From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
23 OCTOBER 2014
I VOLUME 124, NUMBER 17
l l l PLATELETS & THROMBOPOIESIS
Comment on Ortiz-Muñoz et al, page 2625
The fat and the skinny on acute lung injury ----------------------------------------------------------------------------------------------------James C. Zimring
PUGET SOUND BLOOD CENTER RESEARCH INSTITUTE
In this issue of Blood, Ortiz-Muñoz et al take a critical step in evaluating an advanced model of acute lung injury (ALI) pathology, implicating the accumulation of leukocyte-platelet aggregates (LPAs) in alveolar spaces, a central role of bioactive lipids in this process, and a particular identification of 15-epi-lipoxin A4 (LXA4) as a central player in the efficacy of aspirinregulated protection from ALI.1 These events have been previously described in isolation,2-4 but this report synthesizes them together into a central model that sheds new light on the multifactorial landscape of ALI pathogenesis.
E
merging paradigms of inflammationbased pathologies, including the critical issue of ALI, are increasingly evoking the coordinate activity of multiple cellular species in initiating, promoting, and propagating disease. In retrospect, the concept that different circulating blood cell types have biological cross talk and interactions seems obvious and perhaps even inevitable. However, this notion nevertheless represents a progressive conceptual evolution, as traditional models have focused more on the singular contributions of cell types in isolation. An added layer of complexity is evoked with the attempt to identify signaling mediators of disease and/or targets of therapeutic intervention. The generation of a comprehensive and holistic understanding will require the integration of each of these components into a generalized schema. Ortiz-Muñoz et al report significant and provocative data linking specific bioactive lipids to formation of neutrophil-platelet aggregates, followed by an association of the
latter with pulmonary pathology in 2 separate in vivo models of ALI, involving either intratracheal lipopolysaccharide (LPS) or a 2-hit LPS/anti–major histocompatibility complex model of transfusion-related acute lung injury (TRALI). Aspirin has known efficacy in these model systems,4 and the authors present compelling evidence implicating a causal role for diversion of arachidonic acid metabolism away from eicosanoids, which would normally exacerbate ALI, toward 15-epi-LXA4, which has protective properties. The authors make use of sophisticated interventional experiments, including either animals treated with pharmacological inhibitors of or animals with targeted deletions of known receptors for 15-epi-LXA4. Of great importance, aspirin simultaneously attenuated ALI and increased both plasma and bronchiolar 15-epi-LXA4 in these models, whereas blockade of 15-epi-LXA4 by the above approaches attenuated aspirin’s therapeutic effects. An additional intellectual connection can be found in models of antibody-independent
BLOOD, 23 OCTOBER 2014 x VOLUME 124, NUMBER 17
TRALI, where the direct infusion of biologically active lipid mediators is proposed to directly induce ALI through pathways related and analogous to those elucidated in the current studies.5-7 This form of TRALI remains of central interest in the ongoing effort to improve the safety of blood products, because antibody-independent TRALI is not remedied by the prophylactic measure of preferentially using male blood products to avoid women who have been alloimmunized to HLA antigens as a result of pregnancy. As the authors readily point out, ongoing studies are required to refine the interpretation of the observed phenomena, and there are legitimate concerns regarding dose requirements of experimentally administered 15-epi-LXA4. Nevertheless, this report integrates multiple biological players into an integrated model of bioactive lipid generation, LPA formation, and trafficking to alveoli and aspirin efficacy. Perhaps more importantly, this study identifies the potential for using bioactive lipids (or modified chemical agonists of such pathways) as novel interventions. Current available therapies may not allow safe utilization of the identified pathways. Thus, in aggregate, the reported findings represent a conceptual advance of high potential in both general understanding and therapeutic development for ALI prevention and mitigation. Conflict-of-interest disclosure: J.C.Z. has a sponsored research agreement with Immucor Inc. unrelated to this work. n REFERENCES 1. Ortiz-Muñoz G, Mallavia B, Bins A, Headley M, Krummel MF, Looney MR. Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice. Blood. 2014;124(17):2625-2634. 2. Jenne CN, Wong CH, Petri B, Kubes P. The use of spinning-disk confocal microscopy for the intravital analysis of platelet dynamics in response to systemic and local inflammation. PLoS ONE. 2011; 6(9):e25109.
2617
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
3. Serhan CN. Lipoxins and aspirin-triggered 15-epilipoxins are the first lipid mediators of endogenous anti-inflammation and resolution. Prostaglandins Leukot Essent Fatty Acids. 2005;73(3-4):141-162. 4. Looney MR, Nguyen JX, Hu Y, Van Ziffle JA, Lowell CA, Matthay MA. Platelet depletion and aspirin treatment protect mice in a two-event model of transfusion-related acute lung injury. J Clin Invest. 2009;119(11):3450-3461. 5. Silliman CC, Moore EE, Kelher MR, Khan SY, Gellar L, Elzi DJ. Identification of lipids that accumulate during the routine storage of prestorage leukoreduced red blood
cells and cause acute lung injury. Transfusion. 2011;51(12): 2549-2554. 6. Silliman CC, Bjornsen AJ, Wyman TH, et al. Plasma and lipids from stored platelets cause acute lung injury in an animal model. Transfusion. 2003;43(5): 633-640. 7. Silliman CC, Voelkel NF, Allard JD, et al. Plasma and lipids from stored packed red blood cells cause acute lung injury in an animal model. J Clin Invest. 1998;101(7): 1458-1467. © 2014 by The American Society of Hematology
l l l CLINICAL TRIALS & OBSERVATIONS
Comment on van Eijk et al, page 2643
A novel treatment of anemia of inflammation ----------------------------------------------------------------------------------------------------Andrea U. Steinbicker
¨ UNIVERSITY HOSPITAL MUNSTER
In this issue of Blood, van Eijk et al investigate a synthetic compound that inhibits the iron-regulatory hormone hepcidin to fight anemia of inflammation in human endotoxemia.1
Effects of placebo or lexaptepid treatment on inflammatory-mediated hepcidin induction and systemic iron homeostasis. With placebo, acute or chronic inflammations as well as neoplastic disease cause an induction of cytokines. Cytokines, in turn, induce the expression of the iron-regulatory hormone hepcidin. Hepcidin degrades the iron-export channel ferroportin, so that hypoferremia develops. Erythropoiesis and hemoglobin levels decrease. Anemia of inflammation ensues. Patients treated with lexaptepid show the same induction of cytokines. Hepcidin is induced but bound by lexaptepid. The hepcidin-lexaptepid complex is biologically inactive and prevents hypoferremia. Therefore, lexaptepid might be a possible treatment of anemia of inflammation. The effects on erythropoiesis and hemoglobin levels have yet to be determined in clinical trials. TSAT, transferrin saturation. Professional illustration by XavierStudio.
2618
A
nemia is one of the major public health burdens. The World Health Organization estimates the prevalence of anemia at 2 billion people worldwide. Prevalence of anemia in 2010 was estimated at 32.9% in a systemic analysis of the global anemia burden from 1990 to 2010. Anemia caused 68.4 million years lived with disability.2 Iron deficiency anemia is the most frequent form of anemia, typically due to nutritional deficiency and characterized by intact regulation of iron homeostasis and decreased serum iron levels and tissue iron stores. Anemia of inflammation, also known as the anemia of chronic disease, is the second most common form of anemia. In anemia of inflammation, acute or chronic infections or neoplastic disease cause an immune-modulatory response in patients with an induction of cytokine expression. Cytokines, in turn, lead to an increase of the iron-regulatory hormone hepcidin. Synthesized mainly by the liver, hepcidin maintains systemic iron homeostasis by posttranslationally downregulating levels of the sole iron exporter, ferroportin. Hepcidin binds to ferroportin and causes internalization and degradation of the iron exporter. As the 3 sites of ferroportin expression are duodenal enterocytes, hepatocytes, and reticuloendothelial macrophages, dietary iron absorption and iron release from tissue stores is inhibited. Anemia of inflammation ultimately ensues.3,4 Anemia of inflammation is frequent in hospitalized patients. A secondary retrospective analysis of a prospective study of 39 309 patients from 28 European nations on preoperative anemia revealed that 26.5% of women and 31.1% of men were anemic.5 If these patients undergo surgery, preoperative anemia is a risk factor associated with higher in-hospital mortality, longer stay in the hospital, and higher frequency of postoperative admission to the intensive care unit compared with patients without preoperative anemia.5 Fighting anemia therefore is of high clinical relevance and critical, independent of age and country of residence. To date, therapeutic options for anemia of inflammation include treatment of the underlying disease, blood transfusions, intravenous iron supplementation, or erythropoietin, if applicable. Because hepcidin is induced in anemia of inflammation, researchers have tried for several years to identify a means to target and inhibit hepcidin. If hepcidin expression can be inhibited or biologically inactivated, the iron
BLOOD, 23 OCTOBER 2014 x VOLUME 124, NUMBER 17
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2014 124: 2617-2618 doi:10.1182/blood-2014-09-597732
The fat and the skinny on acute lung injury James C. Zimring
Updated information and services can be found at: http://www.bloodjournal.org/content/124/17/2617.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (4041 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
23 OCTOBER 2014
I VOLUME 124, NUMBER 17
l l l PLATELETS & THROMBOPOIESIS
Comment on Ortiz-Muñoz et al, page 2625
The fat and the skinny on acute lung injury ----------------------------------------------------------------------------------------------------James C. Zimring
PUGET SOUND BLOOD CENTER RESEARCH INSTITUTE
In this issue of Blood, Ortiz-Muñoz et al take a critical step in evaluating an advanced model of acute lung injury (ALI) pathology, implicating the accumulation of leukocyte-platelet aggregates (LPAs) in alveolar spaces, a central role of bioactive lipids in this process, and a particular identification of 15-epi-lipoxin A4 (LXA4) as a central player in the efficacy of aspirinregulated protection from ALI.1 These events have been previously described in isolation,2-4 but this report synthesizes them together into a central model that sheds new light on the multifactorial landscape of ALI pathogenesis.
E
merging paradigms of inflammationbased pathologies, including the critical issue of ALI, are increasingly evoking the coordinate activity of multiple cellular species in initiating, promoting, and propagating disease. In retrospect, the concept that different circulating blood cell types have biological cross talk and interactions seems obvious and perhaps even inevitable. However, this notion nevertheless represents a progressive conceptual evolution, as traditional models have focused more on the singular contributions of cell types in isolation. An added layer of complexity is evoked with the attempt to identify signaling mediators of disease and/or targets of therapeutic intervention. The generation of a comprehensive and holistic understanding will require the integration of each of these components into a generalized schema. Ortiz-Muñoz et al report significant and provocative data linking specific bioactive lipids to formation of neutrophil-platelet aggregates, followed by an association of the
latter with pulmonary pathology in 2 separate in vivo models of ALI, involving either intratracheal lipopolysaccharide (LPS) or a 2-hit LPS/anti–major histocompatibility complex model of transfusion-related acute lung injury (TRALI). Aspirin has known efficacy in these model systems,4 and the authors present compelling evidence implicating a causal role for diversion of arachidonic acid metabolism away from eicosanoids, which would normally exacerbate ALI, toward 15-epi-LXA4, which has protective properties. The authors make use of sophisticated interventional experiments, including either animals treated with pharmacological inhibitors of or animals with targeted deletions of known receptors for 15-epi-LXA4. Of great importance, aspirin simultaneously attenuated ALI and increased both plasma and bronchiolar 15-epi-LXA4 in these models, whereas blockade of 15-epi-LXA4 by the above approaches attenuated aspirin’s therapeutic effects. An additional intellectual connection can be found in models of antibody-independent
BLOOD, 23 OCTOBER 2014 x VOLUME 124, NUMBER 17
TRALI, where the direct infusion of biologically active lipid mediators is proposed to directly induce ALI through pathways related and analogous to those elucidated in the current studies.5-7 This form of TRALI remains of central interest in the ongoing effort to improve the safety of blood products, because antibody-independent TRALI is not remedied by the prophylactic measure of preferentially using male blood products to avoid women who have been alloimmunized to HLA antigens as a result of pregnancy. As the authors readily point out, ongoing studies are required to refine the interpretation of the observed phenomena, and there are legitimate concerns regarding dose requirements of experimentally administered 15-epi-LXA4. Nevertheless, this report integrates multiple biological players into an integrated model of bioactive lipid generation, LPA formation, and trafficking to alveoli and aspirin efficacy. Perhaps more importantly, this study identifies the potential for using bioactive lipids (or modified chemical agonists of such pathways) as novel interventions. Current available therapies may not allow safe utilization of the identified pathways. Thus, in aggregate, the reported findings represent a conceptual advance of high potential in both general understanding and therapeutic development for ALI prevention and mitigation. Conflict-of-interest disclosure: J.C.Z. has a sponsored research agreement with Immucor Inc. unrelated to this work. n REFERENCES 1. Ortiz-Muñoz G, Mallavia B, Bins A, Headley M, Krummel MF, Looney MR. Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice. Blood. 2014;124(17):2625-2634. 2. Jenne CN, Wong CH, Petri B, Kubes P. The use of spinning-disk confocal microscopy for the intravital analysis of platelet dynamics in response to systemic and local inflammation. PLoS ONE. 2011; 6(9):e25109.
2617
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
3. Serhan CN. Lipoxins and aspirin-triggered 15-epilipoxins are the first lipid mediators of endogenous anti-inflammation and resolution. Prostaglandins Leukot Essent Fatty Acids. 2005;73(3-4):141-162. 4. Looney MR, Nguyen JX, Hu Y, Van Ziffle JA, Lowell CA, Matthay MA. Platelet depletion and aspirin treatment protect mice in a two-event model of transfusion-related acute lung injury. J Clin Invest. 2009;119(11):3450-3461. 5. Silliman CC, Moore EE, Kelher MR, Khan SY, Gellar L, Elzi DJ. Identification of lipids that accumulate during the routine storage of prestorage leukoreduced red blood
cells and cause acute lung injury. Transfusion. 2011;51(12): 2549-2554. 6. Silliman CC, Bjornsen AJ, Wyman TH, et al. Plasma and lipids from stored platelets cause acute lung injury in an animal model. Transfusion. 2003;43(5): 633-640. 7. Silliman CC, Voelkel NF, Allard JD, et al. Plasma and lipids from stored packed red blood cells cause acute lung injury in an animal model. J Clin Invest. 1998;101(7): 1458-1467. © 2014 by The American Society of Hematology
l l l CLINICAL TRIALS & OBSERVATIONS
Comment on van Eijk et al, page 2643
A novel treatment of anemia of inflammation ----------------------------------------------------------------------------------------------------Andrea U. Steinbicker
¨ UNIVERSITY HOSPITAL MUNSTER
In this issue of Blood, van Eijk et al investigate a synthetic compound that inhibits the iron-regulatory hormone hepcidin to fight anemia of inflammation in human endotoxemia.1
Effects of placebo or lexaptepid treatment on inflammatory-mediated hepcidin induction and systemic iron homeostasis. With placebo, acute or chronic inflammations as well as neoplastic disease cause an induction of cytokines. Cytokines, in turn, induce the expression of the iron-regulatory hormone hepcidin. Hepcidin degrades the iron-export channel ferroportin, so that hypoferremia develops. Erythropoiesis and hemoglobin levels decrease. Anemia of inflammation ensues. Patients treated with lexaptepid show the same induction of cytokines. Hepcidin is induced but bound by lexaptepid. The hepcidin-lexaptepid complex is biologically inactive and prevents hypoferremia. Therefore, lexaptepid might be a possible treatment of anemia of inflammation. The effects on erythropoiesis and hemoglobin levels have yet to be determined in clinical trials. TSAT, transferrin saturation. Professional illustration by XavierStudio.
2618
A
nemia is one of the major public health burdens. The World Health Organization estimates the prevalence of anemia at 2 billion people worldwide. Prevalence of anemia in 2010 was estimated at 32.9% in a systemic analysis of the global anemia burden from 1990 to 2010. Anemia caused 68.4 million years lived with disability.2 Iron deficiency anemia is the most frequent form of anemia, typically due to nutritional deficiency and characterized by intact regulation of iron homeostasis and decreased serum iron levels and tissue iron stores. Anemia of inflammation, also known as the anemia of chronic disease, is the second most common form of anemia. In anemia of inflammation, acute or chronic infections or neoplastic disease cause an immune-modulatory response in patients with an induction of cytokine expression. Cytokines, in turn, lead to an increase of the iron-regulatory hormone hepcidin. Synthesized mainly by the liver, hepcidin maintains systemic iron homeostasis by posttranslationally downregulating levels of the sole iron exporter, ferroportin. Hepcidin binds to ferroportin and causes internalization and degradation of the iron exporter. As the 3 sites of ferroportin expression are duodenal enterocytes, hepatocytes, and reticuloendothelial macrophages, dietary iron absorption and iron release from tissue stores is inhibited. Anemia of inflammation ultimately ensues.3,4 Anemia of inflammation is frequent in hospitalized patients. A secondary retrospective analysis of a prospective study of 39 309 patients from 28 European nations on preoperative anemia revealed that 26.5% of women and 31.1% of men were anemic.5 If these patients undergo surgery, preoperative anemia is a risk factor associated with higher in-hospital mortality, longer stay in the hospital, and higher frequency of postoperative admission to the intensive care unit compared with patients without preoperative anemia.5 Fighting anemia therefore is of high clinical relevance and critical, independent of age and country of residence. To date, therapeutic options for anemia of inflammation include treatment of the underlying disease, blood transfusions, intravenous iron supplementation, or erythropoietin, if applicable. Because hepcidin is induced in anemia of inflammation, researchers have tried for several years to identify a means to target and inhibit hepcidin. If hepcidin expression can be inhibited or biologically inactivated, the iron
BLOOD, 23 OCTOBER 2014 x VOLUME 124, NUMBER 17
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2014 124: 2617-2618 doi:10.1182/blood-2014-09-597732
The fat and the skinny on acute lung injury James C. Zimring
Updated information and services can be found at: http://www.bloodjournal.org/content/124/17/2617.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (4041 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
