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Role of angiopoietin-2 in infection – A double-edged sword?
Cytokine 83 (2016) 61–63
Contents lists available at ScienceDirect
Cytokine journal homepage: www.journals.elsevier.com/cytokine
Cytokine stimulus
Role of angiopoietin-2 in infection – A double-edged sword? Kristina Thamm, Sascha David ⇑ Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
a r t i c l e
i n f o
Article history: Received 9 March 2016 Received in revised form 25 March 2016 Accepted 25 March 2016
Keywords: Sepsis Angiopoietin-2 Infection Endothelium
a b s t r a c t The endothelial angiopoietin (Angpt)/Tie2 ligand receptor system maintains vascular quiescence and modulates the response to injury. Angpt-1 is considered the natural Tie2 agonist and receptor ligation leads to its phosphorylation inducing various protective downstream pathways. The natural antagonist – Angpt-2 – appears to inhibit these protective effects. In sepsis, the balance between both ligands is shifted in favor for Angpt-2 and the vasculature is highly dysfunctional, activated and leaky. Circulating levels of Angpt-2 strongly predict mortality in septic patients. Consistently, experimental strategies that target Angpt-2 (e.g. antibody, RNAi, etc.) can protect the vascular barrier and improve survival. However, in vitro is has also been shown that Angpt-2 can act as a dose-dependent Tie2 agonist/ antagonist. Based on this, people have wondered if Angpt-2 is per se injurious or if it might have protective effects dependent on the scenario. A recent paper by Safioleas and colleagues showed survival benefits after a therapeutic injection of recombinant Angpt-2 in experimental pyelonephritis. Here, we discuss their counter-intuitive but interesting findings and put them into a global context with respect to the existent literature in the angiopoietin/Tie2 sepsis field. Ó 2016 Elsevier Ltd. All rights reserved.
The angiopoietin (Angpt)/Tie2 system and its contribution to endothelial dysfunction in sepsis has gained increasing interest in recent years. Different groups around the globe have consistently reported that circulating levels of the canonical Tie2 antagonist Angpt-2 dramatically increase cross-species during systemic inflammation whereas the Tie2 agonist Angpt-1 appears to decrease [1–3]. It is reasonable to conclude from the majority of available data that excess release of pre-stored (as well as de novo biosynthesized) Angpt-2 contributes to vascular inflammation and barrier breakdown (reviewed in [4]). Our own group could show that Angpt-2 actively contributes to multiple organ dysfunction and death in sepsis [5]. Consistently, these negative effects were reversible in experimental models of the disease by either supplementing the Tie2 agonist or blocking/depleting the Tie2 antagonist. The current study by Safioleas et al. contributes new controversial knowledge to the field [6]. The authors investigated the role of Angpt-2 in pyelonephritis (PN) both in humans and in an experimental rabbit model. Given that Angpt-2 has been shown to be a dose-dependent partial Tie2 agonist/antagonist the idea to analyze the immune-modulatory therapeutic potential is clever. This concept was further supported by their finding in humans suffering ⇑ Corresponding author at: Medical School Hannover, Department of Nephrology & Hypertension, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. E-mail address: [email protected] (S. David). http://dx.doi.org/10.1016/j.cyto.2016.03.019 1043-4666/Ó 2016 Elsevier Ltd. All rights reserved.
from PN that circulating Angpt-2 correlates reciprocally with lipopolysaccharide (LPS) levels. The authors confirmed this observation in an experimental model of septic PN in rabbits. Animals that received recombinant Angpt-2 as therapeutic strategy showed increased survival and decreased LPS compared to vehicle treated rabbits. This could certainly be an epiphenomenon in the complex multi-cellular in vivo situation. However, Safioleas and coworkers performed an interesting mechanistic experiment by challenging immune cells isolated from rabbits with PN with TNFa. In this ex vivo experimental set-up, they observed a blunted inflammatory response in cells that were harvested from animals previously treated with recombinant Angpt-2. In light of the existent body of evidence indicating an injurious role of Angpt-2 in systemic inflammation, the authors provide a theoretical hypothesis to explain the potential benefit of an Angpt-2 treatment in their model by focusing on the heterogeneity of vascular beds. They claim that it is mostly acute respiratory distress syndrome (ARDS) that is negatively affected by Angpt-2 (given the critical role of increased permeability in this vascular bed) and that there might be a completely different situation in the kidney. This is a fair argument in particular as Angpt-2 is an endothelial-derived protein, a cell type that is in a ‘‘per tissue relation” most abundant in the pulmonary capillaries. Consistent with this, the observed Angpt-2 levels in humans with PN were clearly elevated but not to an extent as it has been reported in septic shock patients [7].
62
K. Thamm, S. David / Cytokine 83 (2016) 61–63
Also, we found in sepsis that different organs (liver, lung, spleen, kidney) do respond with a consistent increase in Angpt-2 synthesis (e.g. even if the primary focus is not pulmonary but abdominal) (unpublished data). Nevertheless, we highly appreciate this data on a dual role of Angpt-2 in the modulation of inflammation. In fact, Hellmut Augustin’s group nicely demonstrated that Angpt-2 sensitizes endothelial cells to TNFa [8,9]. The million dollar question is certainly if this is an injurious or adaptive effect. From an evolutionary point of view, Angpt-2 may not exclusively be injurious to the vasculature. Beneficial effects, beside its longknown role in angiogenesis, could be the fine-tuning to fight local infections (i.e. recruitment of inflammatory cells, induction of a moderate permeability to facilitate transmigration, etc.). Whenever such an initial local response transforms to a systemic scenario with a diffuse overwhelming immune reaction Angpt-2’s effects might become harmful. Based on this thought-experiment one might interpret the current results from experimental PN in a different light. It is very well possible that as long as an infection is localized to a certain site, a strategy with Angpt-2 supplementation could be therapeutically helpful. However, whenever systemic response establishes with excess release of pre-stored Angpt-2 from virtually any vascular bed, strategies that block Angpt-2 function/synthesis/release might be indicated [10–12]. The beauty of this theory would implicate that Angpt-2 might be target (of a treatment) and biomarker (to decide if a treatment is indicated) at the same time. In this context, we have recently coined the term ‘‘theragnostic”. Of course, another (but not less exciting) explanation for the benefit of an Angpt-2 treatment could be the simple fact of its dose-dependent Tie2 agonistic properties [13]. In other words, if enough Angpt-2 is given it has been demonstrated in vitro that Angpt-2 can also act as a Tie2 activator (similar to Angpt-1). This is an extremely critical point. In particular as Safioleas et al. report levels about 10 ng/mL in humans with PN but use an approximately 10-fold higher dose as treatment in their later animal model. To our knowledge individual Angpt-2 levels above 50 ng/ mL even in the sickest septic shock patients have not been reported. Therefore, it is of absolute importance to report the phosphorylated fraction of Tie2 in order to be able to interpret the data. Last but not least, the recombinant form of Angpt-2 that is used for these studies is monomeric. However, for adequate binding of the Tie2 receptor it has been demonstrated that Angpt-2 forms disulfide-linked dimers [14]. Therefore, it has to be ascertained that recombinant Angpt-2 is biologically active to the same extent as the endogenous one being able to form multimers. Differences between monomeric and multimeric Angpt-2 might have strong impact on receptor activation or deactivation. Again, highlighting the importance of experiments investigating Tie2 phosphorylation. In line with this current manuscript, the authors reported earlier beneficial therapeutic effects of recombinant Angpt-2 in septic mice challenged with Pseudomonas aeruginosa [15]. These mice treated with recombinant Angpt-2 had improved survival compared to vehicle controls. Given that these two critical studies showing protective properties of Angpt-2 has been performed in infectious models using P. aeruginosa one has to take pathogenspecific effects into account. Last but not least, Kurniati et al. found that Angpt-2 homozygote knockout mice had worse LPS-induced acute kidney injury [16]. Again, indicating that Angpt-2 might have beneficial effects (e.g. modulating the local inflammatory response) that are required for an effective host defense against infection. In this context, it seems reasonable that Angpt-2 heterozygotes, and therapeutic strategies that reduce Angpt-2 expression to a normal level are highly protective in sepsis [10,17]. However, the strongest data supporting an injurious role of elevated Angpt-2 comes from a recent study analyzing the effects of
genetic endothelial-specific Angpt-2 overexpression in the vasculature. Indeed, genetic induction of Angpt-2 in the endothelium was sufficient to mimic septic vascular changes without infection per se (e.g. increased vascular permeability) [11]. Accordingly, recombinant and endogenous-derived Angpt-2 might exhibit different impact on endothelial cells and Tie2 downstream signaling. Furthermore, there could also be a difference between approaches that target local and circulating Angpt-2. At least in our hands, function-blocking Angpt-2 antibodies that are supposed to capture ‘‘free” circulating protein have been less effective than strategies targeting the biosynthesis of the protein. Of note, administration of recombinant Angpt-2 naturally increases circulating Angpt-2 whereas reduction of Angpt-2 mRNA and respective protein might decrease the local protein bound to the extracellular matrix more efficient than the circulating fraction. Importantly, endothelial-derived Angpt-2 binds the nearby Tie2 receptor in an autocrine manner. Further research is needed to better understand the differences between local and circulating Angpt-2. We highly appreciate and enjoyed the current work by Safioleas et al. Again, this study contributes new knowledge to the field and highlights that much more research is needed to better understand the role of Angpt-2 in local and systemic infections. Funding SD is supported by the German Research Foundation (DA 1209/4-1). References [1] A. Lukasz, J. Hellpap, R. Horn, J.T. Kielstein, S. David, H. Haller, et al., Circulating angiopoietin-1 and angiopoietin-2 in critically ill patients: development and clinical application of two new immunoassays, Crit. Care 12 (2008) R94, http:// dx.doi.org/10.1186/cc6966. [2] S.M. Parikh, T. Mammoto, A. Schultz, H.-T. Yuan, D. Christiani, S.A. Karumanchi, et al., Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans, PLoS Med. 3 (2006) e46. [3] M. Van Der Heijden, G.P. Van Nieuw Amerongen, P. Koolwijk, V.W.M. Van Hinsbergh, A.B.J. Groeneveld, Angiopoietin-2, permeability oedema, occurrence and severity of ALI/ARDS in septic and non-septic critically ill patients, Thorax 63 (2008) 903–909. [4] S.M. Parikh, Dysregulation of the angiopoietin–Tie-2 axis in sepsis and ARDS, Virulence 4 (2013) 517–524. [5] S. David, A. Mukherjee, C.C. Ghosh, M. Yano, E.V. Khankin, J.B. Wenger, et al., Angiopoietin-2 may contribute to multiple organ dysfunction and death in sepsis, Crit. Care Med. 40 (2012) 3034–3041. [6] K. Safioleas, E.J. Giamarellos-Bourboulis, D.-P. Carrer, A. Pistiki, L. Sabracos, C. Deliveliotis, et al., Reverse kinetics of angiopoietin-2 and endotoxins in acute pyelonephritis: implications for anti-inflammatory treatment?, Cytokine 81 (2016) 28–34 [7] P. Kümpers, A. Lukasz, S. David, R. Horn, C. Hafer, R. Faulhaber-Walter, et al., Excess circulating angiopoietin-2 is a strong predictor of mortality in critically ill medical patients, Crit. Care 12 (2008) R147. [8] A.V. Benest, K. Kruse, S. Savant, M. Thomas, A.M. Laib, E.K. Loos, et al., Angiopoietin-2 is critical for cytokine-induced vascular leakage, PLoS ONE 8 (2013) e70459. [9] U. Fiedler, Y. Reiss, M. Scharpfenecker, V. Grunow, S. Koidl, G. Thurston, et al., Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation, Nat. Med. 12 (2006) 235–239. [10] T. Stiehl, K. Thamm, J. Kaufmann, U. Schaeper, T. Kirsch, H. Haller, et al., Lungtargeted RNA interference against angiopoietin-2 ameliorates multiple organ dysfunction and death in sepsis, Crit. Care Med. (2014) 1. [11] T. Ziegler, J. Horstkotte, C. Schwab, V. Pfetsch, K. Weinmann, S. Dietzel, et al., Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis, J. Clin. Invest. 123 (8) (2013) 3436–3445. [12] C.C. Ghosh, K. Thamm, A.V. Berghelli, C. Schrimpf, M.R. Maski, T. Abid, et al., Drug repurposing screen identifies Foxo1-dependent angiopoietin-2 regulation in sepsis, Crit. Care Med. 43 (2015) e230–e240. [13] H.-T. Yuan, E.V. Khankin, S.A. Karumanchi, M.S. Parikh, Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in endothelium, Mol. Cell. Biol. 29 (8) (2009) 2011–2022. [14] W.N. Procopio, P.I. Pelavin, W.M. Lee, N.M. Yeilding, Angiopoietin-1 and -2 coiled coil domains mediate distinct homo-oligomerization patterns, but fibrinogen-like domains mediate ligand activity, J. Biol. Chem. 274 (1999) 30196–30201.
K. Thamm, S. David / Cytokine 83 (2016) 61–63 [15] I.-M. Tzepi, E.J. Giamarellos-Bourboulis, D.-P. Carrer, T. Tsaganos, R.A. Claus, I. Vaki, et al., Angiopoietin-2 enhances survival in experimental sepsis induced by multidrug-resistant Pseudomonas aeruginosa, J. Pharmacol. Exp. Ther. 343 (2012) 278–287. [16] N.F. Kurniati, M. van Meurs, F. vom Hagen, R.M. Jongman, J. Moser, P.J. Zwiers, et al., Pleiotropic effects of angiopoietin-2 deficiency do not protect mice
63
against endotoxin-induced acute kidney injury, Nephrol. Dial. Transplant. 28 (2013) 567–575. [17] S. David, P. Kumpers, P. van Slyke, S.M. Parikh, Mending leaky blood vessels: the angiopoietin-Tie2 pathway in sepsis, J. Pharmacol. Exp. Ther. 345 (2013) 2–6.
Contents lists available at ScienceDirect
Cytokine journal homepage: www.journals.elsevier.com/cytokine
Cytokine stimulus
Role of angiopoietin-2 in infection – A double-edged sword? Kristina Thamm, Sascha David ⇑ Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
a r t i c l e
i n f o
Article history: Received 9 March 2016 Received in revised form 25 March 2016 Accepted 25 March 2016
Keywords: Sepsis Angiopoietin-2 Infection Endothelium
a b s t r a c t The endothelial angiopoietin (Angpt)/Tie2 ligand receptor system maintains vascular quiescence and modulates the response to injury. Angpt-1 is considered the natural Tie2 agonist and receptor ligation leads to its phosphorylation inducing various protective downstream pathways. The natural antagonist – Angpt-2 – appears to inhibit these protective effects. In sepsis, the balance between both ligands is shifted in favor for Angpt-2 and the vasculature is highly dysfunctional, activated and leaky. Circulating levels of Angpt-2 strongly predict mortality in septic patients. Consistently, experimental strategies that target Angpt-2 (e.g. antibody, RNAi, etc.) can protect the vascular barrier and improve survival. However, in vitro is has also been shown that Angpt-2 can act as a dose-dependent Tie2 agonist/ antagonist. Based on this, people have wondered if Angpt-2 is per se injurious or if it might have protective effects dependent on the scenario. A recent paper by Safioleas and colleagues showed survival benefits after a therapeutic injection of recombinant Angpt-2 in experimental pyelonephritis. Here, we discuss their counter-intuitive but interesting findings and put them into a global context with respect to the existent literature in the angiopoietin/Tie2 sepsis field. Ó 2016 Elsevier Ltd. All rights reserved.
The angiopoietin (Angpt)/Tie2 system and its contribution to endothelial dysfunction in sepsis has gained increasing interest in recent years. Different groups around the globe have consistently reported that circulating levels of the canonical Tie2 antagonist Angpt-2 dramatically increase cross-species during systemic inflammation whereas the Tie2 agonist Angpt-1 appears to decrease [1–3]. It is reasonable to conclude from the majority of available data that excess release of pre-stored (as well as de novo biosynthesized) Angpt-2 contributes to vascular inflammation and barrier breakdown (reviewed in [4]). Our own group could show that Angpt-2 actively contributes to multiple organ dysfunction and death in sepsis [5]. Consistently, these negative effects were reversible in experimental models of the disease by either supplementing the Tie2 agonist or blocking/depleting the Tie2 antagonist. The current study by Safioleas et al. contributes new controversial knowledge to the field [6]. The authors investigated the role of Angpt-2 in pyelonephritis (PN) both in humans and in an experimental rabbit model. Given that Angpt-2 has been shown to be a dose-dependent partial Tie2 agonist/antagonist the idea to analyze the immune-modulatory therapeutic potential is clever. This concept was further supported by their finding in humans suffering ⇑ Corresponding author at: Medical School Hannover, Department of Nephrology & Hypertension, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. E-mail address: [email protected] (S. David). http://dx.doi.org/10.1016/j.cyto.2016.03.019 1043-4666/Ó 2016 Elsevier Ltd. All rights reserved.
from PN that circulating Angpt-2 correlates reciprocally with lipopolysaccharide (LPS) levels. The authors confirmed this observation in an experimental model of septic PN in rabbits. Animals that received recombinant Angpt-2 as therapeutic strategy showed increased survival and decreased LPS compared to vehicle treated rabbits. This could certainly be an epiphenomenon in the complex multi-cellular in vivo situation. However, Safioleas and coworkers performed an interesting mechanistic experiment by challenging immune cells isolated from rabbits with PN with TNFa. In this ex vivo experimental set-up, they observed a blunted inflammatory response in cells that were harvested from animals previously treated with recombinant Angpt-2. In light of the existent body of evidence indicating an injurious role of Angpt-2 in systemic inflammation, the authors provide a theoretical hypothesis to explain the potential benefit of an Angpt-2 treatment in their model by focusing on the heterogeneity of vascular beds. They claim that it is mostly acute respiratory distress syndrome (ARDS) that is negatively affected by Angpt-2 (given the critical role of increased permeability in this vascular bed) and that there might be a completely different situation in the kidney. This is a fair argument in particular as Angpt-2 is an endothelial-derived protein, a cell type that is in a ‘‘per tissue relation” most abundant in the pulmonary capillaries. Consistent with this, the observed Angpt-2 levels in humans with PN were clearly elevated but not to an extent as it has been reported in septic shock patients [7].
62
K. Thamm, S. David / Cytokine 83 (2016) 61–63
Also, we found in sepsis that different organs (liver, lung, spleen, kidney) do respond with a consistent increase in Angpt-2 synthesis (e.g. even if the primary focus is not pulmonary but abdominal) (unpublished data). Nevertheless, we highly appreciate this data on a dual role of Angpt-2 in the modulation of inflammation. In fact, Hellmut Augustin’s group nicely demonstrated that Angpt-2 sensitizes endothelial cells to TNFa [8,9]. The million dollar question is certainly if this is an injurious or adaptive effect. From an evolutionary point of view, Angpt-2 may not exclusively be injurious to the vasculature. Beneficial effects, beside its longknown role in angiogenesis, could be the fine-tuning to fight local infections (i.e. recruitment of inflammatory cells, induction of a moderate permeability to facilitate transmigration, etc.). Whenever such an initial local response transforms to a systemic scenario with a diffuse overwhelming immune reaction Angpt-2’s effects might become harmful. Based on this thought-experiment one might interpret the current results from experimental PN in a different light. It is very well possible that as long as an infection is localized to a certain site, a strategy with Angpt-2 supplementation could be therapeutically helpful. However, whenever systemic response establishes with excess release of pre-stored Angpt-2 from virtually any vascular bed, strategies that block Angpt-2 function/synthesis/release might be indicated [10–12]. The beauty of this theory would implicate that Angpt-2 might be target (of a treatment) and biomarker (to decide if a treatment is indicated) at the same time. In this context, we have recently coined the term ‘‘theragnostic”. Of course, another (but not less exciting) explanation for the benefit of an Angpt-2 treatment could be the simple fact of its dose-dependent Tie2 agonistic properties [13]. In other words, if enough Angpt-2 is given it has been demonstrated in vitro that Angpt-2 can also act as a Tie2 activator (similar to Angpt-1). This is an extremely critical point. In particular as Safioleas et al. report levels about 10 ng/mL in humans with PN but use an approximately 10-fold higher dose as treatment in their later animal model. To our knowledge individual Angpt-2 levels above 50 ng/ mL even in the sickest septic shock patients have not been reported. Therefore, it is of absolute importance to report the phosphorylated fraction of Tie2 in order to be able to interpret the data. Last but not least, the recombinant form of Angpt-2 that is used for these studies is monomeric. However, for adequate binding of the Tie2 receptor it has been demonstrated that Angpt-2 forms disulfide-linked dimers [14]. Therefore, it has to be ascertained that recombinant Angpt-2 is biologically active to the same extent as the endogenous one being able to form multimers. Differences between monomeric and multimeric Angpt-2 might have strong impact on receptor activation or deactivation. Again, highlighting the importance of experiments investigating Tie2 phosphorylation. In line with this current manuscript, the authors reported earlier beneficial therapeutic effects of recombinant Angpt-2 in septic mice challenged with Pseudomonas aeruginosa [15]. These mice treated with recombinant Angpt-2 had improved survival compared to vehicle controls. Given that these two critical studies showing protective properties of Angpt-2 has been performed in infectious models using P. aeruginosa one has to take pathogenspecific effects into account. Last but not least, Kurniati et al. found that Angpt-2 homozygote knockout mice had worse LPS-induced acute kidney injury [16]. Again, indicating that Angpt-2 might have beneficial effects (e.g. modulating the local inflammatory response) that are required for an effective host defense against infection. In this context, it seems reasonable that Angpt-2 heterozygotes, and therapeutic strategies that reduce Angpt-2 expression to a normal level are highly protective in sepsis [10,17]. However, the strongest data supporting an injurious role of elevated Angpt-2 comes from a recent study analyzing the effects of
genetic endothelial-specific Angpt-2 overexpression in the vasculature. Indeed, genetic induction of Angpt-2 in the endothelium was sufficient to mimic septic vascular changes without infection per se (e.g. increased vascular permeability) [11]. Accordingly, recombinant and endogenous-derived Angpt-2 might exhibit different impact on endothelial cells and Tie2 downstream signaling. Furthermore, there could also be a difference between approaches that target local and circulating Angpt-2. At least in our hands, function-blocking Angpt-2 antibodies that are supposed to capture ‘‘free” circulating protein have been less effective than strategies targeting the biosynthesis of the protein. Of note, administration of recombinant Angpt-2 naturally increases circulating Angpt-2 whereas reduction of Angpt-2 mRNA and respective protein might decrease the local protein bound to the extracellular matrix more efficient than the circulating fraction. Importantly, endothelial-derived Angpt-2 binds the nearby Tie2 receptor in an autocrine manner. Further research is needed to better understand the differences between local and circulating Angpt-2. We highly appreciate and enjoyed the current work by Safioleas et al. Again, this study contributes new knowledge to the field and highlights that much more research is needed to better understand the role of Angpt-2 in local and systemic infections. Funding SD is supported by the German Research Foundation (DA 1209/4-1). References [1] A. Lukasz, J. Hellpap, R. Horn, J.T. Kielstein, S. David, H. Haller, et al., Circulating angiopoietin-1 and angiopoietin-2 in critically ill patients: development and clinical application of two new immunoassays, Crit. Care 12 (2008) R94, http:// dx.doi.org/10.1186/cc6966. [2] S.M. Parikh, T. Mammoto, A. Schultz, H.-T. Yuan, D. Christiani, S.A. Karumanchi, et al., Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans, PLoS Med. 3 (2006) e46. [3] M. Van Der Heijden, G.P. Van Nieuw Amerongen, P. Koolwijk, V.W.M. Van Hinsbergh, A.B.J. Groeneveld, Angiopoietin-2, permeability oedema, occurrence and severity of ALI/ARDS in septic and non-septic critically ill patients, Thorax 63 (2008) 903–909. [4] S.M. Parikh, Dysregulation of the angiopoietin–Tie-2 axis in sepsis and ARDS, Virulence 4 (2013) 517–524. [5] S. David, A. Mukherjee, C.C. Ghosh, M. Yano, E.V. Khankin, J.B. Wenger, et al., Angiopoietin-2 may contribute to multiple organ dysfunction and death in sepsis, Crit. Care Med. 40 (2012) 3034–3041. [6] K. Safioleas, E.J. Giamarellos-Bourboulis, D.-P. Carrer, A. Pistiki, L. Sabracos, C. Deliveliotis, et al., Reverse kinetics of angiopoietin-2 and endotoxins in acute pyelonephritis: implications for anti-inflammatory treatment?, Cytokine 81 (2016) 28–34 [7] P. Kümpers, A. Lukasz, S. David, R. Horn, C. Hafer, R. Faulhaber-Walter, et al., Excess circulating angiopoietin-2 is a strong predictor of mortality in critically ill medical patients, Crit. Care 12 (2008) R147. [8] A.V. Benest, K. Kruse, S. Savant, M. Thomas, A.M. Laib, E.K. Loos, et al., Angiopoietin-2 is critical for cytokine-induced vascular leakage, PLoS ONE 8 (2013) e70459. [9] U. Fiedler, Y. Reiss, M. Scharpfenecker, V. Grunow, S. Koidl, G. Thurston, et al., Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation, Nat. Med. 12 (2006) 235–239. [10] T. Stiehl, K. Thamm, J. Kaufmann, U. Schaeper, T. Kirsch, H. Haller, et al., Lungtargeted RNA interference against angiopoietin-2 ameliorates multiple organ dysfunction and death in sepsis, Crit. Care Med. (2014) 1. [11] T. Ziegler, J. Horstkotte, C. Schwab, V. Pfetsch, K. Weinmann, S. Dietzel, et al., Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis, J. Clin. Invest. 123 (8) (2013) 3436–3445. [12] C.C. Ghosh, K. Thamm, A.V. Berghelli, C. Schrimpf, M.R. Maski, T. Abid, et al., Drug repurposing screen identifies Foxo1-dependent angiopoietin-2 regulation in sepsis, Crit. Care Med. 43 (2015) e230–e240. [13] H.-T. Yuan, E.V. Khankin, S.A. Karumanchi, M.S. Parikh, Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in endothelium, Mol. Cell. Biol. 29 (8) (2009) 2011–2022. [14] W.N. Procopio, P.I. Pelavin, W.M. Lee, N.M. Yeilding, Angiopoietin-1 and -2 coiled coil domains mediate distinct homo-oligomerization patterns, but fibrinogen-like domains mediate ligand activity, J. Biol. Chem. 274 (1999) 30196–30201.
K. Thamm, S. David / Cytokine 83 (2016) 61–63 [15] I.-M. Tzepi, E.J. Giamarellos-Bourboulis, D.-P. Carrer, T. Tsaganos, R.A. Claus, I. Vaki, et al., Angiopoietin-2 enhances survival in experimental sepsis induced by multidrug-resistant Pseudomonas aeruginosa, J. Pharmacol. Exp. Ther. 343 (2012) 278–287. [16] N.F. Kurniati, M. van Meurs, F. vom Hagen, R.M. Jongman, J. Moser, P.J. Zwiers, et al., Pleiotropic effects of angiopoietin-2 deficiency do not protect mice
63
against endotoxin-induced acute kidney injury, Nephrol. Dial. Transplant. 28 (2013) 567–575. [17] S. David, P. Kumpers, P. van Slyke, S.M. Parikh, Mending leaky blood vessels: the angiopoietin-Tie2 pathway in sepsis, J. Pharmacol. Exp. Ther. 345 (2013) 2–6.