Free Radical Biology and Medicine 81 (2015) 156–157
Contents lists available at ScienceDirect
Free Radical Biology and Medicine journal homepage: www.elsevier.com/locate/freeradbiomed
Commentary
Commentary on “Pancreatic ascites hemoglobin contributes to the systemic response in acute pancreatitis” Daniel Closa Department of Experimental Pathology, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Instituto de Investigaciones Biomedicas de Barcelona, Consejo Superior de Investigaciones Cientificas, 08036 Barcelona, Spain
Hemoglobin (Hb) is one of the most important proteins in human physiology, with a pivotal role in the delivery of oxygen and removal of carbon dioxide. Under normal resting conditions, its primary role is to bind oxygen or carbon monoxide reversibly. However, it has long been known that cell-free plasma hemoglobin is a pathogenic factor with relevant vasoactive and redox activities, thus becoming an important endogenous damageassociated molecular pattern [1]. Extracellular Hb becomes a biologically relevant active protein through various mechanisms. The reactive ferric protoporphyrinIX group (hemin) released from Hb is a ligand for nuclear hormone receptors, such as REV-ERB [2]; it could also bind to the transcriptional repressor Bach-1, which regulates the expression of various antioxidant enzymes [3], and finally, it could activate the Toll-like receptor 4 inflammatory pathway [4]. Another important pathogenic mechanism involved in the toxicity of free Hb is the ability to generate free radicals, including superoxide anion (O2 ), hydroxyl radical (OH), ferryl heme radical, and ferryl protein radical, and other reactive derivatives such as lipid peroxides owing to its peroxidase activity [5]. Another effect related to the redox activity of Hb is the depletion of NO that could trigger an acute hypertensive response [6]. There are a number of mechanisms that evolved to control the effects of extracellular Hb released into the plasma. Haptoglobin (Hp) is an acute-phase protein that shows a high affinity toward Hb, resulting in the formation of the Hp–Hb complex. This complex is then removed from the circulation by CD163-positive macrophages in a process that contributes to the recycling of iron and also reduces the inflammatory response [7]. The protective mechanisms are useful to maintain the potential damaging effects of free Hb under physiological conditions. However, there are a number of pathological situations in which the release of free hemoglobin exceeds the buffering capacity of the organism. These include hemolytic anemias, transfusions, preeclampsia, intraventricular hemorrhage, and malaria [5]. The paper in this issue of Free Radical Biology & Medicine entitled “Pancreatic ascites hemoglobin contributes to the systemic response in acute pancreatitis,” by Pérez and colleagues [8],
E-mail address: [email protected] http://dx.doi.org/10.1016/j.freeradbiomed.2014.09.029 0891-5849/& 2014 Elsevier Inc. All rights reserved.
provides evidence that free Hb also is involved in the pathogenesis of severe acute pancreatitis. Using an experimental model of bile salt-induced pancreatitis in rats, the authors demonstrate the hemolytic capacity of the ascitic fluid generated in the early stages of the disease. Removing the ascitic fluid with a peritoneal lavage, they prevented the increase in circulating free Hb, peroxidase activity, and hemin levels. Data presented indicate that free Hb is involved in the induction of lung inflammation and upregulation of various hypoxiainducible factor-related genes, including ho-1, inos, enos, and hexokinase 2. Interestingly, ho-1 was also induced in liver by the action of free Hb. Finally, fat necrosis, a characteristic feature of severe pancreatitis, was significantly increased by the action of free Hb. Severe acute pancreatitis is characterized by the progression of the inflammatory process to distant organs, particularly the lungs [9]. The mechanism that links the local inflammation in pancreas and its effects on distant organs has been the object of intense research for a long time. The initial concept of self-digestive pathology soon was proven insufficient to explain the range of phenomena associated with acute pancreatitis. In addition, the use of hydrolase inhibitors was revealed to be unable to halt the progression of the disease [10]. In the past decades the focus of research has moved to inflammatory mediators, oxygen-derived free radicals, and lipid mediators [11–13], but none of these agents was able to explain by itself the broad spectrum of systemic deleterious effects triggered by the pancreatic damage. Circulating free Hb during acute pancreatitis could help answer a number of questions that remained elusive. The involvement of free radicals was pointed out by the initial work of Sanfey in the 1980s [14,15]. Since then, xanthine oxidase [16], circulating neutrophils [17], nitric oxide synthase [18], and depletion of superoxide dismutase [19] and glutathione [20] have been suggested as potential triggers of oxidative stress, but the final source remains unclear. Although the study by Pérez et al. [8] does not address this question directly, its findings strongly suggest a pivotal role as a source of oxidant stress for free Hb. On the other hand, there are substantial differences between the various experimental models of acute pancreatitis. Taurocholateinduced pancreatitis is characterized by a strong hemorrhagic process mimicking the most severe forms of biliary pancreatitis in human
D. Closa / Free Radical Biology and Medicine 81 (2015) 156–157
patients. The involvement of free Hb in other models, such as ceruleininduced pancreatitis, in which the hemorrhage is not a main feature, remains an open question. In conclusion, the current study [8] provides new information about the link between local pancreatic damage and the subsequent systemic inflammatory response, providing direct evidence on the role of free Hb in the pathogenesis of acute pancreatitis. References [1] Reeder, B. J. The redox activity of hemoglobins: from physiologic functions to pathologic mechanisms. Antioxid. Redox Signaling 13:1087–1123; 2010. [2] Raghuram, S.; Stayrook, K. R.; Huang, P.; Rogers, P. M.; Nosie, A. K.; McClure, D. B.; Burris, L. L.; Khorasanizadeh, S.; Burris, T. P.; Rastinejad, F. Identification of heme as the ligand for the orphan nuclear receptors REVERBalpha and REV-ERBbeta. Nat. Struct. Mol. Biol. 14:1207–1213; 2007. [3] Ogawa, K.; Sun, J.; Taketani, S.; Nakajima, O.; Nishitani, C.; Sassa, S.; Hayashi, N.; Yamamoto, M.; Shibahara, S.; Fujita, H.; Igarashi, K. Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1. EMBO J. 20:2835–2843; 2001. [4] Figueiredo, R. T.; Fernandez, P. L.; Mourao-Sa, D. S.; Porto, B. N.; Dutra, F. F.; Alves, L. S.; Oliveira, M. F.; Oliveira, P. L.; Graça-Souza, A. V.; Bozza, M. T. Characterization of heme as activator of Toll-like receptor 4. J. Biol. Chem. 282:20221–20229; 2007. [5] Olsson, M. G.; Allhorn, M.; Bülow, L.; Hansson, S. R.; Ley, D.; Olsson, M. L.; Schmidtchen, A.; Akerström, B. Pathological conditions involving extracellular hemoglobin: molecular mechanisms, clinical significance, and novel therapeutic opportunities for α(1)-microglobulin. Antioxid. Redox Signaling 17: 813–846; 2012. [6] Doherty, D. H.; Doyle, M. P.; Curry, S. R.; Vali, R. J.; Fattor, T. J.; Olson, J. S.; Lemon, D. D. Rate of reaction with nitric oxide determines the hypertensive effect of cell-free hemoglobin. Nat. Biotechnol. 16:672–676; 1998. [7] Alayash, A. I. Haptoglobin: old protein with new functions. Clin. Chim. Acta 412:493–498; 2011. [8] Pérez, S.; Pereda, J.; Sabater, L.; Sastre, J. Pancreatic ascites hemoglobin contributes to the systemic response in acute pancreatitis. Free Radic. Biol. Med. ; 2014. (in press).
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[9] Bhatia, M.; Wong, F. L.; Cao, Y.; Lau, H. Y.; Huang, J.; Puneet, P.; Chevali, L. Pathophysiology of acute pancreatitis. Pancreatology 5:132–144; 2005. [10] Smith, M.; Kocher, H. M.; Hunt, B. J. Aprotinin in severe acute pancreatitis. Int. J. Clin. Pract. 64:84–92; 2010. [11] Saluja, A. K.; Steer, M. L. Pathophysiology of pancreatitis: role of cytokines and other mediators of inflammation. Digestion 60(Suppl. 1):27–33; 1999. [12] Steer, M. L.; Rutledge, P. L.; Powers, R. E.; Saluja, M.; Saluja, A. K. The role of oxygen-derived free radicals in two models of experimental acute pancreatitis: effects of catalase, superoxide dismutase, dimethylsulfoxide, and allopurinol. Klin. Wochenschr. 69:1012–1017; 1991. [13] Navina, S.; Acharya, C.; DeLany, J. P.; Orlichenko, L. S.; Baty, C. J.; Shiva, S. S.; Durgampudi, C.; Karlsson, J. M.; Lee, K.; Bae, K. T.; Furlan, A.; Behari, J.; Liu, S.; McHale, T.; Nichols, L.; Papachristou, G. I.; Yadav, D.; Singh, V. P. Lipotoxicity causes multisystem organ failure and exacerbates acute pancreatitis in obesity. Sci. Transl. Med. 3; 2011. (107ra110). [14] Sanfey, H.; Bulkley, G. B.; Cameron, J. L. The role of oxygen-derived free radicals in the pathogenesis of acute pancreatitis. Ann. Surg. 200:405–413; 1984. [15] Sanfey, H.; Bulkley, G. B.; Cameron, J. L. The pathogenesis of acute pancreatitis: the source and role of oxygen-derived free radicals in three different experimental models. Ann. Surg. 201:633–639; 1985. [16] Closa, D.; Bulbena, O.; Hotter, G.; Roselló-Catafau, J.; Fernández-Cruz, L.; Gelpí, E. Xanthine oxidase activation in cerulein- and taurocholate-induced acute pancreatitis in rats. Arch. Int. Physiol. Biochim. Biophys. 102: 167–170. [17] Guice, K. S.; Oldham, K. T.; Caty, M. G.; Johnson, K. J.; Ward, P. A. Neutrophildependent, oxygen-radical mediated lung injury associated with acute pancreatitis. Ann. Surg. 210:740–747; 1989. [18] Hegyi, P.; Rakonczay, Z. The role of nitric oxide in the physiology and pathophysiology of the exocrine pancreas. Antioxid. Redox Signaling 15: 2723–2741; 2011. [19] Closa, D.; Bulbena, O.; Rosello-Catafau, J.; Fernandez-Cruz, L.; Gelpi, E. Effect of prostaglandins and superoxide dismutase administration on oxygen free radical production in experimental acute pancreatitis. Inflammation 17: 563–571; 1993. [20] Gómez-Cambronero, L.; Camps, B.; de La Asunción, J. G.; Cerdá, M.; Pellín, A.; Pallardó, F. V.; Calvete, J.; Sweiry, J. H.; Mann, G. E.; Viña, J.; Sastre, J. Pentoxifylline ameliorates cerulein-induced pancreatitis in rats: role of glutathione and nitric oxide. J. Pharmacol. Exp. Ther. 293:670–676; 2000.
Contents lists available at ScienceDirect
Free Radical Biology and Medicine journal homepage: www.elsevier.com/locate/freeradbiomed
Commentary
Commentary on “Pancreatic ascites hemoglobin contributes to the systemic response in acute pancreatitis” Daniel Closa Department of Experimental Pathology, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Instituto de Investigaciones Biomedicas de Barcelona, Consejo Superior de Investigaciones Cientificas, 08036 Barcelona, Spain
Hemoglobin (Hb) is one of the most important proteins in human physiology, with a pivotal role in the delivery of oxygen and removal of carbon dioxide. Under normal resting conditions, its primary role is to bind oxygen or carbon monoxide reversibly. However, it has long been known that cell-free plasma hemoglobin is a pathogenic factor with relevant vasoactive and redox activities, thus becoming an important endogenous damageassociated molecular pattern [1]. Extracellular Hb becomes a biologically relevant active protein through various mechanisms. The reactive ferric protoporphyrinIX group (hemin) released from Hb is a ligand for nuclear hormone receptors, such as REV-ERB [2]; it could also bind to the transcriptional repressor Bach-1, which regulates the expression of various antioxidant enzymes [3], and finally, it could activate the Toll-like receptor 4 inflammatory pathway [4]. Another important pathogenic mechanism involved in the toxicity of free Hb is the ability to generate free radicals, including superoxide anion (O2 ), hydroxyl radical (OH), ferryl heme radical, and ferryl protein radical, and other reactive derivatives such as lipid peroxides owing to its peroxidase activity [5]. Another effect related to the redox activity of Hb is the depletion of NO that could trigger an acute hypertensive response [6]. There are a number of mechanisms that evolved to control the effects of extracellular Hb released into the plasma. Haptoglobin (Hp) is an acute-phase protein that shows a high affinity toward Hb, resulting in the formation of the Hp–Hb complex. This complex is then removed from the circulation by CD163-positive macrophages in a process that contributes to the recycling of iron and also reduces the inflammatory response [7]. The protective mechanisms are useful to maintain the potential damaging effects of free Hb under physiological conditions. However, there are a number of pathological situations in which the release of free hemoglobin exceeds the buffering capacity of the organism. These include hemolytic anemias, transfusions, preeclampsia, intraventricular hemorrhage, and malaria [5]. The paper in this issue of Free Radical Biology & Medicine entitled “Pancreatic ascites hemoglobin contributes to the systemic response in acute pancreatitis,” by Pérez and colleagues [8],
E-mail address: [email protected] http://dx.doi.org/10.1016/j.freeradbiomed.2014.09.029 0891-5849/& 2014 Elsevier Inc. All rights reserved.
provides evidence that free Hb also is involved in the pathogenesis of severe acute pancreatitis. Using an experimental model of bile salt-induced pancreatitis in rats, the authors demonstrate the hemolytic capacity of the ascitic fluid generated in the early stages of the disease. Removing the ascitic fluid with a peritoneal lavage, they prevented the increase in circulating free Hb, peroxidase activity, and hemin levels. Data presented indicate that free Hb is involved in the induction of lung inflammation and upregulation of various hypoxiainducible factor-related genes, including ho-1, inos, enos, and hexokinase 2. Interestingly, ho-1 was also induced in liver by the action of free Hb. Finally, fat necrosis, a characteristic feature of severe pancreatitis, was significantly increased by the action of free Hb. Severe acute pancreatitis is characterized by the progression of the inflammatory process to distant organs, particularly the lungs [9]. The mechanism that links the local inflammation in pancreas and its effects on distant organs has been the object of intense research for a long time. The initial concept of self-digestive pathology soon was proven insufficient to explain the range of phenomena associated with acute pancreatitis. In addition, the use of hydrolase inhibitors was revealed to be unable to halt the progression of the disease [10]. In the past decades the focus of research has moved to inflammatory mediators, oxygen-derived free radicals, and lipid mediators [11–13], but none of these agents was able to explain by itself the broad spectrum of systemic deleterious effects triggered by the pancreatic damage. Circulating free Hb during acute pancreatitis could help answer a number of questions that remained elusive. The involvement of free radicals was pointed out by the initial work of Sanfey in the 1980s [14,15]. Since then, xanthine oxidase [16], circulating neutrophils [17], nitric oxide synthase [18], and depletion of superoxide dismutase [19] and glutathione [20] have been suggested as potential triggers of oxidative stress, but the final source remains unclear. Although the study by Pérez et al. [8] does not address this question directly, its findings strongly suggest a pivotal role as a source of oxidant stress for free Hb. On the other hand, there are substantial differences between the various experimental models of acute pancreatitis. Taurocholateinduced pancreatitis is characterized by a strong hemorrhagic process mimicking the most severe forms of biliary pancreatitis in human
D. Closa / Free Radical Biology and Medicine 81 (2015) 156–157
patients. The involvement of free Hb in other models, such as ceruleininduced pancreatitis, in which the hemorrhage is not a main feature, remains an open question. In conclusion, the current study [8] provides new information about the link between local pancreatic damage and the subsequent systemic inflammatory response, providing direct evidence on the role of free Hb in the pathogenesis of acute pancreatitis. References [1] Reeder, B. J. The redox activity of hemoglobins: from physiologic functions to pathologic mechanisms. Antioxid. Redox Signaling 13:1087–1123; 2010. [2] Raghuram, S.; Stayrook, K. R.; Huang, P.; Rogers, P. M.; Nosie, A. K.; McClure, D. B.; Burris, L. L.; Khorasanizadeh, S.; Burris, T. P.; Rastinejad, F. Identification of heme as the ligand for the orphan nuclear receptors REVERBalpha and REV-ERBbeta. Nat. Struct. Mol. Biol. 14:1207–1213; 2007. [3] Ogawa, K.; Sun, J.; Taketani, S.; Nakajima, O.; Nishitani, C.; Sassa, S.; Hayashi, N.; Yamamoto, M.; Shibahara, S.; Fujita, H.; Igarashi, K. Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1. EMBO J. 20:2835–2843; 2001. [4] Figueiredo, R. T.; Fernandez, P. L.; Mourao-Sa, D. S.; Porto, B. N.; Dutra, F. F.; Alves, L. S.; Oliveira, M. F.; Oliveira, P. L.; Graça-Souza, A. V.; Bozza, M. T. Characterization of heme as activator of Toll-like receptor 4. J. Biol. Chem. 282:20221–20229; 2007. [5] Olsson, M. G.; Allhorn, M.; Bülow, L.; Hansson, S. R.; Ley, D.; Olsson, M. L.; Schmidtchen, A.; Akerström, B. Pathological conditions involving extracellular hemoglobin: molecular mechanisms, clinical significance, and novel therapeutic opportunities for α(1)-microglobulin. Antioxid. Redox Signaling 17: 813–846; 2012. [6] Doherty, D. H.; Doyle, M. P.; Curry, S. R.; Vali, R. J.; Fattor, T. J.; Olson, J. S.; Lemon, D. D. Rate of reaction with nitric oxide determines the hypertensive effect of cell-free hemoglobin. Nat. Biotechnol. 16:672–676; 1998. [7] Alayash, A. I. Haptoglobin: old protein with new functions. Clin. Chim. Acta 412:493–498; 2011. [8] Pérez, S.; Pereda, J.; Sabater, L.; Sastre, J. Pancreatic ascites hemoglobin contributes to the systemic response in acute pancreatitis. Free Radic. Biol. Med. ; 2014. (in press).
157
[9] Bhatia, M.; Wong, F. L.; Cao, Y.; Lau, H. Y.; Huang, J.; Puneet, P.; Chevali, L. Pathophysiology of acute pancreatitis. Pancreatology 5:132–144; 2005. [10] Smith, M.; Kocher, H. M.; Hunt, B. J. Aprotinin in severe acute pancreatitis. Int. J. Clin. Pract. 64:84–92; 2010. [11] Saluja, A. K.; Steer, M. L. Pathophysiology of pancreatitis: role of cytokines and other mediators of inflammation. Digestion 60(Suppl. 1):27–33; 1999. [12] Steer, M. L.; Rutledge, P. L.; Powers, R. E.; Saluja, M.; Saluja, A. K. The role of oxygen-derived free radicals in two models of experimental acute pancreatitis: effects of catalase, superoxide dismutase, dimethylsulfoxide, and allopurinol. Klin. Wochenschr. 69:1012–1017; 1991. [13] Navina, S.; Acharya, C.; DeLany, J. P.; Orlichenko, L. S.; Baty, C. J.; Shiva, S. S.; Durgampudi, C.; Karlsson, J. M.; Lee, K.; Bae, K. T.; Furlan, A.; Behari, J.; Liu, S.; McHale, T.; Nichols, L.; Papachristou, G. I.; Yadav, D.; Singh, V. P. Lipotoxicity causes multisystem organ failure and exacerbates acute pancreatitis in obesity. Sci. Transl. Med. 3; 2011. (107ra110). [14] Sanfey, H.; Bulkley, G. B.; Cameron, J. L. The role of oxygen-derived free radicals in the pathogenesis of acute pancreatitis. Ann. Surg. 200:405–413; 1984. [15] Sanfey, H.; Bulkley, G. B.; Cameron, J. L. The pathogenesis of acute pancreatitis: the source and role of oxygen-derived free radicals in three different experimental models. Ann. Surg. 201:633–639; 1985. [16] Closa, D.; Bulbena, O.; Hotter, G.; Roselló-Catafau, J.; Fernández-Cruz, L.; Gelpí, E. Xanthine oxidase activation in cerulein- and taurocholate-induced acute pancreatitis in rats. Arch. Int. Physiol. Biochim. Biophys. 102: 167–170. [17] Guice, K. S.; Oldham, K. T.; Caty, M. G.; Johnson, K. J.; Ward, P. A. Neutrophildependent, oxygen-radical mediated lung injury associated with acute pancreatitis. Ann. Surg. 210:740–747; 1989. [18] Hegyi, P.; Rakonczay, Z. The role of nitric oxide in the physiology and pathophysiology of the exocrine pancreas. Antioxid. Redox Signaling 15: 2723–2741; 2011. [19] Closa, D.; Bulbena, O.; Rosello-Catafau, J.; Fernandez-Cruz, L.; Gelpi, E. Effect of prostaglandins and superoxide dismutase administration on oxygen free radical production in experimental acute pancreatitis. Inflammation 17: 563–571; 1993. [20] Gómez-Cambronero, L.; Camps, B.; de La Asunción, J. G.; Cerdá, M.; Pellín, A.; Pallardó, F. V.; Calvete, J.; Sweiry, J. H.; Mann, G. E.; Viña, J.; Sastre, J. Pentoxifylline ameliorates cerulein-induced pancreatitis in rats: role of glutathione and nitric oxide. J. Pharmacol. Exp. Ther. 293:670–676; 2000.
