EDITORIAL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59
The Anti-Inflammasome Effect of Lactate and the Lactate GPR81-Receptor in Pancreatic and Liver Inflammation See “Lactate reduces organ injury in Toll-like receptorand inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity,” by Hoque R, Farooq A, Ghani A, et al, on page 000.
W
hen organ injury occurs in the absence of an adequate oxygen supply, the glucose metabolism for energy generation is diverted to lactate, rather than pyruvate, and serum lactate levels rise. Any clinician regards this as an ominous sign for the patient’s prognosis and suspect behind rising lactate levels organ ischemia or microcirculatory failure of some sort. He or she will also be aware that this is often paralleled by progressive acidification (a falling pH) and systemic inflammation. Recent cell biological studies have, indeed, suggested that lactate has a direct pro-inflammatory effect on the Toll-like receptor (TLR)/nuclear factor (NF)-kB/inflammasome signaling cascade that ultimately drives systemic inflammation via the activation of interleukin (IL)–1b.1,2 Acute liver injury and acute pancreatitis are often associated with significant fluid loss into the interstitial space and affected patients accordingly require large intravenous fluid volumes for replacement.3 For pancreatitis, a recent randomized clinical trial has unequivocally shown that Ringer lactate solution is much superior to saline infusion when used as a fluid replacement therapy.4 This seems to contradict the first statement on the negative role and harmful effects of lactate in systemic inflammation and organ failure. Hoque et al5 now provide an explanation for this apparent paradox in an elegant experimental study in this issue of Gastroenterology. They focused their investigation on macrophages/monocytes, which are known to be critically involved in liver and pancreatic inflammation6,7 and used animal disease models for hepatitis (lipopolysaccharide [LPS] and D-galactosamine) and pancreatitis (LPS and cerulean) to test their hypothesis that lactate has anti-inflammatory effects and mediates them through a recently discovered lactate receptor, the plasma membrane Gi protein-coupled receptor 81 (GPR81).8 The authors found that low concentrations of lactate reduce organ injury in both disease models via binding to GPR81. In vitro and in vivo they could show that lactate signaling in macrophages/monocytes is dependent on GPR81 and its adaptor protein ARRB2, and that small interfering RNA blockage of the expression of either protein can regulate this process. Moreover, through this signaling pathway lactate directly inhibited the action of the NLRP3 inflammasome, which is activated via TLR-4 and the action of caspase 1. The consequences were a reduced NF-kB action and diminished conversion of pro–IL-1b to active IL-1b—with a significant beneficial effect on disease severity
in both models. Simply put: Lacate at physiologic concentrations is a terrific anti-inflammatory agent and one with proven efficiency not only in human disease but also in experimental models of inflammation. This study is intriguing for several reasons. For acute pancreatitis and acute hepatitis, the early impact of inflammatory cell activation has recently been highlighted and macrophages seem to play a critical role in the disease initiation and severity.6,7,9 To activate the NLRP3 inflammasome, a 2-checkpoint model of priming and activation has been proposed in which TLR-4 (or TLR-9) represent the second checkpoint. Although the role of TLRs in bacterial infection is unequivocal, research continues on its importance for sterile inflammation, such as the early phase of pancreatitis.10–12 The net effect of NLRP3 inflammasome activation is the proteolytic cleavage and activation of the strongly pro-inflammatory cytokine IL-1b, which regulates most of the systemic inflammatory response syndrome. Constitutive overexpression of IL-1b in the pancreas alone was found to be sufficient to induce spontaneous pancreatitis.13 Reducing the action of the NLRP3 inflammasome would therefore be expected to have a beneficial effect on either the onset or the severity of the disease. Inflammasomes assemble to key signaling platforms that detect pathogenic microorganisms and sterile stressors before leading to downstream activation of IL-1b. The 2step model of priming and activation of the canonical NLRP3 inflammasome predicts that the basal expression of its components is insufficient for its activation in resting cells. An initial activating signal transmitted via pattern recognition receptor on the cell surface results in upregulation of the NLRP3 components and represents the priming reaction. Only thereafter can the NLRP3 inflammasome be activated via LPS stimulation of its receptor, the TLR-4, which then induces activation of TRIF, the binding of NLRP3 to ASC, and the subsequent caspase 1–dependent induction of pro–IL-b1 expression and its activation. Although LPS-stimulated TLR-4 activation is probably the best investigated mechanisms of NLRP3 inflammasome activation, other mechanisms involving bacterial membrane components, the release of cathepsin B from lysosomes, low potassium levels, high intracellular calcium concentrations, or the release of reactive oxygen species from mitochondria have all been implicated in this process (Figure 1). Lactate has long been regarded as critical for energy (ATP) generation when oxygen is in short supply (anaerobic glycolysis) and rising levels in the blood were regarded as an early sign of microcirculatory failure. It was only recently discovered that lactate is also a signaling molecule and a ligand for a dedicated lactate receptor.8 The GPR81 is a 7-transmembrane receptor and binding of lactate leads to recruitment of the intracellular adaptor ARRB2 before downstream signaling is
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print & web 4C=FPO
EDITORIAL
Figure 1. Blockage of NLRP3 inflammasome activation via Gi protein-coupled receptor 81 (GPR81). Inflammasomes are key signaling platforms for the detection of pathogenic microorganisms and sterile stressors leading to activation of the highly proinflammatory cytokine interleukin (IL)-1b. Activation of the canonical NLRP3 inflammasome has been proposed to act according to a 2-checkpoint model of priming and activation. Initially, an activating signal transmitted via pattern recognition receptor (PRR) on the cell surface results in NLRP3 up-regulation as a priming reaction. Thereafter Tool-like receptor (TLR)-4 is activated by lipopolysaccharide, which leads to activation of TRIF and binding of NLRP3 to ASC. Subsequently, pro–IL-b1 expression is upregulated and activated via caspase 1. There are several other stimuli involved in the activation of NLRP3, such as bacterial membrane components, cathepsin B release from lysosomes, low potassium levels, high calcium levels, or reactive oxygen species (ROS) release from mitochondria. The specific ligand of the plasma membrane GPR81, a 7-transmembrane receptor, is lactate. Binding of lactate recruits the intracellular adaptor molecule ARRB2 to the receptor and subsequent inhibition of the NLRP3 inflammasome with a reduction of the IL-b–mediated pro-inflammatory response. NF-kB, nuclear factor-kB.
transmitted. From Hoque et al,5 we learn that this signal ultimately reduces the activation of the NLRP3 inflammasome, with all its beneficial effects on macrophages/monocytes and 2 experimental inflammatory diseases of the liver and pancreas. The exact mechanism through which GPR81 and ARRB2 counteract the NLRP3 and TLR pathways is currently unknown (Figure 1) will require further study. Lactate possesses several chemical and metabolic effects outside this signaling cascade and these include a reduction in pH. A lower pH, on the other hand, could have several unwanted consequences as far as the pancreas is concerned: The pancreatic acinar cell stores its proteases in acidic secretory vesicles and when pancreatitis is induced the pH in intracellular compartment becomes more acidic and a premature protease activation begins.14 For this premature intracellular protease activation, 2 mechanisms have been proposed and involve trypsinogen activation by cathepsin B or trypsinogen autoactivation, both of which are pH dependent.15,16 Chloroquine, an agent that raises the intracellular pH, reduces premature zymogen activation and ameliorates the course of experimental pancreatitis.17 A proton pump, the vacuolar ATPase, regulates zymogen activation in the acinar cell18 and an acid challenge
sensitizes the pancreatic acinar cell to secretagogue-induced zymogen activation and injury.19 All of these observations would suggest that lactate, at concentrations that reduce pH or lead to supraphysiologic lactate concentrations, would have a negative effect on the disease onset or severity. However, the experimental concentrations used by Hoque et al5 would only result in lactate levels of 0.3 mmol/L, which are well within the physiologic range and therefore unlikely to affect pH or have pathologic effects. Beside its role in NF-kB and IL-1b activation, the NRLP3 pathway is closely involved in another essential pathophysiologic mechanism such as the cellular calcium homeostasis. Full activation of the NRLP3 inflammasome requires decreased extracellular Kþ concentrations resulting in decreased osmotic pressure with cell swelling. Cell swelling, in turn, induces a regulatory volume decrease response through transient receptor potential cation channels (TRPM2/7 and TRPV2) that trigger intracellular Caþþ mobilization.20 The mobilized Caþþ has many molecular targets including, in the pancreas, the premature activation of proteases, a hallmark of pancreatitis. Whether a NRLP3 inflammasome triggered disease mechanism and its lactateinduced, GPR81-mediated down-regulation is operative in
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the acinar cell itself is presently unknown. The study of Hoque et al5 have shown this regulation to apply to inflammatory cell, specifically macrophages/monocytes, and the required protein machinery may not be expressed in the epithelial cells of the liver or pancreas. In both models investigated, the co-stimulatory signal for activation of the inflammasome was LPS. However, acute pancreatitis and hepatitis, at least in the initiating phase where fluid resuscitation with Ringer lactate is clinically indicated, are considered to be sterile, that is, non-bacterial, inflammatory processes. Although previous clinical trials suggest that treatment with Ringer lactate is beneficial in this early disease phase and can reduce the systemic proinflammatory response,4 it would be interesting learn whether disease models of pancreatitis and hepatitis, that do not require bacterial LPS as co-stimulatory signal, also benefit from a lactate GPR81–mediated inhibition of the NLPR3 inflammasome. If this were the case, the pathophysiologic basis for the clinical use of Ringer lactate would be even sounder. At present, Paracelsus’ principle that “the dose makes the poison” remains a consideration for the clinical use of Ringer lactate in patients with liver and pancreatic diseases. The hepatotoxic properties of lactate in animal models and the caveats from clinical trials that seem to confirm this potentially negative effect in liver disease21 warrants some caution. In the absence of data from controlled trials and in light of the study by Hoque et al5 a current recommendation would encourage the use of Ringer lactate solution where rapid fluid replacement is required in inflammatory disease of the liver and pancreas. After the initial disease phase and before serum lactate levels rise above physiologic levels or the pH is reduced, the fluid replacement should probably be continued with other crystalloids to avoid impairing liver function and disturbed coagulation. Hoque et al5 have given us a much better understanding of how lactate works, through which mechanisms it transmits its anti-inflammatory function in monocytes, and why inflammatory disorders of the liver and pancreas may benefit from its clinical use. MARKUS M. LERCH Department of Medicine A Ernst-Moritz-Arndt-University Greifswald Greifswald, Germany DARWIN L. CONWELL Pancreatic Disease Centre University of Ohio Columbus, Ohio
2.
3. 4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
JULIA MAYERLE Department of Medicine A Ernst-Moritz-Arndt-University Greifswald Greifswald, Germany
References
15.
16.
1. Samuvel DJ, Sundararaj KP, Nareika A, et al. Lactate boosts TLR4 signaling and NF-kappaB pathway-mediated gene transcription in macrophages via monocarboxylate
transporters and MD-2 up-regulation. J Immunol 2009; 182:2476–2484. Nareika A, He L, Game BA, et al. Sodium lactate increases LPS-stimulated MMP and cytokine expression in U937 histiocytes by enhancing AP-1 and NF-kappaB transcriptional activities. Am J Physiol Endocrinol Metab 2005;289:E534–E542. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology 2013;13:e1–e15. Wu BU, Hwang JQ, Gardner TH, et al. Lactated Ringer’s solution reduces systemic inflammation compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol 2011;9:710–717.e1. Hoque R, Farooq A, Ghani A, et al. Lactate reduces organ injury in Toll-like receptor- and inflammasomemediated inflammation via GPR81-mediated suppression of innate immunity. Gastroenterology 2014. 000: 000–000. Perides G, Weiss ER, Michael ES, et al. TNF-alphadependent regulation of acute pancreatitis severity by Ly-6C(hi) monocytes in mice. J Biol Chem 2011; 286:13327–13335. Sendler M, Dummer A, Weiss FU, et al. Tumour necrosis factor alpha secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice. Gut 2013;62:430–439. Cai TQ, Ren N, Jin L, et al. Role of GPR81 in lactatemediated reduction of adipose lipolysis. Biochem Biophys Res Commun 2008;377:987–991. Neuhofer P, Liang S, Einwachter H, et al. Deletion of IkappaBalpha activates RelA to reduce acute pancreatitis in mice through up-regulation of Spi2A. Gastroenterology 2013;144:192–201. Sharif R, Dawra R, Wasiluk K, et al. Impact of toll-like receptor 4 on the severity of acute pancreatitis and pancreatitis-associated lung injury in mice. Gut 2009;58: 813–819. Szabo G, Mandrekar P, Oak S, et al. Effect of ethanol on inflammatory responses. Implications for pancreatitis. Pancreatology 2007;7:115–123. Guenther A, Aghdassi A, Muddana V, et al. Toll-like receptor 4 polymorphisms in German and US patients are not associated with occurrence or severity of acute pancreatitis. Gut 2010;59:1154–1155. Marrache F, Tu SP, Bhagat G, et al. Overexpression of interleukin-1beta in the murine pancreas results in chronic pancreatitis. Gastroenterology 2008;135: 1277–1287. Kruger B, Lerch MM, Tessenow W. Direct detection of premature protease activation in living pancreatic acinar cells. Lab Invest 1998;78:763–764. Hirano T, Saluja A, Ramarao P, et al. Apical secretion of lysosomal enzymes in rabbit pancreas occurs via a secretagogue regulated pathway and is increased after pancreatic duct obstruction. J Clin Invest 1991;87: 865–869. Halangk W, Lerch MM, Brandt-Nedelev B, et al. Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis. J Clin Invest 2000;106: 773–781.
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17. Lerch MM, Saluja AK, Dawra R, et al. The effect of chloroquine administration on two experimental models of acute pancreatitis. Gastroenterology 1993; 104:1768–1779. 18. Gorelick FS, Shugrue CA, Kolodecik TR, et al. Vacuolar adenosine triphosphatase and pancreatic acinar cell function. J Gastroenterol Hepatol 2006;21(Suppl 3): S18–S21. 19. Bhoomagoud M, Jung T, Atladottir J, et al. Reducing extracellular pH sensitizes the acinar cell to secretagogue-induced pancreatitis responses in rats. Gastroenterology 2009;137:1083–1092. 20. Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat Rev Immunol 2013;13:397–411.
21. Karmaniolou II, Theodoraki KA, Orfanos NF, et al. 417 Resuscitation after hemorrhagic shock: the effect on the 418 liver–a review of experimental data. J Anesth 2013;27: 419 447–460. Reprint requests Markus M. Lerch, MD, FRCP, Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruchstrasse, 17475 Greifswald. e-mail: [email protected]. Conflicts of interest The authors disclose no conflicts. © 2014 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2014.04.025
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The Anti-Inflammasome Effect of Lactate and the Lactate GPR81-Receptor in Pancreatic and Liver Inflammation See “Lactate reduces organ injury in Toll-like receptorand inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity,” by Hoque R, Farooq A, Ghani A, et al, on page 000.
W
hen organ injury occurs in the absence of an adequate oxygen supply, the glucose metabolism for energy generation is diverted to lactate, rather than pyruvate, and serum lactate levels rise. Any clinician regards this as an ominous sign for the patient’s prognosis and suspect behind rising lactate levels organ ischemia or microcirculatory failure of some sort. He or she will also be aware that this is often paralleled by progressive acidification (a falling pH) and systemic inflammation. Recent cell biological studies have, indeed, suggested that lactate has a direct pro-inflammatory effect on the Toll-like receptor (TLR)/nuclear factor (NF)-kB/inflammasome signaling cascade that ultimately drives systemic inflammation via the activation of interleukin (IL)–1b.1,2 Acute liver injury and acute pancreatitis are often associated with significant fluid loss into the interstitial space and affected patients accordingly require large intravenous fluid volumes for replacement.3 For pancreatitis, a recent randomized clinical trial has unequivocally shown that Ringer lactate solution is much superior to saline infusion when used as a fluid replacement therapy.4 This seems to contradict the first statement on the negative role and harmful effects of lactate in systemic inflammation and organ failure. Hoque et al5 now provide an explanation for this apparent paradox in an elegant experimental study in this issue of Gastroenterology. They focused their investigation on macrophages/monocytes, which are known to be critically involved in liver and pancreatic inflammation6,7 and used animal disease models for hepatitis (lipopolysaccharide [LPS] and D-galactosamine) and pancreatitis (LPS and cerulean) to test their hypothesis that lactate has anti-inflammatory effects and mediates them through a recently discovered lactate receptor, the plasma membrane Gi protein-coupled receptor 81 (GPR81).8 The authors found that low concentrations of lactate reduce organ injury in both disease models via binding to GPR81. In vitro and in vivo they could show that lactate signaling in macrophages/monocytes is dependent on GPR81 and its adaptor protein ARRB2, and that small interfering RNA blockage of the expression of either protein can regulate this process. Moreover, through this signaling pathway lactate directly inhibited the action of the NLRP3 inflammasome, which is activated via TLR-4 and the action of caspase 1. The consequences were a reduced NF-kB action and diminished conversion of pro–IL-1b to active IL-1b—with a significant beneficial effect on disease severity
in both models. Simply put: Lacate at physiologic concentrations is a terrific anti-inflammatory agent and one with proven efficiency not only in human disease but also in experimental models of inflammation. This study is intriguing for several reasons. For acute pancreatitis and acute hepatitis, the early impact of inflammatory cell activation has recently been highlighted and macrophages seem to play a critical role in the disease initiation and severity.6,7,9 To activate the NLRP3 inflammasome, a 2-checkpoint model of priming and activation has been proposed in which TLR-4 (or TLR-9) represent the second checkpoint. Although the role of TLRs in bacterial infection is unequivocal, research continues on its importance for sterile inflammation, such as the early phase of pancreatitis.10–12 The net effect of NLRP3 inflammasome activation is the proteolytic cleavage and activation of the strongly pro-inflammatory cytokine IL-1b, which regulates most of the systemic inflammatory response syndrome. Constitutive overexpression of IL-1b in the pancreas alone was found to be sufficient to induce spontaneous pancreatitis.13 Reducing the action of the NLRP3 inflammasome would therefore be expected to have a beneficial effect on either the onset or the severity of the disease. Inflammasomes assemble to key signaling platforms that detect pathogenic microorganisms and sterile stressors before leading to downstream activation of IL-1b. The 2step model of priming and activation of the canonical NLRP3 inflammasome predicts that the basal expression of its components is insufficient for its activation in resting cells. An initial activating signal transmitted via pattern recognition receptor on the cell surface results in upregulation of the NLRP3 components and represents the priming reaction. Only thereafter can the NLRP3 inflammasome be activated via LPS stimulation of its receptor, the TLR-4, which then induces activation of TRIF, the binding of NLRP3 to ASC, and the subsequent caspase 1–dependent induction of pro–IL-b1 expression and its activation. Although LPS-stimulated TLR-4 activation is probably the best investigated mechanisms of NLRP3 inflammasome activation, other mechanisms involving bacterial membrane components, the release of cathepsin B from lysosomes, low potassium levels, high intracellular calcium concentrations, or the release of reactive oxygen species from mitochondria have all been implicated in this process (Figure 1). Lactate has long been regarded as critical for energy (ATP) generation when oxygen is in short supply (anaerobic glycolysis) and rising levels in the blood were regarded as an early sign of microcirculatory failure. It was only recently discovered that lactate is also a signaling molecule and a ligand for a dedicated lactate receptor.8 The GPR81 is a 7-transmembrane receptor and binding of lactate leads to recruitment of the intracellular adaptor ARRB2 before downstream signaling is
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print & web 4C=FPO
EDITORIAL
Figure 1. Blockage of NLRP3 inflammasome activation via Gi protein-coupled receptor 81 (GPR81). Inflammasomes are key signaling platforms for the detection of pathogenic microorganisms and sterile stressors leading to activation of the highly proinflammatory cytokine interleukin (IL)-1b. Activation of the canonical NLRP3 inflammasome has been proposed to act according to a 2-checkpoint model of priming and activation. Initially, an activating signal transmitted via pattern recognition receptor (PRR) on the cell surface results in NLRP3 up-regulation as a priming reaction. Thereafter Tool-like receptor (TLR)-4 is activated by lipopolysaccharide, which leads to activation of TRIF and binding of NLRP3 to ASC. Subsequently, pro–IL-b1 expression is upregulated and activated via caspase 1. There are several other stimuli involved in the activation of NLRP3, such as bacterial membrane components, cathepsin B release from lysosomes, low potassium levels, high calcium levels, or reactive oxygen species (ROS) release from mitochondria. The specific ligand of the plasma membrane GPR81, a 7-transmembrane receptor, is lactate. Binding of lactate recruits the intracellular adaptor molecule ARRB2 to the receptor and subsequent inhibition of the NLRP3 inflammasome with a reduction of the IL-b–mediated pro-inflammatory response. NF-kB, nuclear factor-kB.
transmitted. From Hoque et al,5 we learn that this signal ultimately reduces the activation of the NLRP3 inflammasome, with all its beneficial effects on macrophages/monocytes and 2 experimental inflammatory diseases of the liver and pancreas. The exact mechanism through which GPR81 and ARRB2 counteract the NLRP3 and TLR pathways is currently unknown (Figure 1) will require further study. Lactate possesses several chemical and metabolic effects outside this signaling cascade and these include a reduction in pH. A lower pH, on the other hand, could have several unwanted consequences as far as the pancreas is concerned: The pancreatic acinar cell stores its proteases in acidic secretory vesicles and when pancreatitis is induced the pH in intracellular compartment becomes more acidic and a premature protease activation begins.14 For this premature intracellular protease activation, 2 mechanisms have been proposed and involve trypsinogen activation by cathepsin B or trypsinogen autoactivation, both of which are pH dependent.15,16 Chloroquine, an agent that raises the intracellular pH, reduces premature zymogen activation and ameliorates the course of experimental pancreatitis.17 A proton pump, the vacuolar ATPase, regulates zymogen activation in the acinar cell18 and an acid challenge
sensitizes the pancreatic acinar cell to secretagogue-induced zymogen activation and injury.19 All of these observations would suggest that lactate, at concentrations that reduce pH or lead to supraphysiologic lactate concentrations, would have a negative effect on the disease onset or severity. However, the experimental concentrations used by Hoque et al5 would only result in lactate levels of 0.3 mmol/L, which are well within the physiologic range and therefore unlikely to affect pH or have pathologic effects. Beside its role in NF-kB and IL-1b activation, the NRLP3 pathway is closely involved in another essential pathophysiologic mechanism such as the cellular calcium homeostasis. Full activation of the NRLP3 inflammasome requires decreased extracellular Kþ concentrations resulting in decreased osmotic pressure with cell swelling. Cell swelling, in turn, induces a regulatory volume decrease response through transient receptor potential cation channels (TRPM2/7 and TRPV2) that trigger intracellular Caþþ mobilization.20 The mobilized Caþþ has many molecular targets including, in the pancreas, the premature activation of proteases, a hallmark of pancreatitis. Whether a NRLP3 inflammasome triggered disease mechanism and its lactateinduced, GPR81-mediated down-regulation is operative in
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the acinar cell itself is presently unknown. The study of Hoque et al5 have shown this regulation to apply to inflammatory cell, specifically macrophages/monocytes, and the required protein machinery may not be expressed in the epithelial cells of the liver or pancreas. In both models investigated, the co-stimulatory signal for activation of the inflammasome was LPS. However, acute pancreatitis and hepatitis, at least in the initiating phase where fluid resuscitation with Ringer lactate is clinically indicated, are considered to be sterile, that is, non-bacterial, inflammatory processes. Although previous clinical trials suggest that treatment with Ringer lactate is beneficial in this early disease phase and can reduce the systemic proinflammatory response,4 it would be interesting learn whether disease models of pancreatitis and hepatitis, that do not require bacterial LPS as co-stimulatory signal, also benefit from a lactate GPR81–mediated inhibition of the NLPR3 inflammasome. If this were the case, the pathophysiologic basis for the clinical use of Ringer lactate would be even sounder. At present, Paracelsus’ principle that “the dose makes the poison” remains a consideration for the clinical use of Ringer lactate in patients with liver and pancreatic diseases. The hepatotoxic properties of lactate in animal models and the caveats from clinical trials that seem to confirm this potentially negative effect in liver disease21 warrants some caution. In the absence of data from controlled trials and in light of the study by Hoque et al5 a current recommendation would encourage the use of Ringer lactate solution where rapid fluid replacement is required in inflammatory disease of the liver and pancreas. After the initial disease phase and before serum lactate levels rise above physiologic levels or the pH is reduced, the fluid replacement should probably be continued with other crystalloids to avoid impairing liver function and disturbed coagulation. Hoque et al5 have given us a much better understanding of how lactate works, through which mechanisms it transmits its anti-inflammatory function in monocytes, and why inflammatory disorders of the liver and pancreas may benefit from its clinical use. MARKUS M. LERCH Department of Medicine A Ernst-Moritz-Arndt-University Greifswald Greifswald, Germany DARWIN L. CONWELL Pancreatic Disease Centre University of Ohio Columbus, Ohio
2.
3. 4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
JULIA MAYERLE Department of Medicine A Ernst-Moritz-Arndt-University Greifswald Greifswald, Germany
References
15.
16.
1. Samuvel DJ, Sundararaj KP, Nareika A, et al. Lactate boosts TLR4 signaling and NF-kappaB pathway-mediated gene transcription in macrophages via monocarboxylate
transporters and MD-2 up-regulation. J Immunol 2009; 182:2476–2484. Nareika A, He L, Game BA, et al. Sodium lactate increases LPS-stimulated MMP and cytokine expression in U937 histiocytes by enhancing AP-1 and NF-kappaB transcriptional activities. Am J Physiol Endocrinol Metab 2005;289:E534–E542. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology 2013;13:e1–e15. Wu BU, Hwang JQ, Gardner TH, et al. Lactated Ringer’s solution reduces systemic inflammation compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol 2011;9:710–717.e1. Hoque R, Farooq A, Ghani A, et al. Lactate reduces organ injury in Toll-like receptor- and inflammasomemediated inflammation via GPR81-mediated suppression of innate immunity. Gastroenterology 2014. 000: 000–000. Perides G, Weiss ER, Michael ES, et al. TNF-alphadependent regulation of acute pancreatitis severity by Ly-6C(hi) monocytes in mice. J Biol Chem 2011; 286:13327–13335. Sendler M, Dummer A, Weiss FU, et al. Tumour necrosis factor alpha secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice. Gut 2013;62:430–439. Cai TQ, Ren N, Jin L, et al. Role of GPR81 in lactatemediated reduction of adipose lipolysis. Biochem Biophys Res Commun 2008;377:987–991. Neuhofer P, Liang S, Einwachter H, et al. Deletion of IkappaBalpha activates RelA to reduce acute pancreatitis in mice through up-regulation of Spi2A. Gastroenterology 2013;144:192–201. Sharif R, Dawra R, Wasiluk K, et al. Impact of toll-like receptor 4 on the severity of acute pancreatitis and pancreatitis-associated lung injury in mice. Gut 2009;58: 813–819. Szabo G, Mandrekar P, Oak S, et al. Effect of ethanol on inflammatory responses. Implications for pancreatitis. Pancreatology 2007;7:115–123. Guenther A, Aghdassi A, Muddana V, et al. Toll-like receptor 4 polymorphisms in German and US patients are not associated with occurrence or severity of acute pancreatitis. Gut 2010;59:1154–1155. Marrache F, Tu SP, Bhagat G, et al. Overexpression of interleukin-1beta in the murine pancreas results in chronic pancreatitis. Gastroenterology 2008;135: 1277–1287. Kruger B, Lerch MM, Tessenow W. Direct detection of premature protease activation in living pancreatic acinar cells. Lab Invest 1998;78:763–764. Hirano T, Saluja A, Ramarao P, et al. Apical secretion of lysosomal enzymes in rabbit pancreas occurs via a secretagogue regulated pathway and is increased after pancreatic duct obstruction. J Clin Invest 1991;87: 865–869. Halangk W, Lerch MM, Brandt-Nedelev B, et al. Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis. J Clin Invest 2000;106: 773–781.
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17. Lerch MM, Saluja AK, Dawra R, et al. The effect of chloroquine administration on two experimental models of acute pancreatitis. Gastroenterology 1993; 104:1768–1779. 18. Gorelick FS, Shugrue CA, Kolodecik TR, et al. Vacuolar adenosine triphosphatase and pancreatic acinar cell function. J Gastroenterol Hepatol 2006;21(Suppl 3): S18–S21. 19. Bhoomagoud M, Jung T, Atladottir J, et al. Reducing extracellular pH sensitizes the acinar cell to secretagogue-induced pancreatitis responses in rats. Gastroenterology 2009;137:1083–1092. 20. Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat Rev Immunol 2013;13:397–411.
21. Karmaniolou II, Theodoraki KA, Orfanos NF, et al. 417 Resuscitation after hemorrhagic shock: the effect on the 418 liver–a review of experimental data. J Anesth 2013;27: 419 447–460. Reprint requests Markus M. Lerch, MD, FRCP, Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruchstrasse, 17475 Greifswald. e-mail: [email protected]. Conflicts of interest The authors disclose no conflicts. © 2014 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2014.04.025
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