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Hemolysis and Cell-Free Hemoglobin Drive an Intrinsic Mechanism for Human Disease

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Hemolysis and Cell-Free Hemoglobin Drive an Intrinsic Mechanism for Human Disease Hemolysis and cell-free hemoglobin drive an intrinsic mechanism for human disease Mark T. Gladwin, … , Tamir Kanias, Daniel B. Kim-Shapiro J Clin Invest. 2012;122(4):1205-1208. https://doi.org/10.1172/JCI62972. Commentary Blood transfusion represents the first and most prescribed cell-based therapy; however, clinical safety and efficacy trials are lacking. Clinical cohort studies have suggested that massive transfusion and/or transfusion of aged stored blood may contribute to multiorgan dysfunction in susceptible patients. In this issue of the JCI, Baek and colleagues report that aged stored blood hemolyzes after massive transfusion in a guinea pig model. Hemolysis led to vascular and kidney injury that was mediated by cell-free plasma hemoglobin and prevented by coinfusion of the specific hemoglobin scavenger protein, haptoglobin. These studies support an expanding body of research indicating that intravascular hemolysis is a pathological mechanism in several human diseases, including multiorgan dysfunction after either massive red blood cell transfusion or hemoglobin-based blood substitute therapy, the hemoglobinopathies, malaria, and other acquired and genetic hemolytic conditions. Find the latest version: https://jci.me/62972/pdf commentaries inhibition selectively sensitizes G1 checkpoint-defi- checkpoint signaling through the p38MAPK/MK2 17. Schoppy DW, et al. Oncogenic stress sensitizes cient cells to lethal premature chromatin condensa- pathway for survival after DNA damage. Cancer murine cancers to hypomorphic suppression of tion. Proc Natl Acad Sci U S A. 2001;98(16):9092–9097. Cell. 2007;11(2):175–189. ATR. J Clin Invest. 2012;122(1):241–252. 8. Koniaras K, Cuddihy AR, Christopoulos H, Hogg 13. Gilad O, et al. Combining ATR suppression with 18. Bartkova J, et al. DNA damage response as a candi- A, O’Connell MJ. Inhibition of Chk1-dependent G2 oncogenic Ras synergistically increases genomic date anti-cancer barrier in early human tumorigen- DNA damage checkpoint radiosensitizes p53 mutant instability, causing synthetic lethality or tumori- esis. Nature. 2005;434(7035):864–870. human cells. Oncogene. 2001;20(51):7453–7463. genesis in a dosage-dependent manner. Cancer Res. 19. Gorgoulis VG, et al. Activation of the DNA damage 9. Zhou BB, Bartek J. Targeting the checkpoint kinas- 2010;70(23):9693–9702. checkpoint and genomic instability in human pre- es: chemosensitization versus chemoprotection. 14. Toledo LI, et al. A cell-based screen identifies ATR cancerous lesions. Nature. 2005;434(7035):907–913. Nat Rev Cancer. 2004;4(3):216–225. inhibitors with synthetic lethal properties for 20. Brown EJ, Baltimore D. ATR disruption leads to 10. Ma CX, Janetka JW, Piwnica-Worms H. Death by cancer-associated mutations. Nat Struct Mol Biol. chromosomal fragmentation and early embryonic releasing the breaks: CHK1 inhibitors as cancer 2011;18(6):721–727. lethality. Genes Dev. 2000;14(4):397–402. therapeutics. Trends Mol Med. 2011;17(2):88–96. 15. Ferrao PT, Bukczynska EP, Johnstone RW, McAr- 21. Ruzankina Y, et al. Deletion of the developmen- 11. Fracasso PM, et al. A Phase 1 study of UCN-01 in thur GA. Efficacy of CHK inhibitors as single tally essential gene ATR in adult mice leads to age- combination with irinotecan in patients with resis- agents in MYC-driven lymphoma cells. Oncogene. related phenotypes and stem cell loss. Cell Stem Cell. tant solid tumor malignancies. Cancer Chemother 2012;31(13):1661–1672. 2007;1(1):113–126. Pharmacol. 2010;67(6):1225–1237. 16. Murga M, et al. Exploiting oncogene-induced rep- 22. Reaper PM, et al. Selective killing of ATM- or p53- 12. Reinhardt HC, Aslanian AS, Lees JA, Yaffe MB. p53- licative stress for the selective killing of Myc-driven deficient cancer cells through inhibition of ATR. deficient cells rely on ATM- and ATR-mediated tumors. Nat Struct Mol Biol. 2011;18(12):1331–1335. Nat Chem Biol. 2011;7(7):428–430. Hemolysis and cell-free hemoglobin drive an intrinsic mechanism for human disease Mark T. Gladwin,1 Tamir Kanias,1 and Daniel B. Kim-Shapiro2 1Vascular Medicine Institute and Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 2Department of Physics and Translational Science Center, Wake Forest University, Winston-Salem, North Carolina, USA. Blood transfusion represents the first and most prescribed cell-based ther- membrane integrity (e.g., reducing deform- apy; however, clinical safety and efficacy trials are lacking. Clinical cohort ability and increasing rigidity), alter rheo- studies have suggested that massive transfusion and/or transfusion of logical properties, and cause hemolysis aged stored blood may contribute to multiorgan dysfunction in suscepti- and have been proposed to contribute in ble patients. In this issue of the JCI, Baek and colleagues report that aged some way to the risk of transfusion of aged stored blood hemolyzes after massive transfusion in a guinea pig model. blood. However, the epidemiologically Hemolysis led to vascular and kidney injury that was mediated by cell-free established relationship between age of plasma hemoglobin and prevented by coinfusion of the specific hemoglo- transfused blood and risk of adverse clini- bin scavenger protein, haptoglobin. These studies support an expanding cal outcomes is confounded by a number body of research indicating that intravascular hemolysis is a pathological of important variables. First, transfusion mechanism in several human diseases, including multiorgan dysfunction of multiple units of blood increases the after either massive red blood cell transfusion or hemoglobin-based blood probability that an older unit is given, cre- substitute therapy, the hemoglobinopathies, malaria, and other acquired ating uncertainty about the role of massive and genetic hemolytic conditions. transfusion as opposed to that from a stor- age lesion mechanism (2). Second, sicker Blood transfusion and ischemic heart disease; it is also clearly patients receive more units (3). Finally, the storage lesion beneficial as a supportive and exchange O blood group units are more rare and are Blood transfusion is one of the first and therapy for hemoglobinopathies. However, more rapidly depleted from the inventory, most prescribed cell-based therapies. an increasing number of studies suggest so that patients who have type O blood are Despite the frequency with which blood that massive transfusion — defined as the more likely to receive fresh blood, leading transfusion is prescribed, the timing, dose, transfusion of approximately one complete to fundamental differences among groups and established placebo-adjusted benefits blood volume within the first 24 hours in published case-controlled cohort studies of this “drug” have not been established. of resuscitation — may increase the risk of that may influence outcomes (4). Blood transfusion is clearly beneficial in multiorgan dysfunction, respiratory and In order to address the major variables a multitude of clinical conditions, such as renal insufficiency, and death (1–5). confounding the assessment of risk of massive traumatic and surgical hemorrhage, Studies in patients who have undergone transfusing blood stored for a long time, critical anemia, and anemia associated with cardiac surgery or experienced trauma or NIH-funded well-controlled transfusion critical illness have suggested that the age studies in preclinical animal models and Conflict of interest: Mark T. Gladwin and Daniel B. of the transfused blood may relate to the human placebo-controlled clinical trials Kim-Shapiro are named as co-inventors on an NIH risk of adverse clinical outcomes (1). The are being performed. While the clinical government patent for the use of nitrite salts for cardio- vascular conditions. combined effects of storage on red blood trials are underway, because of safety and Citation for this article: J Clin Invest. 2012; cells have been termed the “red blood cell ethical considerations, these trials evalu- 122(4):1205–1208. doi:10.1172/JCI62972. storage lesion.” These effects modulate ate only modest ranges of storage time as The Journal of Clinical Investigation http://www.jci.org Volume 122 Number 4 April 2012 1205 commentaries Figure 1 Mechanisms by which hemolysis and cell-free hemoglobin can medi- ate vascular injury. Intravascular hemolysis releases cell-free hemo- globin (Hb) into the plasma. The hemoglobin is maintained in the fer- rous redox state, which will react with NO in a near-diffusion limited reaction to inhibit NO signaling. Extravasation of hemoglobin in the subendothelial space and reductive recycling back to the ferrous state may enhance this pathological effect. Oxidation of hemoglobin, particularly in the kidney, from the ferric state to the ferryl state may further drive fenton and peroxidase oxidative cellular injury (involving the lipid peroxyl species, LOO•), leading to acute kidney injury. Free heme and iron promote inflammatory injury via activation of innate immune responses in macrophages and monocytes. Compensatory pathways that normally control these NO dioxygenation and oxidation reactions include haptoglobin- and hemopexin-mediated sequestra- tion of hemoglobin dimer and heme, respectively. Downstream Nrf-2, hemoxygenase, and biliverdin reductase signaling detoxify heme and iron and provide catalytic antioxidant, antiproliferative, and antiinflam- matory protective signaling. well as limited transfusion volumes and Intravascular hemolysis and associated with iron deposition within the
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