Heme-related molecules induce rapid production of neutrophil extracellular traps
Corresponding Author
Mari Kono
Cell Analysis Center, Scientific Affairs, Sysmex Corporation, Kobe, Japan
Address reprint requests to: Mari Kono, 1-3-2 Murotani, Nishi-ku, Kobe 651-2241, Japan; e-mail: [email protected].Search for more papers by this authorKatsuyasu Saigo
Faculty of Pharmacological Sciences, Himeji Dokkyo University, Himeji, Japan
Search for more papers by this authorYuri Takagi
Cell Analysis Center, Scientific Affairs, Sysmex Corporation, Kobe, Japan
Search for more papers by this authorTakayuki Takahashi
Department of Hematology, Shinko Hospital, Kobe, Japan
Search for more papers by this authorSawako Kawauchi
Cell Analysis Center, Scientific Affairs, Sysmex Corporation, Kobe, Japan
Search for more papers by this authorAtsushi Wada
Cell Analysis Center, Scientific Affairs, Sysmex Corporation, Kobe, Japan
Search for more papers by this authorMakoto Hashimoto
Blood Transfusion Division, Kobe University Hospital, Kobe, Japan
Search for more papers by this authorYosuke Minami
Blood Transfusion Division, Kobe University Hospital, Kobe, Japan
Search for more papers by this authorShion Imoto
Department of Health Science, Kobe Tokiwa University, Kobe, Japan
Search for more papers by this authorMariko Takenokuchi
Faculty of Pharmacological Sciences, Himeji Dokkyo University, Himeji, Japan
Search for more papers by this authorTakashi Morikawa
Cell Analysis Center, Scientific Affairs, Sysmex Corporation, Kobe, Japan
Search for more papers by this authorKunihiro Funakoshi
Cell Analysis Center, Scientific Affairs, Sysmex Corporation, Kobe, Japan
Search for more papers by this authorCorresponding Author
Mari Kono
Cell Analysis Center, Scientific Affairs, Sysmex Corporation, Kobe, Japan
Address reprint requests to: Mari Kono, 1-3-2 Murotani, Nishi-ku, Kobe 651-2241, Japan; e-mail: [email protected].Search for more papers by this authorKatsuyasu Saigo
Faculty of Pharmacological Sciences, Himeji Dokkyo University, Himeji, Japan
Search for more papers by this authorYuri Takagi
Cell Analysis Center, Scientific Affairs, Sysmex Corporation, Kobe, Japan
Search for more papers by this authorTakayuki Takahashi
Department of Hematology, Shinko Hospital, Kobe, Japan
Search for more papers by this authorSawako Kawauchi
Cell Analysis Center, Scientific Affairs, Sysmex Corporation, Kobe, Japan
Search for more papers by this authorAtsushi Wada
Cell Analysis Center, Scientific Affairs, Sysmex Corporation, Kobe, Japan
Search for more papers by this authorMakoto Hashimoto
Blood Transfusion Division, Kobe University Hospital, Kobe, Japan
Search for more papers by this authorYosuke Minami
Blood Transfusion Division, Kobe University Hospital, Kobe, Japan
Search for more papers by this authorShion Imoto
Department of Health Science, Kobe Tokiwa University, Kobe, Japan
Search for more papers by this authorMariko Takenokuchi
Faculty of Pharmacological Sciences, Himeji Dokkyo University, Himeji, Japan
Search for more papers by this authorTakashi Morikawa
Cell Analysis Center, Scientific Affairs, Sysmex Corporation, Kobe, Japan
Search for more papers by this authorKunihiro Funakoshi
Cell Analysis Center, Scientific Affairs, Sysmex Corporation, Kobe, Japan
Search for more papers by this authorAbstract
Background
Pulmonary endothelial cell damages caused by neutrophil overactivation could result in acute lung injuries including transfusion-related acute lung injury (TRALI). We previously reported that heme-related molecules derived from hemolysis induced the production of reactive oxygen species from neutrophils. Recently, neutrophil extracellular traps (NETs) have been demonstrated to associate with the onset of TRALI.
Study Design and Methods
In this study, neutrophils' morphologic changes induced by the heme-related molecule hemin were confirmed to be NETs via confocal laser scanning microscopy and electron microscopy (EM). Additionally, concentrations of hemin in red blood cell (RBC) components were measured via enzyme-linked immunosorbent assay and possible contribution of these molecules to the onset of TRALI was discussed.
Results
SYTOX green staining observation via confocal laser scanning microscopy revealed that neutrophil morphology changed rapidly upon addition of hemin. The nuclei began to be enlarged and become segmented after 5 minutes, and NET-like structures were released from neutrophils after 15 minutes. In EM observation, NET-like structures appeared after 10 minutes and the nucleoplasm was partially separated from the nuclear membrane, which were consistent with the features of NET formation. These structures stained positively for both myeloperoxidase and histone H3 antibodies.
Conclusion
Thus, our results suggest that hemin induced NETs in 15 minutes, a quicker reaction than NET induction by phorbol myristate acetate requiring 3 hours. Moreover, since RBC components, especially those with long-term storage, contained sufficient hemin concentration to induce NETs, special attention to hemolysis of stored RBC components is important.
References
- 1 Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005; 353: 1685-1693.
- 2 Luhr OR, Antonsen K, Karlsson M, et al. Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland. The ARF Study Group. Am J Respir Crit Care Med 1999; 159: 1849-1861.
- 3 Villar J, Blanco J, Anon JM, et al. The ALIEN study: incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation. Intensive Care Med 2011; 37: 1932-1941.
- 4 The Irish Critical Care Trials Group. Acute lung injury and the acute respiratory distress syndrome in Ireland: a prospective audit of epidemiology and management. Crit Care 2008; 12: R30.
- 5 Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149: 818-824.
- 6 Singh NR, Johnson A, Peters AM, et al. Acute lung injury results from failure of neutrophil de-priming: a new hypothesis. Eur J Clin Invest 2012; 42: 1342-1349.
- 7 Holness L, Knippen MA, Simmons L, et al. Fatalities caused by TRALI. Transfus Med Rev 2004; 18: 184-188.
- 8 Triulzi DJ. Transfusion-related acute lung injury: current concepts for the clinician. Anesth Analg 2009; 108: 770-776.
- 9 Shaz BH, Stowell SR, Hillyer CD. Transfusion-related acute lung injury: from bedside to bench and back. Blood 2011; 117: 1463-1471.
- 10 Bux J. Antibody-mediated (immune) transfusion-related acute lung injury. Vox Sang 2011; 100: 122-128.
- 11 Sachs UJ, Hattar K, Weissmann N, et al. Antibody-induced neutrophil activation as a trigger for transfusion-related acute lung injury in an ex vivo rat lung model. Blood 2006; 107: 1217-1219.
- 12 Khan SY, Kelher MR, Heal JM, et al. Soluble CD40 ligand accumulates in stored blood components, primes neutrophils through CD40, and is a potential cofactor in the development of transfusion-related acute lung injury. Blood 2006; 108: 2455-2462.
- 13 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: 633-640.
- 14 Hishizawa M, Mitsuhashi R, Ohno T. Transfusion-related acute lung injury (TRALI) induced by donor-derived anti-HLA antibodies in aplastic anemia: possible priming effect of granulocyte-colony stimulating factor (G-CSF) on the recipient neutrophils. Intern Med 2009; 48: 1979-1983.
- 15 Eder AF, Herron R, Strupp A, et al. Transfusion-related acute lung injury surveillance (2003-2005) and the potential impact of the selective use of plasma from male donors in the American Red Cross. Transfusion 2007; 47: 599-607.
- 16 Kono M, Saigo K, Takagi Y, et al. Morphological and flow-cytometric analysis of haemin-induced human neutrophil activation: implications for transfusion-related acute lung injury. Blood Transfus 2013; 11: 53-60.
- 17 Graca-Souza AV, Arruda MA, de Freitas MS, et al. Neutrophil activation by heme: implications for inflammatory processes. Blood 2002; 99: 4160-4165.
- 18 Porto BN, Alves LS, Fernandez PL, et al. Heme induces neutrophil migration and reactive oxygen species generation through signaling pathways characteristic of chemotactic receptors. J Biol Chem 2007; 282: 24430-24436.
- 19 Saigo K, Hashimoto M, Jyokei Y, et al. [Activation of human neutrophils by hemin]. Rinsho Byori 2008; 56: 967-972.
- 20 Zimmermann R, Wintzheimer S, Weisbach V, et al. Influence of prestorage leukoreduction and subsequent irradiation on in vitro red blood cell (RBC) storage variables of RBCs in additive solution saline-adenine-glucose-mannitol. Transfusion 2009; 49: 75-80.
- 21 Gandhi MJ, Shapiro E, Emmert L, et al. Prestorage leukoreduction does not increase hemolysis of stored red cell concentrates. Transfus Apher Sci 2007; 36: 17-22.
- 22 Ghosh S, Adisa OA, Chappa P, et al. Extracellular hemin crisis triggers acute chest syndrome in sickle mice. J Clin Invest 2013; 123: 4809-4820.
- 23 Orino K. Functional binding analysis of human fibrinogen as an iron- and heme-binding protein. Biometals 2013; 26: 789-794.
- 24 Zunszain PA, Ghuman J, Komatsu T, et al. Crystal structural analysis of human serum albumin complexed with hemin and fatty acid. BMC Struct Biol 2003; 3: 6.
- 25 Djalali AG, Moore KA, Kelly E. Report of a patient with severe transfusion-related acute lung injury after multiple transfusions, resuscitated with albumin. Resuscitation 2005; 66: 225-230.
- 26 Walter PB, Macklin EA, Porter J, et al. Inflammation and oxidant-stress in beta-thalassemia patients treated with iron chelators deferasirox (ICL670) or deferoxamine: an ancillary study of the Novartis CICL670A0107 trial. Haematologica 2008; 93: 817-825.
- 27 Zarogiannis SG, Jurkuvenaite A, Fernandez S, et al. Ascorbate and deferoxamine administration after chlorine exposure decrease mortality and lung injury in mice. Am J Respir Cell Mol Biol 2011; 45: 386-392.
- 28 Vlahakos D, Arkadopoulos N, Kostopanagiotou G, et al. Deferoxamine attenuates lipid peroxidation, blocks interleukin-6 production, ameliorates sepsis inflammatory response syndrome, and confers renoprotection after acute hepatic ischemia in pigs. Artif Organs 2012; 36: 400-408.
- 29 Kostopanagiotou GG, Kalimeris KA, Arkadopoulos NP, et al. Desferrioxamine attenuates minor lung injury following surgical acute liver failure. Eur Respir J 2009; 33: 1429-1436.
- 30 Saigo K, Kono M, Takagi Y, et al. Deferasirox reduces oxidative stress in patients with transfusion dependency. J. Clin Med Res 2013; 5: 57-60.
- 31 Thomas GM, Carbo C, Curtis BR, et al. Extracellular DNA traps are associated with the pathogenesis of TRALI in humans and mice. Blood 2012; 119: 6335-6343.
- 32 Caudrillier A, Kessenbrock K, Gilliss BM, et al. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J Clin Invest 2012; 122: 2661-2671.
- 33 Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303: 1532-1535.
- 34 Gardiner EE, Andrews RK. Neutrophil extracellular traps (NETs) and infection-related vascular dysfunction. Blood Rev 2012; 26: 255-259.
- 35 Fuchs TA, Abed U, Goosmann C, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 2007; 176: 231-241.
- 36 Brinkmann V, Zychlinsky A. Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol 2007; 5: 577-582.
- 37 Pilsczek FH, Salina D, Poon KK, et al. A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus. J Immunol 2010; 185: 7413-7425.
- 38 Hirayama J, Abe H, Azuma H, et al. Leakage of potassium from red blood cells following gamma ray irradiation in the presence of dipyridamole, trolox, human plasma or mannitol. Biol Pharm Bull 2005; 28: 1318-1320.
- 39 Nakamura A, Abe K, Masuya M, et al. Efficiency of diversion of the first aliquot of blood and prestorage leukoreduction for preventing bacterial contamination in red blood cell concentrates assessed using a rapid polymerase chain reaction-based bacterial detection system. Transfus Med 2011; 21: 365-370.
- 40 Lombardo ME, Araujo LS, Ciccarelli AB, et al. A spectrophotometric method for estimating hemin in biological systems. Anal Biochem 2005; 341: 199-203.
- 41 Silliman CC, Ambruso DR, Boshkov LK. Transfusion-related acute lung injury. Blood 2005; 105: 2266-2273.
- 42 Zimmerman JL, Shen MC. Rhabdomyolysis. Chest 2013; 144: 1058-1065.
- 43 Almyroudis NG, Grimm MJ, Davidson BA, et al. NETosis and NADPH oxidase: at the intersection of host defense, inflammation, and injury. Front Immunol 2013; 4: 45.
- 44 Marcos V, Zhou Z, Yildirim AO, et al. CXCR2 mediates NADPH oxidase-independent neutrophil extracellular trap formation in cystic fibrosis airway inflammation. Nat Med 2010; 16: 1018-1023.
- 45 Chaudhary R, Katharia R. Oxidative injury as contributory factor for red cells storage lesion during twenty eight days of storage. Blood Transfus 2012; 10: 59-62.
Citing Literature
