased activation of these inflammatory cells[24].

Direct measurement of circulating monocytes also revealed a significant degree of activation. Increased expression of iNOS[25] and TLR4[26] was reported in blood monocytes obtained from human patients with severe acute pancreatitis. In an experimental model of taurocholate-induced pancreatitis, the activation of NFκB and p38 MAPK signalling pathways in circulating monocytes has also been observed[27].

These results indicate that during acute pancreatitis there are mediators released with the capability to activate these inflammatory cells. When activated, macrophages could act to amplify the inflammatory response triggered in the pancreas through the generation of more cytokines and inflammatory mediators in systemic organs[28]. The importance of this activation on the progression of the disease was shown by the use of different inhibitors.

In this line, the administration of drugs as the macrophage-pacifying compound CNI-1493 prior to the induction of severe acute pancreatitis in rats results in an increased survival and a reduction in the severity of the process characterized by lower levels of circulating enzymes, cytokines as well as transaminases[29,30]. A protective effect was also observed by depleting macrophages with the injection of liposome-encapsulated dichloromethylene-diphosphonate, a macrophage-depleting agent, in a mice model of virus -induced pancreatitis[31]. However, in this case, a reduction in the levels of potentially protective cytokines as IL-10 was also observed.


During the progression of acute pancreatitis from local pancreatic damage to systemic organ inflammation, several macrophage populations are of particular importance. Peritoneal macrophages are in direct contact with ascitic fluid secreted by the pancreas. This fluid generated in severe acute pancreatitis contains pancreatic enzymes and cytokines in a concentration that exceeds that observed in plasma in an order of magnitude[32]. Consequently, peritoneal macrophages are exposed to an intense pro-inflammatory environment and strong activation could be expected. The importance of this activation is the fact that mediators released by these macrophages to the peritoneal cavity could easily achieve the bloodstream through mesenteric absorption, thus contributing to the inflammatory response associated with acute pancreatitis[32].

A number of studies using different models of acute pancreatitis confirmed an early and intense M1 activation of peritoneal macrophages, reflected in the high expression of proinflammatory cytokines such as TNFα, IL1β, IL6 and enzymes such as iNOS[33]. The contribution of peritoneal macrophage-derived mediators to the toxicity of ascitic fluid was shown when a peritoneal lavage was carried out before the induction of pancreatitis in order to remove the macrophages[34]. In these conditions, ascitic fluid was generated by the effect of acute pancreatitis but the cytotoxic effects of this fluid, and in particular its apoptosis-inducing activity, was significantly reduced.

Another population of macrophages that has been involved in the pathogenesis of acute pancreatitis are Kupffer cells. They are the resident macrophages in the liver and participate in the acute response of this organ to toxic compounds. Since mediators released by a damaged pancreas or present in ascitic fluid are carried to the systemic circulation via the portal vein, the Kupffer cells could interact with all these products before they become diluted into the systemic circulation[26]. In vitro analysis of Kupffer cell activity revealed that these macrophages could also be activated by pancreatic enzymes[35,36].

Several works reported on the effect of gadolinium chloride administration to inhibit Kupffer cells activity before the induction of acute pancreatitis[37-41]. This inhibition results in lower levels of circulating cytokines and the pathological injury of the lung was ameliorated. By contrast, pancreatic damage was not affected by Kupffer cell blockage. These results indicate that the liver acts to amplify the inflammatory signal triggered by the pancreas in a process that is mediated by the activation of hepatic macrophages. Interestingly, the liver itself is not affected by this process and hepatic damage is not evident in early stages of pancreatitis.

The third family of macrophages involved in the progression of acute pancreatitis is alveolar macrophages. The capacity of alveolar macrophages to mobilize a large amount of leukocytes and release secretory products such as cytokines, arachidonic acid metabolites and nitric oxide (NO) after their activation in the course of different pulmonary inflammatory diseases suggests that these cells can be involved in the lung damage associated with AP. These macrophages exhibit particular characteristics, probably as a consequence of their anatomical situation, in direct contact with the environmental pollutants present in the breathing air.

A number of works reported on the changes presented by these cells during the acute lung injury secondary to pancreatitis. In particular, increased NO synthesis related to the induction of iNOS has been shown[42,43]. The use of phospholipase A2 inhibitors indicates that this enzyme could be involved in the activation of alveolar macrophages to generate nitric oxide[44]. However, the role of alveolar macrophages in the progression of acute lung injury during pancreatitis remains controversial. The use of inhibitors could affect other pulmonary cells involved in the generation of cytokines and the level of activation observed in alveolar macrophages seems to be lower than that observed in peritoneal or hepatic macrophages.


The role of macrophages in the progression from local inflammation of the pancreas to a systemic inflammation and multiple-organ dysfunction made these cells interesting therapeutical targets. In particular, the capacity of macrophages to sequentially exhibit pro- and anti- inflammatory properties is of interest. This capacity suggests that macrophages not only are mediators in the inflammatory injury but can be induced to modify the sequence of events that occurs during acute pancreatitis.

Initial strategies were focused on the inhibition of macrophages. In experimental models, the use of gadolinium chloride to inhibit Kupffer cells[28,35], liposome-encapsulated dichloromethylene-diphosphonate to act on peritoneal macrophages[26] or PAF antagonists to block the activation of alveolar macrophages[45] resulted in the modulation of the systemic inflammatory response. Unfortunately, in these studies macrophage inhibitors were administered before the induction of pancreatitis and the application of this approach in clinical practice is difficult. Another problem is the long time needed to effectively inhibit macrophage activity or to deplete the macrophage population. Consequently, other approaches have been assayed based on the capability of macrophages to modify its phenotype.

The administration of IL-4 and IL-13 has been evaluated in order to derivate the pancreatitis-activated M1 peritoneal macrophages to a reparative M2a phenotype. However, despite this treatment effectively reverting the M1 pro-inflammatory macrophages to M2b reparative cells in vitro, it failed when assayed in vivo[33]. The reason for this failure seems to be the related to the ascitic fluid present in the peritoneal cavity. The high concentration of hydrolytic enzymes in this fluid result in the degradation of cytokines and its activity was lost before any effect on the macrophages could be observed.

Another interesting strategy was to programme macrophages ex vivo with anti-inflammatory or protective characteristics and to transfer these cells into pancreatitis-induced animals. This has been carried out using an experimental model of diet- induced pancreatitis in mice and transferring heme-activated macrophages before starting the diet[46]. Heme activated macrophages express high amount of heme-oxygenase-1 that unveil several potential protective mechanisms mediated by IL-10 and p38 MAPK activity. This approach results in a reduction of histological score and in the levels of circulating amylase. However, despite these data confirming the role of inflammatory cells on the progression of local pancreatic damage during pancreatitis, the long time needed to obtain heme-activated macrophages is a challenge to apply this approach as a therapeutical strategy.


Different populations of resident macrophages are involved in the progression of acute pancreatitis from local pancreatic damage to a multiple organ failure response. The plasticity of these cells makes them an attractive target to manipulate the systemic inflammatory response associated with acute pancreatitis. Therefore, future studies are needed to improve the manipulation or selective depletion of macrophages.


Peer reviewers: Ilker Tasci, MD, Associate Professor, Department of Internal Medicine, Gulhane School of Medicine, Etlik 06018, Ankara, Turkey; Maxim Petrov, MD, MPH, Department of Surgery, University of Auckland, Private Bag 921019, Auckland 1142, New Zealand

S- Editor Wang JL L- Editor Roemmele A E- Editor Yang C

1.  Bhatia M, Wong FL, Cao Y, Lau HY, Huang J, Puneet P, Chevali L. Pathophysiology of acute pancreatitis. Pancreatology. 2005;5:132-144.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Shah AU, Sarwar A, Orabi AI, Gautam S, Grant WM, Park AJ, Shah AU, Liu J, Mistry PK, Jain D. Protease activation during in vivo pancreatitis is dependent on calcineurin activation. Am J Physiol Gastrointest Liver Physiol. 2009;297:G967-G973.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Saluja AK, Bhagat L, Lee HS, Bhatia M, Frossard JL, Steer ML. Secretagogue-induced digestive enzyme activation and cell injury in rat pancreatic acini. Am J Physiol. 1999;276:G835-G842.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Kyriakides C, Jasleen J, Wang Y, Moore FD Jr, Ashley SW, Hechtman HB. Neutrophils, not complement, mediate the mortality of experimental hemorrhagic pancreatitis. Pancreas. 2001;22:40-46.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Makhija R, Kingsnorth AN. Cytokine storm in acute pancreatitis. J Hepatobiliary Pancreat Surg. 2002;9:401-410.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Mikami Y, Takeda K, Shibuya K, Qiu-Feng H, Egawa S, Sunamura M, Matsuno S. Peritoneal inflammatory cells in acute pancreatitis: Relationship of infiltration dynamics and cytokine production with severity of illness. Surgery. 2002;132:86-92.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Hirota M, Nozawa F, Okabe A, Shibata M, Beppu T, Shimada S, Egami H, Yamaguchi Y, Ikei S, Okajima T. Relationship between plasma cytokine concentration and multiple organ failure in patients with acute pancreatitis. Pancreas. 2000;21:141-146.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Satoh A, Shimosegawa T, Kimura K, Moriizumi S, Masamune A, Koizumi M, Toyota T. Nitric oxide is overproduced by peritoneal macrophages in rat taurocholate pancreatitis: the mechanism of inducible nitric oxide synthase expression. Pancreas. 1998;17:402-411.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Sugita H, Yamaguchi Y, Ikei S, Yamada S, Ogawa M. Enhanced expression of cytokine-induced neutrophil chemoattractant (CINC) by bronchoalveolar macrophages in cerulein-induced pancreatitis rats. Dig Dis Sci. 1997;42:154-160.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Murr MM, Yang J, Fier A, Kaylor P, Mastorides S, Norman JG. Pancreatic elastase induces liver injury by activating cytokine production within Kupffer cells via nuclear factor-Kappa B. J Gastrointest Surg. 2002;6:474-480.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958-969.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Edwards JP, Zhang X, Frauwirth KA, Mosser DM. Biochemical and functional characterization of three activated macrophage populations. J Leukoc Biol. 2006;80:1298-1307.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Stein M, Keshav S, Harris N, Gordon S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med. 1992;176:287-292.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3:23-35.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest. 1998;101:890-898.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Mylonas KJ, Nair MG, Prieto-Lafuente L, Paape D, Allen JE. Alternatively activated macrophages elicited by helminth infection can be reprogrammed to enable microbial killing. J Immunol. 2009;182:3084-3094.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Stout RD, Jiang C, Matta B, Tietzel I, Watkins SK, Suttles J. Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J Immunol. 2005;175:342-349.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Lin EY, Li JF, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA, Qian H, Xue XN, Pollard JW. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 2006;66:11238-11246.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Lundberg AH, Eubanks JW 3rd, Henry J, Sabek O, Kotb M, Gaber L, Norby-Teglund A, Gaber AO. Trypsin stimulates production of cytokines from peritoneal macrophages in vitro and in vivo. Pancreas. 2000;21:41-51.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Jaffray C, Mendez C, Denham W, Carter G, Norman J. Specific pancreatic enzymes activate macrophages to produce tumor necrosis factor-alpha: role of nuclear factor kappa B and inhibitory kappa B proteins. J Gastrointest Surg. 2000;4:370-377; discussion 377-378.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Hietaranta A, Mustonen H, Puolakkainen P, Haapiainen R, Kemppainen E. Proinflammatory effects of pancreatic elastase are mediated through TLR4 and NF-kappaB. Biochem Biophys Res Commun. 2004;323:192-196.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Liang T, Liu TF, Xue DB, Sun B, Shi LJ. Different cell death modes of pancreatic acinar cells on macrophage activation in rats. Chin Med J (Engl). 2008;121:1920-1924.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Satoh A, Shimosegawa T, Masamune A, Fujita M, Koizumi M, Toyota T. Ascitic fluid of experimental severe acute pancreatitis modulates the function of peritoneal macrophages. Pancreas. 1999;19:268-275.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Gutierrez PT, Folch-Puy E, Bulbena O, Closa D. Oxidised lipids present in ascitic fluid interfere with the regulation of the macrophages during acute pancreatitis, promoting an exacerbation of the inflammatory response. Gut. 2008;57:642-648.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Tanjoh K, Tomita R, Izumi T, Kinoshita K, Kawahara Y, Moriya T, Utagawa A. The expression of the inducible nitric oxide synthase messenger RNA on monocytes in severe acute pancreatitis. Hepatogastroenterology. 2007;54:927-931.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Li HG, Zhou ZG, Li Y, Zheng XL, Lei S, Zhu L, Wang Y. Alterations of Toll-like receptor 4 expression on peripheral blood monocytes during the early stage of human acute pancreatitis. Dig Dis Sci. 2007;52:1973-1978.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Liu HS, Pan CE, Liu QG, Yang W, Liu XM. Effect of NF-kappaB and p38 MAPK in activated monocytes/macrophages on pro-inflammatory cytokines of rats with acute pancreatitis. World J Gastroenterol. 2003;9:2513-2518.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Gloor B, Blinman TA, Rigberg DA, Todd KE, Lane JS, Hines OJ, Reber HA. Kupffer cell blockade reduces hepatic and systemic cytokine levels and lung injury in hemorrhagic pancreatitis in rats. Pancreas. 2000;21:414-420.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Yang J, Denham W, Tracey KJ, Wang H, Kramer AA, Salhab KF, Norman J. The physiologic consequences of macrophage pacification during severe acute pancreatitis. Shock. 1998;10:169-175.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Yang J, Denham W, Carter G, Tracey KJ, Norman J. Macrophage pacification reduces rodent pancreatitis-induced hepatocellular injury through down-regulation of hepatic tumor necrosis factor alpha and interleukin-1beta. Hepatology. 1998;28:1282-1288.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Shifrin AL, Chirmule N, Zhang Y, Raper SE. Macrophage ablation attenuates adenoviral vector-induced pancreatitis. Surgery. 2005;137:545-551.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Dugernier T, Laterre PF, Reynaert MS. Ascites fluid in severe acute pancreatitis: from pathophysiology to therapy. Acta Gastroenterol Belg. 2000;63:264-268.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Gea-Sorlí S, Closa D. In vitro, but not in vivo, reversibility of peritoneal macrophages activation during experimental acute pancreatitis. BMC Immunol. 2009;10:42.  [PubMed]  [DOI]  [Cited in This Article: ]
34.  Takeyama Y, Nishikawa J, Ueda T, Hori Y, Yamamoto M, Kuroda Y. Involvement of peritoneal macrophage in the induction of cytotoxicity due to apoptosis in ascitic fluid associated with severe acute pancreatitis. J Surg Res. 1999;82:163-171.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Folch-Puy E. Importance of the liver in systemic complications associated with acute pancreatitis: the role of Kupffer cells. J Pathol. 2007;211:383-388.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Murr MM, Yang J, Fier A, Gallagher SF, Carter G, Gower WR Jr, Norman JG. Regulation of Kupffer cell TNF gene expression during experimental acute pancreatitis: the role of p38-MAPK, ERK1/2, SAPK/JNK, and NF-kappaB. J Gastrointest Surg. 2003;7:20-25.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Peng Y, Gallagher SF, Landmann R, Haines K, Murr MM. The role of p65 NF-kappaB/RelA in pancreatitis-induced Kupffer cell apoptosis. J Gastrointest Surg. 2006;10:837-847.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  Gloor B, Todd KE, Lane JS, Lewis MP, Reber HA. Hepatic Kupffer cell blockade reduces mortality of acute hemorrhagic pancreatitis in mice. J Gastrointest Surg. 1998;2:430-435.  [PubMed]  [DOI]  [Cited in This Article: ]
39.  Folch E, Prats N, Hotter G, López S, Gelpi E, Roselló-Catafau J, Closa D. P-selectin expression and Kupffer cell activation in rat acute pancreatitis. Dig Dis Sci. 2000;45:1535-1544.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Liu HB, Cui NQ, Li DH, Chen C. Role of Kupffer cells in acute hemorrhagic necrotizing pancreatitis-associated lung injury of rats. World J Gastroenterol. 2006;12:403-407.  [PubMed]  [DOI]  [Cited in This Article: ]
41.  Pastor CM, Vonlaufen A, Georgi F, Hadengue A, Morel P, Frossard JL. Neutrophil depletion--but not prevention of Kupffer cell activation--decreases the severity of cerulein-induced acute pancreatitis. World J Gastroenterol. 2006;12:1219-1224.  [PubMed]  [DOI]  [Cited in This Article: ]
42.  Tsukahara Y, Horita Y, Anan K, Morisaki T, Tanaka M, Torisu M. Role of nitric oxide derived from alveolar macrophages in the early phase of acute pancreatitis. J Surg Res. 1996;66:43-50.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  Closa D, Sabater L, Fernández-Cruz L, Prats N, Gelpí E, Roselló-Catafau J. Activation of alveolar macrophages in lung injury associated with experimental acute pancreatitis is mediated by the liver. Ann Surg. 1999;229:230-236.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Tsukahara Y, Morisaki T, Horita Y, Torisu M, Tanaka M. Phospholipase A2 mediates nitric oxide production by alveolar macrophages and acute lung injury in pancreatitis. Ann Surg. 1999;229:385-392.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Wereszczynska-Siemiatkowska U, Dlugosz JW, Siemiatkowski A, Chyczewski L, Gabryelewicz A. Lysosomal activity of pulmonary alveolar macrophages in acute experimental pancreatitis in rats with reference to positive PAF-antagonist (BN 52021) effect. Exp Toxicol Pathol. 2000;52:119-125.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Nakamichi I, Habtezion A, Zhong B, Contag CH, Butcher EC, Omary MB. Hemin-activated macrophages home to the pancreas and protect from acute pancreatitis via heme oxygenase-1 induction. J Clin Invest. 2005;115:3007-3014.  [PubMed]  [DOI]  [Cited in This Article: ]