Improving CORM technology for the treatment of delayed hemolytic transfusion reaction

IF 7.6 2区 医学 Q1 HEMATOLOGY HemaSphere Pub Date : 2024-08-05 DOI:10.1002/hem3.140
Michela Asperti, Francesca Vinchi
{"title":"Improving CORM technology for the treatment of delayed hemolytic transfusion reaction","authors":"Michela Asperti,&nbsp;Francesca Vinchi","doi":"10.1002/hem3.140","DOIUrl":null,"url":null,"abstract":"<p>Delayed hemolytic transfusion reaction (DHTR) is a severe and potentially fatal complication triggered by red blood cells (RBC) transfusions<span><sup>1</sup></span> in patients with sickle cell disease (SCD). Transfusions remain a major therapeutic intervention in the clinical management of anemia as well as both acute and chronic disease-related complications in SCD.<span><sup>1-3</sup></span> Typically, DHTR occurs days to weeks after a RBC transfusion due to the sudden destruction of both transfused and patients' RBCs, with a consequent drastic drop in hemoglobin (Hb), seriously threatening the life of SCD patients.<span><sup>4, 5</sup></span> During DHTR with hyperhemolysis, the release of free Hb and heme has deleterious impact on the vasculature, causing vasculo-toxicity and leading to vasculopathy due to intravascular oxidative stress, endothelial damage, increased expression of proadhesive, proinflammatory and chemotactic factors and reduced nitric oxide (NO) bioavailability. Upon RBC exposure, one or more alloantibodies are produced in SCD patients, which contribute to DHTR. In one-third of RBC transfused patients, complement activation—rather than alloantibodies production—plays a role in DHTR, both through the canonic pathway, whereby complement fixed antibody binds to RBCs, and the alternative pathway, whereby free heme-induced TLR4 signaling on endothelial cells activates the complement system.<span><sup>1</sup></span> Patients experience symptoms such as fever, pain, fatigue, mild jaundice or dark urine and a drastic Hb drop. The current treatment options for DHTRs are based on supportive care, erythropoiesis optimization, immunomodulatory treatments, including complement inhibition, steroids, intravenous immunoglobulin, and/or B cell depletion, and future transfusion avoidance, even if the latest may be not always feasible in some clinical conditions related to cardiac or respiratory failure.<span><sup>1, 3</sup></span></p><p>Among the therapeutic strategies proposed to overcome DHTR, carbon monoxide administration in the form of inhalation or carbon-monoxide-releasing molecules (CO-RMs) has shown promising results in preclinical studies.<span><sup>6</sup></span> A plethora of CORMs has been generated, structurally designed with a central transition metal such as iron, manganese, or cobalt, surrounded by CO as a ligand.<span><sup>6</sup></span> CO is a stable molecule that is continuously produced after the catabolism of heme by heme-oxygenases (HO), a family of enzymes with established anti-inflammatory and cytoprotective functions. Mechanistically, CO decreases the expression of proinflammatory and increases the expression of anti-inflammatory cytokines by activating the MKK3/p38β MAPK pathway and inducing PPARγ. In addition, it reduces TLR4 activation by inhibiting TLR4 trafficking, and its interaction with caveolin-1 at the plasma membrane. CO also serves as a bioactive signaling molecule acting as intracellular mediator in a variety of physiological functions, including vasodilation and cardiac protection through the activation of the soluble guanylyl cyclase, regulation of the nervous system through the activation of potassium channels, and control of neurotransmitters, as well as gastrointestinal and respiratory tracts.<span><sup>7</sup></span></p><p>In vitro as well as preclinical studies provide evidence of significant anti-inflammatory, antioxidant, and antiapoptotic effects as well as vasodilation and antiadhesion action of CO on the vasculature, resulting in the preservation of vascular flow, with major implications for SCD.<span><sup>8</sup></span> In this context, Nguyen Kim-Anh and coauthors recently reported the beneficial effect of CORM-401 on endothelial activation, tissue damage, and inflammation caused by acute hyperhemolysis in SCD.<span><sup>9</sup></span> CORM-401 has the capability to carry and deliver controlled amounts of CO to biological systems leading to the activation of endothelial calcium signaling and increased NO bioavailability, with consequent therapeutic benefit.<span><sup>6, 10-12</sup></span></p><p>The novelty of this study lies in the development of in vitro and in vivo models that reflect endothelial damage and organ dysfunction occurring during the early phase of hyper-hemolysis in SCD. The authors reproduced vascular activation and dysfunction in the early DHTR phase taking advantage of a new in vitro fluidic model whereby umbilical vein endothelial cells (HUVEC) were exposed to hemolysates containing RBC membrane-derived particles with negligible levels of free oxidized hemoglobin or heme.<span><sup>9</sup></span> The pre-exposure of HUVEC cells to CORM-401 significantly increased the content of COHb and prevented hemolysates-induced upregulation of proinflammatory cytokines such as IL6, IL1, and IL8, and adhesive molecules, including Vascular and Intercellular Cell Adhesion Molecules-1 (VCAM-1, ICAM-1). Moreover, due to an overall reduction of oxidative stress, it inhibited the expression of the acute phase redox-sensitive transcription factor nuclear factor erythroid-2-related factor 2, Nrf2.<span><sup>9</sup></span></p><p>To corroborate in vitro findings, the authors evaluated the beneficial effects of the CO-released by CORM-401 in a humanized SCD mouse model exposed to hemolysate. CORM-401 effectively released CO in several tissues, including liver, kidney, lung, cecum, and colon, with no sign of toxicity. Pretreatment of SCD mice with CORM-401<span><sup>9</sup></span> prevented hemolysate-induced acute damage in target organs commonly affected during DHTR, namely lung, liver, and kidney. In particular, CORM-401 efficiently resolved inflammation by modulating NF-κB and Nrf2 signaling pathways, and the expression of downstream target genes, including proinflammatory and adhesive molecules (VCAM-1, ICAM-1, endothelin-1, thromboxane) and antioxidants enzymes (HO-1, Gpx1).<span><sup>9</sup></span> In detail, CORM-401 administration provided a protective effect against lung injury, by preventing alveolar dilation and septum wall thickening due to hemolysate exposure. Overall, CORM-401 decreased inflammatory cell infiltrates, thrombi formation, and macrophage iron accumulation in the lung. CORM-401 decreased the active form of Nrf2 and NF-kB, reduced HO-1 and thromboxane synthase (TBXS) expression, and decreased VCAM-1, ICAM-1, and ET-1, important for the endothelial cell activation. Similarly, CORM-401 treatment increased CO content in the liver with consequent reduction of inflammation, thrombi formation, and iron accumulation in hepatic macrophages. A significant reduction of hepatic Nrf2 and NF- kB was also observed in the liver. Kidney is another organ affected by the hemolysate-induced acute damage and CORM-401 treatment led to a reduction in glomerular inflammatory cell infiltration, and a mild decrement in tubular iron accumulation. Nrf2 activation, ICAM-1 expression as well as the induction of the antioxidant enzymes HO-1 and NAD(P)H dehydrogenase (quinone)-1 were reduced by CORM-401 therapy. CORM-401 was also effective in suppressing the induction of P-Selectin and VCAM-1 in SCD exposed to hemolysate, protecting against hemolysate-induced vascular dysfunction.<span><sup>9</sup></span> In summary in a DHTR model in SCD mice, CORM-401 treatment showed therapeutic benefits, limiting organ damage in commonly affected tissues, and ameliorating endothelial dysfunction and inflammatory vasculopathy Figure 1.</p><p>The advent of CORMs significantly improved the route of CO administration, allowing the delivery of controlled and not-toxic amount of CO to tissues.<span><sup>6</sup></span> This significantly augmented the potential to use CO-related therapies in SCD for the amelioration of inflammatory vasculopathy and the prevention of vaso-occlusive crises.<span><sup>8</sup></span> This study provides a proof of concept for the applications of CORMs in severe sickle complications such as DHTR. Limiting early DHTR consequences is key to the prevention of end-organ damage, and CORM-401 exhibited extensive therapeutic benefit in multiple organs. The additional advantages of the specific Mn-containing CORM-401 consist in the easy chemical synthesis, increased water solubility, and stability of the compound, combined to a safe CO delivery with no significant toxic or adverse events. While most CORMs tested in SCD mainly exhibited beneficial effects on hemolysis-driven endothelial dysfunction, this study shows for the first time a broader protective effect of CORMs against hemolysis-induced tissue injury.<span><sup>9</sup></span> Overall, the reduction of the deleterious effects of acute hyperhemolysis—rather than the toxicities associated with chronic hemolysis—suggests that CORMs can be valuable therapeutic approaches for the treatment and eventually prevention of acute high-risk complications such as DHTR in SCD patients. Whether combination treatment with this novel CORM and other agents such as heme scavengers or antisickling compounds provides further advantage for both chronic hemolysis and hyperhemolytic events remains to be explored.</p><p>Michela Asperti and Francesca Vinchi wrote the HemaTopic and drafted the figure, which was professionally drawn by Somersault18:24 BV.</p><p>Dr. Vinchi is a member of the advisory board of Silence Therapeutics and a consultant for RallyBio and Pharmacosmos. None of these relationships is relevant to the current publication.</p><p>This research received no funding.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":null,"pages":null},"PeriodicalIF":7.6000,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299068/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"HemaSphere","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/hem3.140","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Delayed hemolytic transfusion reaction (DHTR) is a severe and potentially fatal complication triggered by red blood cells (RBC) transfusions1 in patients with sickle cell disease (SCD). Transfusions remain a major therapeutic intervention in the clinical management of anemia as well as both acute and chronic disease-related complications in SCD.1-3 Typically, DHTR occurs days to weeks after a RBC transfusion due to the sudden destruction of both transfused and patients' RBCs, with a consequent drastic drop in hemoglobin (Hb), seriously threatening the life of SCD patients.4, 5 During DHTR with hyperhemolysis, the release of free Hb and heme has deleterious impact on the vasculature, causing vasculo-toxicity and leading to vasculopathy due to intravascular oxidative stress, endothelial damage, increased expression of proadhesive, proinflammatory and chemotactic factors and reduced nitric oxide (NO) bioavailability. Upon RBC exposure, one or more alloantibodies are produced in SCD patients, which contribute to DHTR. In one-third of RBC transfused patients, complement activation—rather than alloantibodies production—plays a role in DHTR, both through the canonic pathway, whereby complement fixed antibody binds to RBCs, and the alternative pathway, whereby free heme-induced TLR4 signaling on endothelial cells activates the complement system.1 Patients experience symptoms such as fever, pain, fatigue, mild jaundice or dark urine and a drastic Hb drop. The current treatment options for DHTRs are based on supportive care, erythropoiesis optimization, immunomodulatory treatments, including complement inhibition, steroids, intravenous immunoglobulin, and/or B cell depletion, and future transfusion avoidance, even if the latest may be not always feasible in some clinical conditions related to cardiac or respiratory failure.1, 3

Among the therapeutic strategies proposed to overcome DHTR, carbon monoxide administration in the form of inhalation or carbon-monoxide-releasing molecules (CO-RMs) has shown promising results in preclinical studies.6 A plethora of CORMs has been generated, structurally designed with a central transition metal such as iron, manganese, or cobalt, surrounded by CO as a ligand.6 CO is a stable molecule that is continuously produced after the catabolism of heme by heme-oxygenases (HO), a family of enzymes with established anti-inflammatory and cytoprotective functions. Mechanistically, CO decreases the expression of proinflammatory and increases the expression of anti-inflammatory cytokines by activating the MKK3/p38β MAPK pathway and inducing PPARγ. In addition, it reduces TLR4 activation by inhibiting TLR4 trafficking, and its interaction with caveolin-1 at the plasma membrane. CO also serves as a bioactive signaling molecule acting as intracellular mediator in a variety of physiological functions, including vasodilation and cardiac protection through the activation of the soluble guanylyl cyclase, regulation of the nervous system through the activation of potassium channels, and control of neurotransmitters, as well as gastrointestinal and respiratory tracts.7

In vitro as well as preclinical studies provide evidence of significant anti-inflammatory, antioxidant, and antiapoptotic effects as well as vasodilation and antiadhesion action of CO on the vasculature, resulting in the preservation of vascular flow, with major implications for SCD.8 In this context, Nguyen Kim-Anh and coauthors recently reported the beneficial effect of CORM-401 on endothelial activation, tissue damage, and inflammation caused by acute hyperhemolysis in SCD.9 CORM-401 has the capability to carry and deliver controlled amounts of CO to biological systems leading to the activation of endothelial calcium signaling and increased NO bioavailability, with consequent therapeutic benefit.6, 10-12

The novelty of this study lies in the development of in vitro and in vivo models that reflect endothelial damage and organ dysfunction occurring during the early phase of hyper-hemolysis in SCD. The authors reproduced vascular activation and dysfunction in the early DHTR phase taking advantage of a new in vitro fluidic model whereby umbilical vein endothelial cells (HUVEC) were exposed to hemolysates containing RBC membrane-derived particles with negligible levels of free oxidized hemoglobin or heme.9 The pre-exposure of HUVEC cells to CORM-401 significantly increased the content of COHb and prevented hemolysates-induced upregulation of proinflammatory cytokines such as IL6, IL1, and IL8, and adhesive molecules, including Vascular and Intercellular Cell Adhesion Molecules-1 (VCAM-1, ICAM-1). Moreover, due to an overall reduction of oxidative stress, it inhibited the expression of the acute phase redox-sensitive transcription factor nuclear factor erythroid-2-related factor 2, Nrf2.9

To corroborate in vitro findings, the authors evaluated the beneficial effects of the CO-released by CORM-401 in a humanized SCD mouse model exposed to hemolysate. CORM-401 effectively released CO in several tissues, including liver, kidney, lung, cecum, and colon, with no sign of toxicity. Pretreatment of SCD mice with CORM-4019 prevented hemolysate-induced acute damage in target organs commonly affected during DHTR, namely lung, liver, and kidney. In particular, CORM-401 efficiently resolved inflammation by modulating NF-κB and Nrf2 signaling pathways, and the expression of downstream target genes, including proinflammatory and adhesive molecules (VCAM-1, ICAM-1, endothelin-1, thromboxane) and antioxidants enzymes (HO-1, Gpx1).9 In detail, CORM-401 administration provided a protective effect against lung injury, by preventing alveolar dilation and septum wall thickening due to hemolysate exposure. Overall, CORM-401 decreased inflammatory cell infiltrates, thrombi formation, and macrophage iron accumulation in the lung. CORM-401 decreased the active form of Nrf2 and NF-kB, reduced HO-1 and thromboxane synthase (TBXS) expression, and decreased VCAM-1, ICAM-1, and ET-1, important for the endothelial cell activation. Similarly, CORM-401 treatment increased CO content in the liver with consequent reduction of inflammation, thrombi formation, and iron accumulation in hepatic macrophages. A significant reduction of hepatic Nrf2 and NF- kB was also observed in the liver. Kidney is another organ affected by the hemolysate-induced acute damage and CORM-401 treatment led to a reduction in glomerular inflammatory cell infiltration, and a mild decrement in tubular iron accumulation. Nrf2 activation, ICAM-1 expression as well as the induction of the antioxidant enzymes HO-1 and NAD(P)H dehydrogenase (quinone)-1 were reduced by CORM-401 therapy. CORM-401 was also effective in suppressing the induction of P-Selectin and VCAM-1 in SCD exposed to hemolysate, protecting against hemolysate-induced vascular dysfunction.9 In summary in a DHTR model in SCD mice, CORM-401 treatment showed therapeutic benefits, limiting organ damage in commonly affected tissues, and ameliorating endothelial dysfunction and inflammatory vasculopathy Figure 1.

The advent of CORMs significantly improved the route of CO administration, allowing the delivery of controlled and not-toxic amount of CO to tissues.6 This significantly augmented the potential to use CO-related therapies in SCD for the amelioration of inflammatory vasculopathy and the prevention of vaso-occlusive crises.8 This study provides a proof of concept for the applications of CORMs in severe sickle complications such as DHTR. Limiting early DHTR consequences is key to the prevention of end-organ damage, and CORM-401 exhibited extensive therapeutic benefit in multiple organs. The additional advantages of the specific Mn-containing CORM-401 consist in the easy chemical synthesis, increased water solubility, and stability of the compound, combined to a safe CO delivery with no significant toxic or adverse events. While most CORMs tested in SCD mainly exhibited beneficial effects on hemolysis-driven endothelial dysfunction, this study shows for the first time a broader protective effect of CORMs against hemolysis-induced tissue injury.9 Overall, the reduction of the deleterious effects of acute hyperhemolysis—rather than the toxicities associated with chronic hemolysis—suggests that CORMs can be valuable therapeutic approaches for the treatment and eventually prevention of acute high-risk complications such as DHTR in SCD patients. Whether combination treatment with this novel CORM and other agents such as heme scavengers or antisickling compounds provides further advantage for both chronic hemolysis and hyperhemolytic events remains to be explored.

Michela Asperti and Francesca Vinchi wrote the HemaTopic and drafted the figure, which was professionally drawn by Somersault18:24 BV.

Dr. Vinchi is a member of the advisory board of Silence Therapeutics and a consultant for RallyBio and Pharmacosmos. None of these relationships is relevant to the current publication.

This research received no funding.

Abstract Image

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
改进用于治疗延迟性溶血性输血反应的 CORM 技术。
延迟溶血性输血反应(DHTR)是镰状细胞病(SCD)患者因输注红细胞1 而引发的一种严重且可能致命的并发症。1-3 通常情况下,DHTR 在输注 RBC 后数天至数周内发生,原因是输注的 RBC 和患者的 RBC 突然遭到破坏,血红蛋白(Hb)随之急剧下降,严重威胁 SCD 患者的生命、5 在伴有高溶血的 DHTR 期间,游离 Hb 和血红素的释放会对血管产生有害影响,引起血管毒性,并由于血管内氧化应激、内皮损伤、促粘附因子、促炎因子和趋化因子的表达增加以及一氧化氮(NO)生物利用度降低而导致血管病变。SCD 患者在接触红细胞后会产生一种或多种异体抗体,从而导致 DHTR。在三分之一输注了 RBC 的患者中,补体激活(而非同种抗体的产生)在 DHTR 中起着一定的作用,这种作用可通过补体固定抗体与 RBC 结合的 "补体途径 "和内皮细胞上游离血红素诱导的 TLR4 信号激活补体系统的 "替代途径 "1 来实现。目前治疗 DHTR 的方法包括支持性护理、优化红细胞生成、免疫调节治疗(包括补体抑制、类固醇、静脉注射免疫球蛋白和/或 B 细胞耗竭)以及避免输血,尽管在某些与心脏或呼吸衰竭相关的临床病例中,最新的治疗方法并不总是可行、3 在为克服 DHTR 而提出的治疗策略中,一氧化碳吸入或一氧化碳释放分子(CO-RMs)给药已在临床前研究中显示出良好的效果。6 一氧化碳是一种稳定的分子,在血红素氧化酶(HO)分解血红素后持续产生,血红素氧化酶家族具有公认的抗炎和细胞保护功能。从机理上讲,CO 可通过激活 MKK3/p38β MAPK 通路和诱导 PPARγ 减少促炎细胞因子的表达,增加抗炎细胞因子的表达。此外,它还能抑制 TLR4 的贩运及其与质膜上的洞穴素-1 的相互作用,从而减少 TLR4 的激活。CO 还是一种生物活性信号分子,在多种生理功能中充当细胞内介质,包括通过激活可溶性鸟苷酸环化酶扩张血管和保护心脏、通过激活钾通道调节神经系统、控制神经递质以及胃肠道和呼吸道。体外和临床前研究证明,一氧化碳对血管具有显著的抗炎、抗氧化和抗细胞凋亡作用以及血管扩张和抗粘连作用,从而保护血管流动,对 SCD 具有重要意义。在此背景下,Nguyen Kim-Anh 和合作者最近报告了 CORM-401 对 SCD 急性高溶血引起的内皮活化、组织损伤和炎症的有益影响。9 CORM-401 能够携带并向生物系统输送可控量的 CO,从而激活内皮细胞钙信号传导并增加 NO 的生物利用度,从而产生治疗效果、10-12本研究的新颖之处在于建立了体外和体内模型,以反映 SCD 高溶血早期发生的内皮损伤和器官功能障碍。作者利用一种新的体外流体模型,将脐静脉内皮细胞(HUVEC)暴露于含有 RBC 膜衍生颗粒的溶血液中,其中的游离氧化血红蛋白或血红素含量可忽略不计,从而再现了 DHTR 早期的血管活化和功能障碍。将HUVEC细胞预先暴露于CORM-401可显著增加COHb的含量,并防止溶血物诱导的促炎细胞因子(如IL6、IL1和IL8)和粘附分子(包括血管和细胞间细胞粘附分子-1(VCAM-1和ICAM-1))的上调。此外,由于全面降低了氧化应激,它还抑制了急性期氧化还原敏感转录因子核因子红细胞-2相关因子2(Nrf2)的表达。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
HemaSphere
HemaSphere Medicine-Hematology
CiteScore
6.10
自引率
4.50%
发文量
2776
审稿时长
7 weeks
期刊介绍: HemaSphere, as a publication, is dedicated to disseminating the outcomes of profoundly pertinent basic, translational, and clinical research endeavors within the field of hematology. The journal actively seeks robust studies that unveil novel discoveries with significant ramifications for hematology. In addition to original research, HemaSphere features review articles and guideline articles that furnish lucid synopses and discussions of emerging developments, along with recommendations for patient care. Positioned as the foremost resource in hematology, HemaSphere augments its offerings with specialized sections like HemaTopics and HemaPolicy. These segments engender insightful dialogues covering a spectrum of hematology-related topics, including digestible summaries of pivotal articles, updates on new therapies, deliberations on European policy matters, and other noteworthy news items within the field. Steering the course of HemaSphere are Editor in Chief Jan Cools and Deputy Editor in Chief Claire Harrison, alongside the guidance of an esteemed Editorial Board comprising international luminaries in both research and clinical realms, each representing diverse areas of hematologic expertise.
期刊最新文献
30-Minute infusion of isatuximab in patients with newly diagnosed multiple myeloma: Results of a Phase 1b study analysis How to diagnose acid sphingomyelinase deficiency (ASMD) and Niemann–Pick disease type C from bone marrow and peripheral blood smears GPRASP protein deficiency triggers lymphoproliferative disease by affecting B-cell differentiation Issue Information Mitochondrial retention in mature red blood cells from patients with sickle cell disease is associated with stress erythropoiesis but not with proinflammatory state
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1