Novel Hemoglobin-Based Oxygen Carrier Bound With Albumin Shows Neuroprotection With Possible Antioxidant Effects
Abstract
Background and Purpose—
A hemoglobin-albumin cluster, 1 core of hemoglobin covalently bound with 3 shell albumins, designated as HemoAct was developed as a hemoglobin-based oxygen carrier. We aim to investigate neuroprotection by HemoAct in transient cerebral ischemia and elucidate its underlying mechanisms.
Methods—
Male rats were subjected to 2-hour transient middle cerebral artery occlusion and were then administered HemoAct transarterially at the onset of reperfusion. Neurological and pathological findings were examined after 24 hours of reperfusion to identify neuroprotection by HemoAct. Intermittent measurements of cortical blood flow and oxygen content were performed, and a histopathologic analysis was conducted on rats during the early phase of reperfusion to assess the therapeutic mechanism of HemoAct. In addition, the antioxidant effects of HemoAct were examined in hypoxia/reoxygenation-treated rat brain microvascular endothelial cells.
Results—
Neurological deterioration, infarct and edema development, and the activation of MMP-9 (matrix metalloprotease-9) and lipid peroxidation after 24 hours of reperfusion were significantly ameliorated by the HemoAct treatment. Reductions in blood flow and tissue partial oxygen pressure in the cortical penumbra after 6 hours of reperfusion were significantly ameliorated by the HemoAct treatment. The histopathologic analysis of the cortical penumbra revealed that HemoAct in HemoAct-treated rats showed superior microvascular perfusion with the mitigation of microvascular narrowing changes than autologous erythrocytes in nontreated rats. Although HemoAct extravasated into the ischemic core with serum protein, it did not induce an increase in serum extravasation or reactive oxygen species production in the ischemic core. In vitro experiments with rat brain microvascular endothelial cells revealed that HemoAct significantly suppressed cellular reactive oxygen species production in hypoxia/reoxygenation-treated cells, similar to albumin.
Conclusions—
HemoAct exerted robust neuroprotection in transient cerebral ischemia. Superior microvascular perfusion with an oxygen delivery capability and possible antioxidant effects appear to be the underlying neuroprotective mechanisms.
Graphical Abstract
Introduction
Because several randomized controlled trials on endovascular thrombectomy for acute ischemic stroke provided clear evidence of therapeutic efficacy,1–4 therapeutic approaches to ischemic stroke have markedly changed. Endovascular thrombectomy achieved higher rates of angiographically demonstrated revascularization and provided better functional outcomes.5 Although high recanalization rates are favorable for tissue salvage, delayed recanalization after severe ischemia contributes to tissue injury based on microvascular perfusion disorders. Severe neurological disorders and poor outcomes because of ischemia/reperfusion (I/R) injury have increased the need for neuroprotective therapeutic strategies against I/R injury.
Among various neuroprotective therapeutic strategies, artificial oxygen carriers, mainly hemoglobin-based oxygen carriers (HBOCs), have been used in anticipation of improvements in microvascular perfusion, more efficient oxygen delivery, and increases in collateral flow.6–8 We previously demonstrated that liposome-encapsulated Hb, a cellular-type HBOC, reduced I/R injury in a rat transient middle cerebral artery occlusion (tMCAO) model.9,10 In the present study, we used a novel cell-free HBOC, 1 core of Hb covalently bound with 3 human serum albumin molecules, designated as HemoAct.11 Because HemoAct is covered with albumin shells, its surface net charge becomes negative and induces electrostatic repulsion against the endothelial surface, resulting in suppressed leakage through the endothelium. This property prevents marked elevations in blood pressure and promotes a long period of blood retention.12 HemoAct may also exert beneficial effects in the treatment of microvascular perfusion disorders based on the albumin characteristics of volume expander and antioxidant.13 We herein aim to investigate the neuroprotection of HemoAct and its underlying mechanisms in the rat tMCAO model.
Methods
The data that support the findings of this study are available from the corresponding author on reasonable request. A detailed description of Materials and Methods can be found in the online-only Data Supplement.
Animals
All animal experiment protocols were approved by the Animal Studies Ethics Committee at the Hokkaido University Graduate School of Medicine. All procedures used in the present study were performed in accordance with the institutional guidelines for animal experimentation and the Guidelines for Proper Conduct of Animal Experiments by the Science Council of Japan. A total of 125 rats were subjected to experiments which are described in the online-only Data Supplement.
HemoAct
HemoAct is an HBOC and its physical property is described in the online-only Data Supplement.
tMCAO Model
Transient focal cerebral ischemia was induced by right MCAO using a silicone rubber-coated nylon filament. Detailed procedures are described in the online-only Data Supplement.
In Vivo Experimental Protocol
Analysis of Effects of HemoAct on tMCAO Rats After 24 Hours of Reperfusion
The effects of HemoAct on the neurological and pathological findings were investigated after 24 hours of reperfusion in the 4 (control, vehicle, 50% HemoAct, and HemoAct) groups. Detailed procedures are described in the online-only Data Supplement.
Analysis of Effects of HemoAct on tMCAO Rats During the Early Phase of Reperfusion
The effects of HemoAct on the cortical blood flow, tissue oxygen content, and microvascular perfusion were investigated during the early phase of reperfusion in the control and HemoAct groups. Detailed procedures are described in the online-only Data Supplement.
Neurological Scores
A neurological assessment was performed using an 18-point scale score. Detailed procedures are described in the online-only Data Supplement.
Evaluation of Brain Injury and Edema Volume
Infarct and edema volumes were evaluated using 2,3,5-triphenyltetrazolium chloride staining. Detailed procedures are described in the online-only Data Supplement.
Western Blotting
Western blotting was performed using anti–MMP-9 (matrix metalloproteinase-9) antibody and anti–4-hydroxynonenal (4-HNE) antibody. Detailed procedures are described in the online-only Data Supplement.
Cerebral Blood Flow Measurements
Cerebral blood flow was measured by Laser Doppler flowmetry in the middle cerebral artery territories. Detailed procedures are described in the online-only Data Supplement.
Tissue Partial Oxygen Pressure Measurement
Brain tissue partial oxygen pressure (Pto2) was measured by an oxygen electrode method. Detailed procedures are described in the online-only Data Supplement.
Immunohistochemical Staining
Immunohistochemical staining was performed with paraffin sections of the brain fixed in 4% paraformaldehyde. Detailed procedures are described in the online-only Data Supplement.
Analysis of Microvascular Perfusion and Narrowing Changes
Microvascular perfusion and narrowing changes were examined by immunohistochemical analysis in the control and HemoAct groups. Detailed procedures are described in the online-only Data Supplement.
Analysis of the Distribution of HemoAct and Its Related Effects in the Ischemic Core
The distribution of HemoAct, IgG, and 8-hydroxy-2′-deoxyguanosine in the ischemic core was examined by immunohistochemical analysis in the control and HemoAct groups. Detailed procedures are described in the online-only Data Supplement.
In Vitro Cellular Hypoxia-Reoxygenation Injury Model
The antioxidant effects of HemoAct were examined in hypoxia/reoxygenation-treated rat brain microvascular endothelial cells (RBMECs). Detailed procedures are described in the online-only Data Supplement.
Measurement of Reactive Oxygen Species Production in RBMECs
The measurement of reactive oxygen species (ROS) production was performed using 3 different methods: dihydroethidium fluorescent staining, an 8-hydroxy-2′-deoxyguanosine ELISA, and 4-HNE Western blotting. Detailed procedures are described in the online-only Data Supplement.
Analysis of Effects of Albumin on tMCAO Rats After 24 Hours of Reperfusion
The effects of albumin itself on tMCAO rats were examined and compared with the result in the analysis of the effects of HemoAct on tMCAO rats. Detailed procedures are described in the online-only Data Supplement.
Data Collection and Statistical Analysis
All data were collected by investigators blinded to the experimental groups and were presented as means±SD. Two group comparisons were performed by the Mann-Whitney U test. Multiple comparisons were conducted by a 1-way ANOVA followed by Bonferroni test or the Kruskal-Wallis test and then by the Steel-Dwass test. Sample sizes were selected based on our previous experiments. Values of P<0.05 were considered to be significant.
Results
Physiological Parameters
No significant differences were observed in the values of basic physiological parameters including blood gas and blood pressure before tMCAO or in the degree of cerebral blood flow (CBF) reductions during tMCAO between the 4 groups. Physiological parameters after the treatments were also not significantly different between the 4 groups, indicating that HemoAct did not cause adverse effects (Table II in the online-only Data Supplement).
Neurological Status and Infarct and Edema Volumes After 24 Hours of Reperfusion
The effects of HemoAct on the neurological status and infarct and edema volumes were investigated in the 4 groups (Figure 1A). No significant differences were observed in neurological scores between the 4 groups at the early phase of tMCAO or early phase of reperfusion (Figure 1B). However, the neurological status was significantly superior in the HemoAct group than in the control group (P<0.01), vehicle group (P<0.01), and 50% HemoAct group (P<0.05) after 24 hours of reperfusion (Figure 1B). Brain infarct volumes were significantly smaller in the HemoAct group (20.2±3.1%) and 50% HemoAct group (27.1±4.7%) than in the control group (55.2±3.6%; P<0.01) and vehicle group (53.2±4.3%; P<0.01; Figure 1C and 1D). The mean infarction volume of the HemoAct group was 37% that of the control group. Edema volumes were also significantly smaller in the HemoAct group than in the control group (P<0.01) and vehicle group (P<0.01; Figure 1D).
Activation of MMP-9 and Lipid Peroxidation After 24 Hours of Reperfusion
The effects of HemoAct on the activation of MMP-9 and lipid peroxidation were investigated by Western blotting of MMP-9 and 4-HNE. The immunoblot intensity of MMP-9 was significantly lower in the HemoAct group than in the control group (P<0.05; Figure 2A). The immunoblot intensity of 4-HNE was significantly lower in the HemoAct group than in the vehicle group (P<0.05) and control group (P<0.05; Figure 2B).
CBF and Tissue Pto2 in the Cortical Penumbra During the Early Phase of Reperfusion
CBF and tissue Pto2 were measured intermittently from just before tMCAO to 6 hours after reperfusion in the cortical penumbra of the control and HemoAct groups (Figure 3A). CBF and Pto2 were reduced after 6 hours of reperfusion in the control group, which indicated postischemic delayed hypoperfusion (Figure 3B and 3C). However, the reductions observed in CBF and Pto2 were suppressed in the HemoAct group, resulting in significant differences (P<0.01) in the values of CBF and Pto2 between the control and HemoAct groups after 6 hours of reperfusion (Figure 3B and 3C).
Microvascular Perfusion in the Cortical Penumbra During the Early Phase of Reperfusion
The status of microvascular perfusion in the cortical penumbra during the early phase of reperfusion was examined in the control and HemoAct groups (Figure 4A). Microvessels filled with rat autologous erythrocytes immunostained with the anti-rat Hb antibody decreased in number as time elapsed in the control group. However, microvessels filled with HemoAct immunostained with the anti-human albumin antibody did not decrease in number in the HemoAct group (Figure 4B). A quantitative analysis showed that the total number of Rat-Hb–positive vessels in the control group was significantly lower after 2 hours (P<0.01) and 6 hours (P<0.01) of reperfusion than at 0 hours of reperfusion. The number of positive vessels was significantly greater (P<0.01) in the HemoAct group than in the control group after 2 and 6 hours of reperfusion (Figure 4C).
Microvascular Narrowing Changes in the Cortical Penumbra During the Early Phase of Reperfusion
Microvascular morphological changes in the cortical penumbra during the early phase of reperfusion were examined in the control and HemoAct groups with von Willebrand factor immunohistochemistry (Figure 5A). Microvascular narrowing with an enlarged perivascular halo was observed in both groups during reperfusion (Figure 5B). A quantitative analysis showed that the cross-sectional width of microvessels was significantly smaller, whereas the cross-sectional width ratio of the perivascular halo to microvessels was significantly larger in both groups after 2 to 6 hours of reperfusion than in the control group at 0 hours of reperfusion (Figure 5C and 5D). In comparisons of the cross-sectional width of microvessels and the cross-sectional width ratio of the perivascular halo to microvessels between the control and HemoAct groups, the former was significantly greater (P<0.01) and the latter was significantly smaller (P<0.01) in the HemoAct group than in the control group after 6 hours of reperfusion (Figure 5C and 5D).
Distribution of HemoAct and Its Related Effects in the Ischemic Core During the Early Phase of Reperfusion
The distribution of HemoAct and its related effects on serum extravasation and ROS production in the ischemic core during the early phase of reperfusion was examined in an immunohistochemical analysis. HemoAct clearly extravasated into the ischemic core after 2 and 6 hours of reperfusion in most of the HemoAct-treated rats (Figure IIA in the online-only Data Supplement). HemoAct extravasation was sometimes accompanied by the extravasation of serum IgG (Figure IIA in the online-only Data Supplement). The intensity grade of IgG immunohistochemistry was somewhat, but not significantly, lower in HemoAct-treated rats than in control rats (Figure IIB in the online-only Data Supplement), suggesting that the extent of serum IgG extravasation in HemoAct-treated rats was similar or less than that in control rats. ROS production evaluated by 8-hydroxy-2′-deoxyguanosine immunohistochemistry was occasionally observed in control rats (2 out of 8 rats), but not in HemoAct-treated rats (0 out of 8 rats) (Figure IIA in the online-only Data Supplement). Therefore, HemoAct extravasation did not cause an increase in serum extravasation or ROS production in the ischemic core.
Effects of HemoAct on ROS Production in Cultured RBMECs Treated With Hypoxia-Reoxygenation
The antioxidant characteristics of HemoAct were examined in cultured RBMECs treated with hypoxia-reoxygenation. We used 2 hours of 1% O2 hypoxia and 6 hours of normoxic reoxygenation for the experimental conditions and conducted 4 treatments (control, Hb, albumin, and HemoAct) on RBMECs during the reoxygenation period (Figure 6A). Three assays to evaluate ROS production, dihydroethidium fluorescent staining, an 8-hydroxy-2′-deoxyguanosine ELISA, and 4-HNE Western blotting, showed similar results in this experiment. Although ROS production in the Hb group was similar to that in the control group, it was significantly lower in the albumin and HemoAct groups than in the control group, suggesting that HemoAct has similar antioxidant characteristics to albumin (Figure 6B through 6D).
Discussion
HBOCs were originally studied and developed as a substitute for blood transfusion for blood loss because of injury and surgery. However, because HBOCs were found to have better and faster oxygenation capabilities than erythrocytes,14,15 the therapeutic potential of HBOCs in ischemic diseases has been actively examined.6–8,16 These studies demonstrated that HBOCs were beneficial for providing sufficient microcirculation and ameliorating I/R injury. We also previously reported that the infusion of liposome-encapsulated Hb exerted neuroprotective effects with superior microvascular perfusion in a rat tMCAO model.9,10 In line with these findings, we showed that HemoAct ameliorated neurological disorders and brain infarction because of I/R injury in the present study. Therefore, HBOCs have therapeutic potential for ischemic diseases with microvascular perfusion disorders.
Postischemic microvascular perfusion disorders after delayed recanalization are complex and sometimes exhibit contradictory responses, namely hyperperfusion or hypoperfusion.17–19 Hyperperfusion is considered to increases in permeability and cellular extravasation, leading to the formation of edema and hemorrhagic transformation.20,21 On the other hand, hypoperfusion sometimes occurs after hyperperfusion, resulting in secondary ischemia because of a microvascular perfusion disturbance. This phenomenon has been known as the no-reflow phenomenon, which was demonstrated as microvascular occlusion by leukocyte adhesion, platelet accumulation, and fibrin formation in a primate transient ischemic model.22 However, another potential cause of microvascular perfusion disturbances was recently demonstrated in electron microscopic studies. Microvessels were transiently compressed and narrowed by swollen astrocyte end-feet after several hours of reperfusion, which may reduce microvascular perfusion.23,24 In the present study, we observed delayed postischemic hypoperfusion, represented as reductions in cortical CBF and Pto2 and a decrease in the appearance of erythrocytes in microvessels, which showed narrowing changes with an enlarged perivascular space after 6 hours of reperfusion. Considering the characteristics of HBOCs with small particle sizes, the conditions observed with microvascular narrowing changes in the I/R region are suitable for treatments with HBOCs to rescue brain tissue from irreversible damage.
To date, many HBOCs under development25–28 have not yet been approved for clinical use because they cannot avoid increasing blood pressure because of the capture of nitric oxide by Hb. On the other hand, HemoAct covered with albumin shells has shown no increase of blood pressure in normal animals12 and even in the I/R injury model in the present study. On the basis of the characteristics of albumin, such as a negative net charge and high electrostatic repulsion, HemoAct may prevent to capture nitric oxide and increase blood pressure. In addition, albumin exerts neuroprotective effects on cerebral I/R injury because of its functions as a volume expander and antioxidant.29,30 As shown in Figure III in the online-only Data Supplement, 20% albumin, which was a comparable total protein mass concentration of albumin (20%=20 g/dL) to that in the administrated HemoAct (20 g/dL), alone moderately reduced infarction volumes in the same I/R injury model. Therefore, it is reasonable to consider HemoAct to have additive neuroprotective effects over other HBOCs. In the present study, we demonstrated the suppression of ROS production in in vivo and in vitro experiments (Figures 2B and 6). Therefore, HemoAct has an advantage for the treatment of ischemic diseases among HBOCs.
Albumin, which is either endogenous or exogenous, is extravasated into parenchyma and is taken up by neurons in rodent transient ischemic models.31,32 Although it has been unclear whether the extravasation and neuronal uptake of albumin are directly related to its neuroprotective effects, the administration of exogenous albumin exerted apparent neuroprotection without a change in the degree of IgG extravasation.31 This finding is similar to the present result showing that HemoAct extravasation did not cause an increase in IgG extravasation in the ischemic core, suggesting that HemoAct extravasation is a phenomenon based on albumin characteristics and does not enhance the deterioration of microvascular integrity and parenchymal cell viability. Although there are concerns that extracellular Hb results in an oxidative stress condition and neurotoxicity,33 HemoAct extravasation observed in the present study was not associated with ROS production, at least during the examination period (Figure II in the online-only Data Supplement; Figure 2B). Therefore, HemoAct extravasation in the ischemic core does not seem to have any adverse effects.
It is important to clarify how to apply HemoAct in stroke clinical practice. The experimental model we used in the present study is similar to patients who are treated with endovascular thrombectomy and receive transarterial drug infusions through a catheter after recanalization of the occluded artery. The reason why we selected a transarterial drug infusion was because we aimed to deliver HemoAct to postischemic tissue as rapidly and at as high a volume as possible. On the basis of the results of the present study, the transarterial HemoAct infusion had no adverse effects.
The limitations of the present study are as follows. The follow-up period was limited to the acute phase, up to 24 hours of reperfusion. One reason for the time limitation was the high death rate in this model after >24 hours of reperfusion. In future preclinical studies, long-term follow-ups will be needed using a less severe ischemic model. The next limitation is a lack of information on glucose levels, which is related to reperfusion state in stroke models (vascular effects of hyperglycemia) and could be 1 reason for the poor reperfusion. Another limitation is that experiments with different ischemic models, such as a permanent ischemic model, and different administration routes, including an intravenous infusion, need to be performed to expand indications for the HemoAct treatment. Furthermore, the long-term safety of HemoAct not only in normal animals but also in animals with cerebral ischemia is another issue that needs to be clarified.
In conclusion, HemoAct exerted strong neuroprotective effects on short-term I/R injury without Hb adverse effects. Superior microvascular perfusion and O2 transport as well as possible antioxidant effects seem to be the underlying neuroprotective mechanisms against I/R injury. HemoAct has potential as an HBOC in the treatment of ischemic diseases.
Acknowledgments
We thank Rika Nagashima for her technical assistance.
Supplemental Material
File (str_stroke-2018-021467_supp1.pdf)
- Download
- 586.36 KB
References
1.
Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi Net al; EXTEND-IA Investigators. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372:1009–1018. doi: https://doi.org/10.1056/NEJMoa1414792.
2.
Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton Jet al; ESCAPE Trial Investigators. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372:1019–1030. doi: https://doi.org/10.1056/NEJMoa1414905.
3.
Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira Aet al; REVASCAT Trial Investigators. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372:2296–2306. doi: https://doi.org/10.1056/NEJMoa1503780.
4.
Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VMet al; SWIFT PRIME Investigators. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372:2285–2295. doi: https://doi.org/10.1056/NEJMoa1415061.
5.
Badhiwala JH, Nassiri F, Alhazzani W, Selim MH, Farrokhyar F, Spears Jet al. Endovascular thrombectomy for acute ischemic stroke: a meta-analysis. JAMA. 2015;314:1832–1843. doi: https://doi.org/10.1001/jama.2015.13767.
6.
Cipolla MJ, Linfante I, Abuchowski A, Jubin R, Chan SL. Pharmacologically increasing collateral perfusion during acute stroke using a carboxyhemoglobin gas transfer agent (Sanguinate™) in spontaneously hypertensive rats. J Cereb Blood Flow Metab. 2018;38:755–766. doi: https://doi.org/10.1177/0271678X17705567.
7.
Powanda DD, Chang TM. Cross-linked polyhemoglobin-superoxide dismutase-catalase supplies oxygen without causing blood-brain barrier disruption or brain edema in a rat model of transient global brain ischemia-reperfusion. Artif Cells Blood Substit Immobil Biotechnol. 2002;30:23–37.
8.
Xie Z, Liu L, Zhu W, Liu H, Wang L, Zhang Jet al. The protective effect of polymerized porcine hemoglobin (pPolyHb) on transient focal cerebral ischemia/reperfusion injury. Artif Cells Nanomed Biotechnol. 2015;43:180–185. doi: https://doi.org/10.3109/21691401.2015.1037886.
9.
Shimbo D, Abumiya T, Kurisu K, Osanai T, Shichinohe H, Nakayama Net al. Superior microvascular perfusion of infused liposome-encapsulated hemoglobin prior to reductions in infarctions after transient focal cerebral ischemia. J Stroke Cerebrovasc Dis. 2017;26:2994–3003. doi: https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.07.026.
10.
Shimbo D, Abumiya T, Shichinohe H, Nakayama N, Kazumata K, Houkin K. Post-ischemic intra-arterial infusion of liposome-encapsulated hemoglobin can reduce ischemia reperfusion injury. Brain Res. 2014;1554:59–66. doi: https://doi.org/10.1016/j.brainres.2014.01.038.
11.
Tomita D, Kimura T, Hosaka H, Daijima Y, Haruki R, Ludwig Ket al. Covalent core-shell architecture of hemoglobin and human serum albumin as an artificial O2 carrier. Biomacromolecules. 2013;14:1816–1825. doi: https://doi.org/10.1021/bm400204y.
12.
Haruki R, Kimura T, Iwasaki H, Yamada K, Kamiyama I, Kohno Met al. Safety evaluation of hemoglobin-albumin cluster “HemoAct” as a red blood cell substitute. Sci Rep. 2015;5:12778. doi: https://doi.org/10.1038/srep12778.
13.
Gum ET, Swanson RA, Alano C, Liu J, Hong S, Weinstein PRet al. Human serum albumin and its N-terminal tetrapeptide (DAHK) block oxidant-induced neuronal death. Stroke. 2004;35:590–595. doi: https://doi.org/10.1161/01.STR.0000110790.05859.DA.
14.
Moore EE, Johnson JL, Cheng AM, Masuno T, Banerjee A. Insights from studies of blood substitutes in trauma. Shock. 2005;24:197–205.
15.
Standl T, Freitag M, Burmeister MA, Horn EP, Wilhelm S, Am Esch JS. Hemoglobin-based oxygen carrier HBOC-201 provides higher and faster increase in oxygen tension in skeletal muscle of anemic dogs than do stored red blood cells. J Vasc Surg. 2003;37:859–865. doi: https://doi.org/10.1067/mva.2003.127.
16.
Caswell JE, Strange MB, Rimmer DM, Gibson MF, Cole P, Lefer DJ. A novel hemoglobin-based blood substitute protects against myocardial reperfusion injury. Am J Physiol Heart Circ Physiol. 2005;288:H1796–H1801. doi: https://doi.org/10.1152/ajpheart.00905.2004.
17.
Dirnagl U, Niwa K, Sixt G, Villringer A. Cortical hypoperfusion after global forebrain ischemia in rats is not caused by microvascular leukocyte plugging. Stroke. 1994;25:1028–1038.
18.
Karibe H, Zarow GJ, Graham SH, Weinstein PR. Mild intraischemic hypothermia reduces postischemic hyperperfusion, delayed postischemic hypoperfusion, blood-brain barrier disruption, brain edema, and neuronal damage volume after temporary focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 1994;14:620–627. doi: https://doi.org/10.1038/jcbfm.1994.77.
19.
Traupe H, Kruse E, Heiss WD. Reperfusion of focal ischemia of varying duration: postischemic hyper- and hypo-perfusion. Stroke. 1982;13:615–622.
20.
Burggraf D, Trinkl A, Burk J, Martens HK, Dichgans M, Hamann GF. Vascular integrin immunoreactivity is selectively lost on capillaries during rat focal cerebral ischemia and reperfusion. Brain Res. 2008;1189:189–197. doi: https://doi.org/10.1016/j.brainres.2007.10.085.
21.
Gasche Y, Copin JC, Sugawara T, Fujimura M, Chan PH. Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2001;21:1393–1400. doi: https://doi.org/10.1097/00004647-200112000-00003.
22.
del Zoppo GJ, Schmid-Schönbein GW, Mori E, Copeland BR, Chang CM. Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke. 1991;22:1276–1283.
23.
Kurisu K, Abumiya T, Nakamura H, Shimbo D, Shichinohe H, Nakayama Net al. Transarterial regional brain hypothermia inhibits acute aquaporin-4 surge and sequential microvascular events in ischemia/reperfusion injury. Neurosurgery. 2016;79:125–134. doi: https://doi.org/10.1227/NEU.0000000000001088.
24.
Ito U, Hakamata Y, Kawakami E, Oyanagi K. Temporary [corrected] cerebral ischemia results in swollen astrocytic end-feet that compress microvessels and lead to delayed [corrected] focal cortical infarction. J Cereb Blood Flow Metab. 2011;31:328–338. doi: https://doi.org/10.1038/jcbfm.2010.97.
25.
Chen JY, Scerbo M, Kramer G. A review of blood substitutes: examining the history, clinical trial results, and ethics of hemoglobin-based oxygen carriers. Clinics (Sao Paulo). 2009;64:803–813. doi: https://doi.org/10.1590/S1807-59322009000800016.
26.
Freilich D, Pearce LB, Pitman A, Greenburg G, Berzins M, Bebris Let al. HBOC-201 vasoactivity in a phase III clinical trial in orthopedic surgery subjects–extrapolation of potential risk for acute trauma trials. J Trauma. 2009;66:365–376. doi: https://doi.org/10.1097/TA.0b013e3181820d5c.
27.
Keipert PE. Hemoglobin-Based Oxygen Carrier (HBOC) development in trauma: previous regulatory challenges, lessons learned, and a path forward. Adv Exp Med Biol. 2017;977:343–350. doi: https://doi.org/10.1007/978-3-319-55231-6_45.
28.
Moore EE, Moore FA, Fabian TC, Bernard AC, Fulda GJ, Hoyt DBet al; PolyHeme Study Group. Human polymerized hemoglobin for the treatment of hemorrhagic shock when blood is unavailable: the USA multicenter trial. J Am Coll Surg. 2009;208:1–13. doi: https://doi.org/10.1016/j.jamcollsurg.2008.09.023.
29.
Belayev L, Liu Y, Zhao W, Busto R, Ginsberg MD. Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke. 2001;32:553–560.
30.
Belayev L, Pinard E, Nallet H, Seylaz J, Liu Y, Riyamongkol Pet al. Albumin therapy of transient focal cerebral ischemia: in vivo analysis of dynamic microvascular responses. Stroke. 2002;33:1077–1084.
31.
Remmers M, Schmidt-Kastner R, Belayev L, Lin B, Busto R, Ginsberg MD. Protein extravasation and cellular uptake after high-dose human-albumin treatment of transient focal cerebral ischemia in rats. Brain Res. 1999;827:237–242.
32.
Kitagawa K, Matsumoto M, Tagaya M, Ueda H, Oku N, Kuwabara Ket al. Temporal profile of serum albumin extravasation following cerebral ischemia in a newly established reproducible gerbil model for vasogenic brain edema: a combined immunohistochemical and dye tracer analysis. Acta Neuropathol. 1991;82:164–171.
33.
Lara FA, Kahn SA, da Fonseca AC, Bahia CP, Pinho JP, Graca-Souza AVet al. On the fate of extracellular hemoglobin and heme in brain. J Cereb Blood Flow Metab. 2009;29:1109–1120. doi: https://doi.org/10.1038/jcbfm.2009.34.
Information & Authors
Information
Published In
Copyright
© 2018 American Heart Association, Inc.
Versions
You are viewing the most recent version of this article.
History
Received: 17 March 2018
Revision received: 4 June 2018
Accepted: 8 June 2018
Published online: 10 July 2018
Published ahead of print: 12 July 2018
Published in print: August 2018
Keywords
Subjects
Authors
Disclosures
None.
Sources of Funding
This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI (Grants-in-Aid for Scientific Research) Grant Number 16K10708.
Metrics & Citations
Metrics
Citations
Download Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.
- Conjugating Hemoglobin and Albumin by Strain‐Promoted Azide‐ Alkyne Cycloaddition, ChemBioChem, 25, 16, (2024).https://doi.org/10.1002/cbic.202400206
- Nanomaterial-related hemoglobin-based oxygen carriers, with emphasis on liposome and nano-capsules, for biomedical applications: current status and future perspectives, Journal of Nanobiotechnology, 22, 1, (2024).https://doi.org/10.1186/s12951-024-02606-1
- Controlled oxygen delivery to power tissue regeneration, Nature Communications, 15, 1, (2024).https://doi.org/10.1038/s41467-024-48719-x
- Neuroprotective effects of a hemoglobin-based oxygen carrier (stroma-free hemoglobin nanoparticle) on ischemia reperfusion injury, Brain Research, 1821, (148592), (2023).https://doi.org/10.1016/j.brainres.2023.148592
- Direct targeting of DOCK4 by miRNA-181d in oxygen-glucose deprivation/reoxygenation-mediated neuronal injury, Lipids in Health and Disease, 22, 1, (2023).https://doi.org/10.1186/s12944-023-01794-3
- Neurointerventional infusion of hemoglobin oxygen carrier prevents brain damage from acute cerebral ischemia in rats, Frontiers in Surgery, 10, (2023).https://doi.org/10.3389/fsurg.2023.1050935
- d-allose protects brain microvascular endothelial cells from hypoxic/reoxygenated injury by inhibiting endoplasmic reticulum stress, Neuroscience Letters, 793, (137000), (2023).https://doi.org/10.1016/j.neulet.2022.137000
- Clinical significance of albumin to globulin ratio among patients with stroke-associated pneumonia, Frontiers in Nutrition, 9, (2022).https://doi.org/10.3389/fnut.2022.970573
- Artificial red blood cells, Nanotechnology for Hematology, Blood Transfusion, and Artificial Blood, (397-427), (2022).https://doi.org/10.1016/B978-0-12-823971-1.00018-0
- microRNA‐186 alleviates oxygen‐glucose deprivation/reoxygenation‐induced injury by directly targeting hypoxia‐inducible factor‐1α, Journal of Biochemical and Molecular Toxicology, 35, 6, (1-11), (2021).https://doi.org/10.1002/jbt.22752
- See more
Loading...
View Options
Login options
Check if you have access through your login credentials or your institution to get full access on this article.
Personal login Institutional LoginPurchase Options
Purchase this article to access the full text.
eLetters(0)
eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.
Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.