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Copyright © 2014 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.
Guest Editorial
Artificial Oxygen Carrier to Regulate Hypoxic Signal Transduction Enthusiasm toward developing artificial oxygen (O2) carriers (AOCs) was depressed by a meta-analysis report (1) of five different clinical trials with a total of some 2000 patients receiving the first generation of AOCs. However, recent recognition of the deterioration of stored human red blood cells (RBCs) (2) has aggravated the already keen demand/supply imbalance of donated blood for transfusion, fueling the continuing endeavor to come up with new concepts and technologies to overcome problems (1) or fulfill new requirements proclaimed by the National Institutes of Health (NIH) (3). In this issue, it is encouraging to report new utilities and recently developed AOCs from recycled human RBCs (4–17), unlimited hemoglobin (Hb) from bovine RBCs (18– 21), and other sources (22–24). Some of them are close to or are currently under clinical trial (20). In addition, there was a newly recognized concept introduced in this issue that appears to be distinct from previous functions of AOC as RBC substitutes or O2 therapeutics, namely, a regulator of intracellular hypoxic signal transduction. It has been our consistent observation that liposome-encapsulated hemoglobin (LEH), specifically with high O2 affinity (h-LEH, P50O2 = 8– 17 mm Hg), has been associated with suppressed inflammation to promote wound healing (5–8), reduce damage after ischemia/reperfusion (9–13), and enhance antitumor therapies (14–16). Whereas LEH with low O2 affinity (l-LEH, P50O2 = 40– 50 mm Hg) was able to maintain O2 delivery as a whole in rabbits under hemorrhagic shock, it was not associated with improved peripheral perfusion or extended survival (4). Although AOC with high O2 affinity promotes targeted O2 delivery (25), subsequent mechanism(s) remained unclear. As a clue for clarifying the link between O2 delivery to hypoxic cells and subsequent tamed inflammation, unique observations are presented in this issue (5,15) regarding the presence of O2 promoting degradation
doi:10.1111/aor.12372
of hypoxia-inducible factor 1-alfa (HIF-1α) by O2-dependent hydroxylation (Fig. 1A). However, the absence of O2 or hypoxia allows accumulation of HIF-1α in cytoplasm, which is transferred to the nucleus to initiate hypoxic responses (Fig. 1B), including cytokine production to promote erythropoiesis (18), vasculogenesis (26), phagocytosis (27), and many other biological responses related to inflammation. Cellular response to innate immunity (28), as well as nuclear factor kappa-B, has also been interrelated with HIF-1α (29) to control the microenvironment against hypoxia, infection, and inflammation (30). Observations compatible with this theory include milder wound adhesion (5,7,8), decreased inflammatory cell infiltration (5,8), reduced proinflammatory cytokines (8), and a widened therapeutic window late after ischemic events (11) involving reperfusion (4–13) rather than permanent ischemia. The extended dose-response relationship (minimal effective dose as little as 0.4 mL/kg [5,10)]), and plateaued efficacy at the other end suggests that aerobic energy generation per se was not the sole mechanism(s) behind the benefits so far accredited to AOC or its O2 delivery. Although the new concept may better account for the above observations (4–16) in favor of h-LEH over l-LEH, either of the mechanisms alone, but more likely both, may be operating since l-LEH was less, but still beneficial (9–13). Therefore, a trace amount of O2 is able to regulate the HIF-1α signal transduction system (Fig. 1A) to suppress successive hypoxic responses, resulting in immediate attenuation of inflammation and late suppression of nitric oxide (NO) synthase induction, thus balancing in favor of reduced apoptosis (10,11) , aerobic de novo protein synthesis (7) and accelerated tissue regeneration. Not only in hypoxic somatic cells but also in tumor cell oxygenation was it demonstrated in a mouse model using near-infrared spectroscopy (16) that tumor Hb saturation increased in the order of intravenous h-LEH, homologous RBC, and l-LEH. Combined use of h-LEH-enhanced radiotherapy for tumor growth (14) and strengthened chemotherapy Artificial Organs 2014, 38(8):617–620
618
GUEST EDITORIAL
$
$2&2
1RUPR[LD HIF-1α
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O2
HIF-1α HIF 1α
&HOO 0HPEUDQH
HIF-1α
O2 Hydroxylase OH
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Phagocytosis Innate Immunity
Inflammation
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VEGF
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MMP2
%
+\SR[LD +\SR[LD HIF-1α
1R2 1R 2
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O2
O2
HIF-1α HIF 1α
&HOO 0HPEUDQH
FIG. 1. Oxygen and HIF-1α relation in the microenvironment. HIF-1α is considered to be degenerated by oxygen-dependent hydroxylation (A). Under hypoxia (B), however, HIF-1α is accumulated in the cytoplasm and transduced to the nucleus where the cascade of hypoxic responses is initiated. Thus, the presence or delivery of O2 (normoxia) may suppress hypoxic responses by degradation of HIF-1α in the cytoplasm thus preventing its transduction. The numbers represent the referenced literature in the present editorial. Asterisks (*) indicate the materials under ongoing experimental investigation.
HIF-1α Signal Transduction
Degradation
1XFOHXV
1)N%
HIF-1α
\ S &\WRSODVP
Phagocytosis Innate Immunity
Hypoxic Response
Inflammation
Erythropoietin
VEGF
NOS
IL-1β INFг IL-6
MMP2
of metastasis (15), when metastatic foci, HIF-1α accumulation as well as matrix-metalloproteinase 2 (MMP2) expression (Fig. 1A) were all suppressed in mice treated with h-LEH alone or in combination with chemotherapeutic agents. As tumor tissue has unique vascular development and energy generation, Artif Organs, Vol. 38, No. 8, 2014
AOC may be useful in studying, modifying, and hopefully suppressing its invasion, growth (14,26), and metastasis (15) as a new antitumor agent. Suppression of hypoxic signal transduction may be the common mechanism(s) of the non-AOC materials reported in this issue (24,31) as being
GUEST EDITORIAL beneficial/effective in similar situations: hypoxia, ischemia, and reperfusion. Okada et al. (11) hypothesized that NO synthase induction would be involved (Fig. 1A), as administration of LEH 60 min after reperfusion turned out to be functionally sheltering and morphologically protective of inner hair cells 7 days later in a way similar to the effects in a pretreatment model (12). Thus, a more convincing argument might be that improvements in the microenvironment may foster and accelerate the process of regeneration after surgery (5,6), trauma (7,8), hemorrhage (4,24), or ischemia/reperfusion injury (9–13). As speculated in each of these experimental studies, the wound healing process is a sum of various factors; while the surgically obtained strength (Fig. 2) will only decrease, the healing process will increase the anastomotic strength; the sum of them represents the total mechanical strength of the wound, which was measured as the surrogate of tissue healing (5,6). While clinical gastrointestinal leakage or bronchial dehiscence usually occurs 1–2 weeks after surgery when the total mechanical strength passes under the threshold, experimental animals showed the lowest bursting pressure at 2 days in the stomach (5) as well
%XUVWLQ QJ3UHVVVXUH
'HOD\HG1RUPDO$FFHOHUDWHG
as with bronchial surgery (6). Such accelerated healing in animals or delayed dehiscence in humans may be accounted for by the difference in body size (32); the unit of time after surgery/trauma (Fig. 2) may be in the order of days for rodents and weeks for humans. It has been recognized that any living cell larger than 1 mm in diameter needs to have blood or cytoplasm circulated for aerobic energy generation, supplying O2 as well as substrates (32). Although O2 intake by respiration and delivery by circulation are the most important functions of RBCs in larger animals, AOCs may serve better than RBCs in some unusual and/or pathological conditions in circulation, respiration, and oncology as their new utilities. In addition, O2 is important not only as the substrate to generate aerobic energy synthesis, but also to regulate the microenvironment in somatic and tumor cells as a regulator of hypoxic signal transduction through the HIF-1α system. Thus, O2 supply and control by AOC may shed light on the ischemia/reperfusion pathology and control of malignancies as one of the potent biological diatomic molecules, such as NO, carbon monoxide (33), or cyanide (34), all involved in the regulation of energy generation and metabolism in the intracellular microenvironment. Akira T. Kawaguchi, MD, PhD Cell Transplantation and Regenerative Medicine Tokai University School of Medicine Isehara, Kanagawa 259-1193, Japan E-mail: [email protected]
7RWDO 6WUHQJWK
%XUVWLQJ 7KUHVKROG 7K K OG
619
Healing Surgical Strength
Surgical Strength
Healing
0
1
2
3
4 0
1
2
3
4
0
1
2
3
4
'D\VDIWHU6XUJHU\ FIG. 2. Changes in bursting pressure after surgery. Total mechanical strength (solid lines) after surgery may comprise the strength derived from surgical manipulation (surgical strength, broken lines) and tissue regeneration (healing, masked lines). Although surgical strength will only decrease, tissue regeneration and/or healing determine total strength: delayed (left), normal (middle), and accelerated healing (right), depending on the environment. Although mechanical strength may pass under the threshold, resulting in leaking and/or dehiscence in delayed healing (left), accelerated healing (right) may be advantageous for avoiding such adverse events. This may account for the observations in rat stomach (5) and bronchus (6), which differed at 2 days, but no longer at 4 days after surgery. This timing is much earlier in the rat compared with humans, where wound dehiscence/leakage usually occurs 1–2 weeks after surgery, when the total mechanical strength hits a nadir. The difference in timing may be accounted for by the body size of the host (32); time unit after surgery may be in days for rats and weeks for humans.
REFERENCES 1. Natanson C, Kern SJ, Lurie P, Banks SM, Wolfe SM. Cell-free hemoglobin-based blood substitute and risk of myocardial infarction and death: a meta-analysis. J Am Med Assoc 2008;299:2304–12. 2. Wang D, Sun J, Solomon SB, Klein HG, Natanson C. Transfusion of older stored blood and risk of death: a meta-analysis. Transfusion 2012;52:1184–95. 3. NIH/FDA/DOD. Interagency Working Group on Oxygen Therapeutics. July 26, 2011; MGH, Harvard. Available at: http://www.nhlbi.nih.gov/meetings/workshops/therapeutics .htm. Accessed July 10, 2014. 4. Ikegawa H, Kuwagata Y, Hayakawa K, Noguchi K, Ogura H, Sugimoto H. Effects of exchange transfusion with liposomeencapsulated hemoglobin on VO2/DO2. Artif Organs 2012;36:130–8. 5. Kawaguchi AT, Okamoto Y, Kise Y, et al. Effects of liposome-encapsulated hemoglobin on gastric wound healing in the rat. Artif Organs 2014;38:641–9. 6. Takeichi H, Kawaguchi AT, Murayama C, et al. Liposomeencapsulated hemoglobin accelerates bronchial healing after pneumonectomy in the rat without or with preoperative radiotherapy. Artif Organs 2014;38:634–40. 7. Fukui T, Kawaguchi AT, Takekoshi S, Miyasaka M, Tanaka R. Efficacy of liposome-encapsulated hemoglobin accelerates skin wound healing in mice. Artif Organs 2012;36:161–9. Artif Organs, Vol. 38, No. 8, 2014
620
GUEST EDITORIAL
8. Fukui T, Kawaguchi AT, Takekoshi S, Miyasaka M, Tanaka R. Liposome-encapsulated hemoglobin accelerates skin wound healing in dBdB mice. Abstracts, ASAIO 60th Annual Conference 2014. Abstract 235, p. 18. Available at: http:// journals.lww.com/asaiojournal/Documents/MAT _ABSTRACTS(3).pdf. Accessed July 10, 2014. 9. Kawaguchi AT, Endo H, Aikawa H, et al. Effects of liposome encapsulated hemoglobin on learning ability in Tokai highavoider rat after total brain ischemia and reperfusion. Artif Organs 2014;38:667–74. 10. Fukumoto D, Kawaguchi AT, Haida M, et al. Liposomeencapsulated hemoglobin reduces the size of cerebral infarction in rats: effect of oxygen affinity. Artif Organs 2009;33:159–63. 11. Okada M, Kawaguchi AT, Hakuba N, Hyodo J, Hato N, Gyo K. Liposome-encapsulated hemoglobin alleviates hearing loss after transient cochlear ischemia: an experimental study in the gerbil. Neurosci Lett 2013;553:176–80. 12. Okada M, Kawaguchi AT, Hakuba N, et al. Liposomeencapsulated hemoglobin alleviates hearing loss after transient cochlear ischemia and reperfusion in the gerbil. Artif Organs 2012;36:178–84. 13. Kaneda S, Ishizuka T, Sekiguchi A, Morimoto K, Kasukawa H. Efficacy of liposome-encapsulated hemoglobin (LEH) in a rat model of cerebral ischemia. Artif Organs 2014;38:650–5. 14. Murayama C, Kawaguchi AT, Ishikawa K, et al. Liposomeencapsulated hemoglobin ameliorates tumor hypoxia and enhances radiation therapy to suppress tumor growth in mice. Artif Organs 2012;36:170–7. 15. Murayama C, Kawaguchi AT, Kamijo A, et al. Liposomeencapsulated hemoglobin enhances chemotherapy to suppress metastasis in mice. Artif Organs 2014;38:656–61. 16. Kawaguchi F, Kawaguchi AT, Kamijo A, Haida M, Kurita D, Murayama C. Liposome-encapsulated hemoglobin improves tumor oxygenation as detected by near-infrared spectroscopy (NIRS) in colon carcinoma in mice. Abstracts, ASAIO 60th Annual Conference 2014. Abstract 240, p. 19. Available at: http://journals.lww.com/asaiojournal/Documents/MAT _ABSTRACTS(3).pdf. Accessed July 10, 2014. 17. Yadav VR, Nag O, Awasthi V. Biological evaluation of liposome-encapsulated hemoglobin surface-modified with a novel PEGylated non-phospholipid amphiphile. Artif Organs 2014;38:625–33. 18. Simoni J, Simoni G, Moeller JF, Griswold JA, Wesson DE. Adenosine-5’–triphosphate-adenosine-glutathione crosslinked hemoglobin as erythropoiesis-stimulating agent. Artif Organs 2012;36:139–50. 19. Simoni J, Simoni G, Moeller JF, Feola M, Wesson DE. Artificial oxygen carrier with pharmacologic actions of ATP,
Artif Organs, Vol. 38, No. 8, 2014
20. 21. 22. 23. 24.
25. 26. 27. 28. 29. 30. 31.
32. 33. 34.
adenosine and reduced glutathione formulated to treat an array of medical conditions. Artif Organs 2014;38:684– 90. Misra H, Lickliter J, Kazo F, Abuchowski A. PEGylated carboxyhemoglobin bovine (SANGUINATETM): results of a phase I clinical trial. Artif Organs 2014;38:702–7. Baumler H, Xiang Y, Liu ZZ, Patzak A, Georgieva R. Novel hemoglobin particles—promising new-generation hemoglobin based oxygen carriers. Artif Organs 2014;38:708–14. Mallet V, Dutheil D, Polard V, et al. Dose ranging study of the performance of the naturaloxygen transporter HEMO2Life in organ preservation. Artif Organs 2014;38:691–701. Neya S, Yonetani T, Kawaguchi AT. Usefulness of myoglobin containing cobalt heme cofactor in designing myoglobin-based artificial oxygen carrier. Artif Organs 2014;38:715–19. Yadav VR, Vilekar P, Awasthi S, Awasthi V. Hemorrhageinduced interleukin-1 receptor pathway in lung is suppressed by 3,5-bis(2-fluoro-benzylidine)-4-piperidone in a rat model of hypovolemic shock. Artif Organs 2014;38:675–83. Tsai AG, Vandegriff K, Intagrietta M, Winslow RM. Targeted O2 delivery by low-P50 hemoglobin: a new basis for O2 therapeutics. Am J Physiol 2003;285:H1411–9. Tang N, Wang L, Esco J, et al. Loss of HIF-1α in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 2004;6:485–94. Peyssonnaux C, Datta V, Cramer T, et al. HIF-1α expression regulates the bactericidal capacity of phagocytes. J Clin Invest 2005;115:1806–15. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006;124:783–801. Rius J, Guma M, Schachtrup C, et al. NFkB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature 2008;543:807–11. Cramer T, Yamanishi Y, Clausen BE, et al. HIF-1α is essential for myeloid cell-mediated inflammation. Cell 2003;112:645– 57. Fukuta T, Ishii T, Asai T, et al. Real-time trafficking of PEGylated liposomes in the rodent focal brain ischemia analyzed by positron-emission tomography. Artif Organs 2014;38: 662–6. Lindstedt SL, Calder WA III. Body size, physiological time, and longevity of homeothermic animals. Q Rev Biol 1981;56:1–16. Kitagishi H, Negi S, Kiriyama A, et al. A diatomic molecule receptor that removes CO in a living organism. Angew Chem Int Ed Engl 2010;49:1312–5. Yamagiwa T, Kawaguchi AT, Saito T, et al. Supramolecular ferric porphyrins and a cyclodextrin dimer as an antidote for cyanide poisoning. Hum Exp Toxicol 2014;33:360–8.
Copyright © 2014 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.
Guest Editorial
Artificial Oxygen Carrier to Regulate Hypoxic Signal Transduction Enthusiasm toward developing artificial oxygen (O2) carriers (AOCs) was depressed by a meta-analysis report (1) of five different clinical trials with a total of some 2000 patients receiving the first generation of AOCs. However, recent recognition of the deterioration of stored human red blood cells (RBCs) (2) has aggravated the already keen demand/supply imbalance of donated blood for transfusion, fueling the continuing endeavor to come up with new concepts and technologies to overcome problems (1) or fulfill new requirements proclaimed by the National Institutes of Health (NIH) (3). In this issue, it is encouraging to report new utilities and recently developed AOCs from recycled human RBCs (4–17), unlimited hemoglobin (Hb) from bovine RBCs (18– 21), and other sources (22–24). Some of them are close to or are currently under clinical trial (20). In addition, there was a newly recognized concept introduced in this issue that appears to be distinct from previous functions of AOC as RBC substitutes or O2 therapeutics, namely, a regulator of intracellular hypoxic signal transduction. It has been our consistent observation that liposome-encapsulated hemoglobin (LEH), specifically with high O2 affinity (h-LEH, P50O2 = 8– 17 mm Hg), has been associated with suppressed inflammation to promote wound healing (5–8), reduce damage after ischemia/reperfusion (9–13), and enhance antitumor therapies (14–16). Whereas LEH with low O2 affinity (l-LEH, P50O2 = 40– 50 mm Hg) was able to maintain O2 delivery as a whole in rabbits under hemorrhagic shock, it was not associated with improved peripheral perfusion or extended survival (4). Although AOC with high O2 affinity promotes targeted O2 delivery (25), subsequent mechanism(s) remained unclear. As a clue for clarifying the link between O2 delivery to hypoxic cells and subsequent tamed inflammation, unique observations are presented in this issue (5,15) regarding the presence of O2 promoting degradation
doi:10.1111/aor.12372
of hypoxia-inducible factor 1-alfa (HIF-1α) by O2-dependent hydroxylation (Fig. 1A). However, the absence of O2 or hypoxia allows accumulation of HIF-1α in cytoplasm, which is transferred to the nucleus to initiate hypoxic responses (Fig. 1B), including cytokine production to promote erythropoiesis (18), vasculogenesis (26), phagocytosis (27), and many other biological responses related to inflammation. Cellular response to innate immunity (28), as well as nuclear factor kappa-B, has also been interrelated with HIF-1α (29) to control the microenvironment against hypoxia, infection, and inflammation (30). Observations compatible with this theory include milder wound adhesion (5,7,8), decreased inflammatory cell infiltration (5,8), reduced proinflammatory cytokines (8), and a widened therapeutic window late after ischemic events (11) involving reperfusion (4–13) rather than permanent ischemia. The extended dose-response relationship (minimal effective dose as little as 0.4 mL/kg [5,10)]), and plateaued efficacy at the other end suggests that aerobic energy generation per se was not the sole mechanism(s) behind the benefits so far accredited to AOC or its O2 delivery. Although the new concept may better account for the above observations (4–16) in favor of h-LEH over l-LEH, either of the mechanisms alone, but more likely both, may be operating since l-LEH was less, but still beneficial (9–13). Therefore, a trace amount of O2 is able to regulate the HIF-1α signal transduction system (Fig. 1A) to suppress successive hypoxic responses, resulting in immediate attenuation of inflammation and late suppression of nitric oxide (NO) synthase induction, thus balancing in favor of reduced apoptosis (10,11) , aerobic de novo protein synthesis (7) and accelerated tissue regeneration. Not only in hypoxic somatic cells but also in tumor cell oxygenation was it demonstrated in a mouse model using near-infrared spectroscopy (16) that tumor Hb saturation increased in the order of intravenous h-LEH, homologous RBC, and l-LEH. Combined use of h-LEH-enhanced radiotherapy for tumor growth (14) and strengthened chemotherapy Artificial Organs 2014, 38(8):617–620
618
GUEST EDITORIAL
$
$2&2
1RUPR[LD HIF-1α
O2
O2
HIF-1α HIF 1α
&HOO 0HPEUDQH
HIF-1α
O2 Hydroxylase OH
Signal Transduction
Degradation
1XFOHXV
1)N%
HIF-1α
\ S &\WRSODVP
Hypoxic Response
Phagocytosis Innate Immunity
Inflammation
Erythropoietin
IL-1β INFг IL-6
VEGF
NOS
MMP2
%
+\SR[LD +\SR[LD HIF-1α
1R2 1R 2
O2
O2
O2
HIF-1α HIF 1α
&HOO 0HPEUDQH
FIG. 1. Oxygen and HIF-1α relation in the microenvironment. HIF-1α is considered to be degenerated by oxygen-dependent hydroxylation (A). Under hypoxia (B), however, HIF-1α is accumulated in the cytoplasm and transduced to the nucleus where the cascade of hypoxic responses is initiated. Thus, the presence or delivery of O2 (normoxia) may suppress hypoxic responses by degradation of HIF-1α in the cytoplasm thus preventing its transduction. The numbers represent the referenced literature in the present editorial. Asterisks (*) indicate the materials under ongoing experimental investigation.
HIF-1α Signal Transduction
Degradation
1XFOHXV
1)N%
HIF-1α
\ S &\WRSODVP
Phagocytosis Innate Immunity
Hypoxic Response
Inflammation
Erythropoietin
VEGF
NOS
IL-1β INFг IL-6
MMP2
of metastasis (15), when metastatic foci, HIF-1α accumulation as well as matrix-metalloproteinase 2 (MMP2) expression (Fig. 1A) were all suppressed in mice treated with h-LEH alone or in combination with chemotherapeutic agents. As tumor tissue has unique vascular development and energy generation, Artif Organs, Vol. 38, No. 8, 2014
AOC may be useful in studying, modifying, and hopefully suppressing its invasion, growth (14,26), and metastasis (15) as a new antitumor agent. Suppression of hypoxic signal transduction may be the common mechanism(s) of the non-AOC materials reported in this issue (24,31) as being
GUEST EDITORIAL beneficial/effective in similar situations: hypoxia, ischemia, and reperfusion. Okada et al. (11) hypothesized that NO synthase induction would be involved (Fig. 1A), as administration of LEH 60 min after reperfusion turned out to be functionally sheltering and morphologically protective of inner hair cells 7 days later in a way similar to the effects in a pretreatment model (12). Thus, a more convincing argument might be that improvements in the microenvironment may foster and accelerate the process of regeneration after surgery (5,6), trauma (7,8), hemorrhage (4,24), or ischemia/reperfusion injury (9–13). As speculated in each of these experimental studies, the wound healing process is a sum of various factors; while the surgically obtained strength (Fig. 2) will only decrease, the healing process will increase the anastomotic strength; the sum of them represents the total mechanical strength of the wound, which was measured as the surrogate of tissue healing (5,6). While clinical gastrointestinal leakage or bronchial dehiscence usually occurs 1–2 weeks after surgery when the total mechanical strength passes under the threshold, experimental animals showed the lowest bursting pressure at 2 days in the stomach (5) as well
%XUVWLQ QJ3UHVVVXUH
'HOD\HG1RUPDO$FFHOHUDWHG
as with bronchial surgery (6). Such accelerated healing in animals or delayed dehiscence in humans may be accounted for by the difference in body size (32); the unit of time after surgery/trauma (Fig. 2) may be in the order of days for rodents and weeks for humans. It has been recognized that any living cell larger than 1 mm in diameter needs to have blood or cytoplasm circulated for aerobic energy generation, supplying O2 as well as substrates (32). Although O2 intake by respiration and delivery by circulation are the most important functions of RBCs in larger animals, AOCs may serve better than RBCs in some unusual and/or pathological conditions in circulation, respiration, and oncology as their new utilities. In addition, O2 is important not only as the substrate to generate aerobic energy synthesis, but also to regulate the microenvironment in somatic and tumor cells as a regulator of hypoxic signal transduction through the HIF-1α system. Thus, O2 supply and control by AOC may shed light on the ischemia/reperfusion pathology and control of malignancies as one of the potent biological diatomic molecules, such as NO, carbon monoxide (33), or cyanide (34), all involved in the regulation of energy generation and metabolism in the intracellular microenvironment. Akira T. Kawaguchi, MD, PhD Cell Transplantation and Regenerative Medicine Tokai University School of Medicine Isehara, Kanagawa 259-1193, Japan E-mail: [email protected]
7RWDO 6WUHQJWK
%XUVWLQJ 7KUHVKROG 7K K OG
619
Healing Surgical Strength
Surgical Strength
Healing
0
1
2
3
4 0
1
2
3
4
0
1
2
3
4
'D\VDIWHU6XUJHU\ FIG. 2. Changes in bursting pressure after surgery. Total mechanical strength (solid lines) after surgery may comprise the strength derived from surgical manipulation (surgical strength, broken lines) and tissue regeneration (healing, masked lines). Although surgical strength will only decrease, tissue regeneration and/or healing determine total strength: delayed (left), normal (middle), and accelerated healing (right), depending on the environment. Although mechanical strength may pass under the threshold, resulting in leaking and/or dehiscence in delayed healing (left), accelerated healing (right) may be advantageous for avoiding such adverse events. This may account for the observations in rat stomach (5) and bronchus (6), which differed at 2 days, but no longer at 4 days after surgery. This timing is much earlier in the rat compared with humans, where wound dehiscence/leakage usually occurs 1–2 weeks after surgery, when the total mechanical strength hits a nadir. The difference in timing may be accounted for by the body size of the host (32); time unit after surgery may be in days for rats and weeks for humans.
REFERENCES 1. Natanson C, Kern SJ, Lurie P, Banks SM, Wolfe SM. Cell-free hemoglobin-based blood substitute and risk of myocardial infarction and death: a meta-analysis. J Am Med Assoc 2008;299:2304–12. 2. Wang D, Sun J, Solomon SB, Klein HG, Natanson C. Transfusion of older stored blood and risk of death: a meta-analysis. Transfusion 2012;52:1184–95. 3. NIH/FDA/DOD. Interagency Working Group on Oxygen Therapeutics. July 26, 2011; MGH, Harvard. Available at: http://www.nhlbi.nih.gov/meetings/workshops/therapeutics .htm. Accessed July 10, 2014. 4. Ikegawa H, Kuwagata Y, Hayakawa K, Noguchi K, Ogura H, Sugimoto H. Effects of exchange transfusion with liposomeencapsulated hemoglobin on VO2/DO2. Artif Organs 2012;36:130–8. 5. Kawaguchi AT, Okamoto Y, Kise Y, et al. Effects of liposome-encapsulated hemoglobin on gastric wound healing in the rat. Artif Organs 2014;38:641–9. 6. Takeichi H, Kawaguchi AT, Murayama C, et al. Liposomeencapsulated hemoglobin accelerates bronchial healing after pneumonectomy in the rat without or with preoperative radiotherapy. Artif Organs 2014;38:634–40. 7. Fukui T, Kawaguchi AT, Takekoshi S, Miyasaka M, Tanaka R. Efficacy of liposome-encapsulated hemoglobin accelerates skin wound healing in mice. Artif Organs 2012;36:161–9. Artif Organs, Vol. 38, No. 8, 2014
620
GUEST EDITORIAL
8. Fukui T, Kawaguchi AT, Takekoshi S, Miyasaka M, Tanaka R. Liposome-encapsulated hemoglobin accelerates skin wound healing in dBdB mice. Abstracts, ASAIO 60th Annual Conference 2014. Abstract 235, p. 18. Available at: http:// journals.lww.com/asaiojournal/Documents/MAT _ABSTRACTS(3).pdf. Accessed July 10, 2014. 9. Kawaguchi AT, Endo H, Aikawa H, et al. Effects of liposome encapsulated hemoglobin on learning ability in Tokai highavoider rat after total brain ischemia and reperfusion. Artif Organs 2014;38:667–74. 10. Fukumoto D, Kawaguchi AT, Haida M, et al. Liposomeencapsulated hemoglobin reduces the size of cerebral infarction in rats: effect of oxygen affinity. Artif Organs 2009;33:159–63. 11. Okada M, Kawaguchi AT, Hakuba N, Hyodo J, Hato N, Gyo K. Liposome-encapsulated hemoglobin alleviates hearing loss after transient cochlear ischemia: an experimental study in the gerbil. Neurosci Lett 2013;553:176–80. 12. Okada M, Kawaguchi AT, Hakuba N, et al. Liposomeencapsulated hemoglobin alleviates hearing loss after transient cochlear ischemia and reperfusion in the gerbil. Artif Organs 2012;36:178–84. 13. Kaneda S, Ishizuka T, Sekiguchi A, Morimoto K, Kasukawa H. Efficacy of liposome-encapsulated hemoglobin (LEH) in a rat model of cerebral ischemia. Artif Organs 2014;38:650–5. 14. Murayama C, Kawaguchi AT, Ishikawa K, et al. Liposomeencapsulated hemoglobin ameliorates tumor hypoxia and enhances radiation therapy to suppress tumor growth in mice. Artif Organs 2012;36:170–7. 15. Murayama C, Kawaguchi AT, Kamijo A, et al. Liposomeencapsulated hemoglobin enhances chemotherapy to suppress metastasis in mice. Artif Organs 2014;38:656–61. 16. Kawaguchi F, Kawaguchi AT, Kamijo A, Haida M, Kurita D, Murayama C. Liposome-encapsulated hemoglobin improves tumor oxygenation as detected by near-infrared spectroscopy (NIRS) in colon carcinoma in mice. Abstracts, ASAIO 60th Annual Conference 2014. Abstract 240, p. 19. Available at: http://journals.lww.com/asaiojournal/Documents/MAT _ABSTRACTS(3).pdf. Accessed July 10, 2014. 17. Yadav VR, Nag O, Awasthi V. Biological evaluation of liposome-encapsulated hemoglobin surface-modified with a novel PEGylated non-phospholipid amphiphile. Artif Organs 2014;38:625–33. 18. Simoni J, Simoni G, Moeller JF, Griswold JA, Wesson DE. Adenosine-5’–triphosphate-adenosine-glutathione crosslinked hemoglobin as erythropoiesis-stimulating agent. Artif Organs 2012;36:139–50. 19. Simoni J, Simoni G, Moeller JF, Feola M, Wesson DE. Artificial oxygen carrier with pharmacologic actions of ATP,
Artif Organs, Vol. 38, No. 8, 2014
20. 21. 22. 23. 24.
25. 26. 27. 28. 29. 30. 31.
32. 33. 34.
adenosine and reduced glutathione formulated to treat an array of medical conditions. Artif Organs 2014;38:684– 90. Misra H, Lickliter J, Kazo F, Abuchowski A. PEGylated carboxyhemoglobin bovine (SANGUINATETM): results of a phase I clinical trial. Artif Organs 2014;38:702–7. Baumler H, Xiang Y, Liu ZZ, Patzak A, Georgieva R. Novel hemoglobin particles—promising new-generation hemoglobin based oxygen carriers. Artif Organs 2014;38:708–14. Mallet V, Dutheil D, Polard V, et al. Dose ranging study of the performance of the naturaloxygen transporter HEMO2Life in organ preservation. Artif Organs 2014;38:691–701. Neya S, Yonetani T, Kawaguchi AT. Usefulness of myoglobin containing cobalt heme cofactor in designing myoglobin-based artificial oxygen carrier. Artif Organs 2014;38:715–19. Yadav VR, Vilekar P, Awasthi S, Awasthi V. Hemorrhageinduced interleukin-1 receptor pathway in lung is suppressed by 3,5-bis(2-fluoro-benzylidine)-4-piperidone in a rat model of hypovolemic shock. Artif Organs 2014;38:675–83. Tsai AG, Vandegriff K, Intagrietta M, Winslow RM. Targeted O2 delivery by low-P50 hemoglobin: a new basis for O2 therapeutics. Am J Physiol 2003;285:H1411–9. Tang N, Wang L, Esco J, et al. Loss of HIF-1α in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 2004;6:485–94. Peyssonnaux C, Datta V, Cramer T, et al. HIF-1α expression regulates the bactericidal capacity of phagocytes. J Clin Invest 2005;115:1806–15. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006;124:783–801. Rius J, Guma M, Schachtrup C, et al. NFkB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature 2008;543:807–11. Cramer T, Yamanishi Y, Clausen BE, et al. HIF-1α is essential for myeloid cell-mediated inflammation. Cell 2003;112:645– 57. Fukuta T, Ishii T, Asai T, et al. Real-time trafficking of PEGylated liposomes in the rodent focal brain ischemia analyzed by positron-emission tomography. Artif Organs 2014;38: 662–6. Lindstedt SL, Calder WA III. Body size, physiological time, and longevity of homeothermic animals. Q Rev Biol 1981;56:1–16. Kitagishi H, Negi S, Kiriyama A, et al. A diatomic molecule receptor that removes CO in a living organism. Angew Chem Int Ed Engl 2010;49:1312–5. Yamagiwa T, Kawaguchi AT, Saito T, et al. Supramolecular ferric porphyrins and a cyclodextrin dimer as an antidote for cyanide poisoning. Hum Exp Toxicol 2014;33:360–8.
