Hypoxia (Auckland, N.Z.)最新文献

英文中文

Frequently asked questions in hypoxia research 缺氧研究中的常见问题

Hypoxia (Auckland, N.Z.)

Pub Date : 2015-09-18 DOI: 10.2147/HP.S92198

R. Wenger, V. Kurtcuoglu, Carsten C. Scholz, H. H. Marti, D. Hoogewijs

“What is the O2 concentration in a normoxic cell culture incubator?” This and other frequently asked questions in hypoxia research will be answered in this review. Our intention is to give a simple introduction to the physics of gases that would be helpful for newcomers to the field of hypoxia research. We will provide background knowledge about questions often asked, but without straightforward answers. What is O2 concentration, and what is O2 partial pressure? What is normoxia, and what is hypoxia? How much O2 is experienced by a cell residing in a culture dish in vitro vs in a tissue in vivo? By the way, the O2 concentration in a normoxic incubator is 18.6%, rather than 20.9% or 20%, as commonly stated in research publications. And this is strictly only valid for incubators at sea level.

"常氧细胞培养箱中的氧浓度是多少? "这篇综述将回答这个和其他在缺氧研究中经常被问到的问题。我们的目的是给一个简单的介绍气体的物理，这将有助于新手缺氧领域的研究。我们将提供关于经常被问到的问题的背景知识，但没有直接的答案。O2浓度是多少，O2分压是多少?什么是常氧，什么是缺氧?体外培养皿中的细胞与体内组织中的细胞经历了多少O2 ?顺便说一下，常压培养箱中的氧气浓度是18.6%，而不是研究出版物中通常所说的20.9%或20%。这只对海平面上的孵化器有效。

引用次数: 160

Resistance of subventricular neural stem cells to chronic hypoxemia despite structural disorganization of the germinal center and impairment of neuronal and oligodendrocyte survival. 尽管生殖中心结构紊乱，神经元和少突胶质细胞存活能力受损，但室管膜下神经干细胞对慢性低氧血症仍有抵抗力。

Hypoxia (Auckland, N.Z.)

Pub Date : 2015-06-08 eCollection Date: 2015-01-01 DOI: 10.2147/HP.S78248

Xavier d'Anglemont de Tassigny, M Salomé Sirerol-Piquer, Ulises Gómez-Pinedo, Ricardo Pardal, Sonia Bonilla, Vivian Capilla-Gonzalez, Ivette López-López, Francisco Javier De la Torre-Laviana, José Manuel García-Verdugo, José López-Barneo

Chronic hypoxemia, as evidenced in de-acclimatized high-altitude residents or in patients with chronic obstructive respiratory disorders, is a common medical condition that can produce serious neurological alterations. However, the pathogenesis of this phenomenon is unknown. We have found that adult rodents exposed for several days/weeks to hypoxia, with an arterial oxygen tension similar to that of chronically hypoxemic patients, manifest a partially irreversible structural disarrangement of the subventricular neurogenic niche (subventricular zone) characterized by displacement of neurons and myelinated axons, flattening of the ependymal cell layer, and thinning of capillary walls. Despite these abnormalities, the number of neuronal and oligodendrocyte progenitors, neuroblasts, and neurosphere-forming cells as well as the proliferative activity in subventricular zone was unchanged. These results suggest that neural stem cells and their undifferentiated progeny are resistant to hypoxia. However, in vivo and in vitro experiments indicate that severe chronic hypoxia decreases the survival of newly generated neurons and oligodendrocytes, with damage of myelin sheaths. These findings help explain the effects of hypoxia on adult neurogenesis and provide new perspectives on brain responsiveness to persistent hypoxemia.

慢性低氧血症是一种常见的病症，可导致严重的神经系统改变，这在不适应高海拔环境的居民或慢性阻塞性呼吸系统疾病患者身上都有体现。然而，这种现象的发病机理尚不清楚。我们发现，成年啮齿动物在缺氧环境中暴露数天/数周，动脉血氧张力与慢性低氧血症患者的动脉血氧张力相似时，脑室下神经源龛（脑室下区）会出现部分不可逆的结构紊乱，其特征是神经元和髓鞘轴突移位、上皮细胞层变平以及毛细血管壁变薄。尽管出现了这些异常，但室管膜下区的神经元和少突胶质细胞祖细胞、神经母细胞和神经球形成细胞的数量以及增殖活性均保持不变。这些结果表明，神经干细胞及其未分化的后代对缺氧具有抵抗力。然而，体内和体外实验表明，严重的慢性缺氧会降低新生成神经元和少突胶质细胞的存活率，并损伤髓鞘。这些发现有助于解释缺氧对成人神经发生的影响，并为大脑对持续低氧血症的反应提供了新的视角。

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引用次数: 0

Therapeutic inhibition of prolyl hydroxylase domain-containing enzymes in surgery: putative applications and challenges 手术中含有脯氨酰羟化酶结构域的酶的治疗抑制:推测的应用和挑战

Hypoxia (Auckland, N.Z.)

Pub Date : 2015-01-30 DOI: 10.2147/HP.S60872

J. Harnoss, Moritz J. Strowitzki, P. Radhakrishnan, L. K. Platzer, J. Harnoss, T. Hank, Jun Cai, A. Ulrich, Martin Schneider

Oxygen is essential for metazoans to generate energy. Upon oxygen deprivation adaptive and protective pathways are induced, mediated by hypoxia-inducible factors (HIFs) and prolyl hydroxylase domain-containing enzymes (PHDs). Both play a pivotal role in various conditions associated with prolonged ischemia and inflammation, and are promising targets for therapeutic intervention. This review focuses on aspects of therapeutic PHD modulation in surgically relevant disease conditions such as hepatic and intestinal disorders, wound healing, innate immune responses, and tumorigenesis, and discusses the therapeutic potential and challenges of PHD inhibition in surgical patients.

氧气是后生动物产生能量所必需的。缺氧时，缺氧诱导因子(hif)和脯氨酰羟化酶结构域酶(PHDs)介导的适应性和保护性途径被诱导。两者都在与长时间缺血和炎症相关的各种疾病中发挥关键作用，并且是治疗干预的有希望的靶点。本文综述了在外科相关疾病如肝脏和肠道疾病、伤口愈合、先天免疫反应和肿瘤发生等方面的治疗性PHD调节，并讨论了PHD抑制在外科患者中的治疗潜力和挑战。

引用次数: 26

Signaling hypoxia by hypoxia-inducible factor protein hydroxylases: a historical overview and future perspectives 缺氧诱导因子蛋白羟化酶的缺氧信号:历史回顾和未来展望

Hypoxia (Auckland, N.Z.)

Pub Date : 2014-12-05 DOI: 10.2147/HP.S47598

T. Bishop, P. Ratcliffe

By the early 1900s, the close matching of oxygen supply with demand was recognized to be a fundamental requirement for physiological function, and multiple adaptive responses to environment hypoxia had been described. Nevertheless, the widespread operation of mechanisms that directly sense and respond to levels of oxygen in animal cells was not appreciated for most of the twentieth century with investigators generally stressing the regulatory importance of metabolic products. Work over the last 25 years has overturned that paradigm. It has revealed the existence of a set of “oxygen-sensing” 2-oxoglutarate dependent dioxygenases that catalyze the hydroxylation of specific amino acid residues and thereby control the stability and activity of hypoxia-inducible factor. The hypoxia-inducible factor hydroxylase pathway regulates a massive transcriptional cascade that is operative in essentially all animal cells. It transduces a wide range of responses to hypoxia, extending well beyond the classical boundaries of hypoxia physiology. Here we review the discovery and elucidation of these pathways, and consider the opportunities and challenges that have been brought into focus by the findings, including new implications for the integrated physiology of hypoxia and therapeutic approaches to ischemic/hypoxic disease.

到20世纪初，氧气供给与需求的密切匹配被认为是生理功能的基本要求，并描述了对环境缺氧的多种适应性反应。然而，在20世纪的大部分时间里，由于研究人员普遍强调代谢产物的调节重要性，直接感知和响应动物细胞中氧气水平的机制的广泛运作并没有得到重视。过去25年的工作颠覆了这种模式。揭示了一组“感氧”的2-氧戊二酸依赖双加氧酶的存在，这些酶能催化特定氨基酸残基的羟基化，从而控制缺氧诱导因子的稳定性和活性。缺氧诱导因子羟化酶途径调节了大量的转录级联反应，基本上在所有动物细胞中都有效。它对缺氧的反应范围很广，远远超出了缺氧生理学的经典界限。在这里，我们回顾了这些途径的发现和阐明，并考虑了这些发现所带来的机遇和挑战，包括对缺氧综合生理学和缺血性/缺氧疾病治疗方法的新含义。

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引用次数: 39

Macrophage-mediated response to hypoxia in disease 巨噬细胞介导的疾病缺氧反应

Hypoxia (Auckland, N.Z.)

Pub Date : 2014-11-15 DOI: 10.2147/HP.S49717

S. Tazzyman, C. Murdoch, J. Yeomans, Jack Harrison, M. Muthana

Hypoxia plays a critical role in the pathobiology of various inflamed, diseased tissues, including malignant tumors, atherosclerotic plaques, myocardial infarcts, the synovia of rheumatoid arthritic joints, healing wounds, and sites of bacterial infection. These areas of hypoxia form when the blood supply is occluded and/or the oxygen supply is unable to keep pace with cell growth and/or infiltration of inflammatory cells. Macrophages are ubiquitous in all tissues of the body and exhibit great plasticity, allowing them to perform divergent functions, including, among others, patrolling tissue, combating invading pathogens and tumor cells, orchestrating wound healing, and restoring homeostasis after an inflammatory response. The number of tissue macrophages increases markedly with the onset and progression of many pathological states, with many macrophages accumulating in avascular and necrotic areas, where they are exposed to hypoxia. Recent studies show that these highly versatile cells then respond rapidly to the hypoxia present by altering their expression of a wide array of genes. Here we review the evidence for hypoxia-driven macrophage inflammatory responses in various disease states, and how this influences disease progression and treatment.

缺氧在各种炎症、病变组织的病理生物学中起着关键作用，包括恶性肿瘤、动脉粥样硬化斑块、心肌梗死、类风湿关节炎关节的滑膜、伤口愈合和细菌感染部位。当血液供应被阻塞和/或氧气供应无法跟上细胞生长和/或炎症细胞浸润的步伐时，这些缺氧区域就会形成。巨噬细胞普遍存在于身体的所有组织中，并表现出极大的可塑性，使它们能够执行不同的功能，包括巡逻组织，对抗入侵的病原体和肿瘤细胞，协调伤口愈合，以及在炎症反应后恢复体内平衡。随着许多病理状态的发生和进展，组织巨噬细胞的数量显著增加，大量巨噬细胞聚集在缺氧的无血管和坏死区域。最近的研究表明，这些高度多样化的细胞通过改变其广泛基因的表达，对缺氧做出快速反应。在这里，我们回顾了各种疾病状态下缺氧驱动的巨噬细胞炎症反应的证据，以及它如何影响疾病进展和治疗。

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引用次数: 11

Regulation of obesity and insulin resistance by hypoxia-inducible factors 低氧诱导因子对肥胖和胰岛素抵抗的调节

Hypoxia (Auckland, N.Z.)

Pub Date : 2014-11-13 DOI: 10.2147/HP.S68771

J. Ban, Robin J. Ruthenborg, Kevin w Cho, Jung-whan Kim

In obesity, dysregulated metabolism and aberrant expansion of adipose tissue lead to the development of tissue hypoxia that plays an important role in contributing to obesity-associated metabolic disorders. Recent studies utilizing adipocyte-specific hypoxia-inducible factor-α (HIF-α) gain- or loss-of-function animal models highlight the pivotal involvement of hypoxic responses in the pathogenesis of obesity-associated inflammation and insulin resistance. HIF-1α, a master transcription factor of oxygen homeostasis, induces inflammation and insulin resistance in obesity, whereas its isoform, HIF-2α, exerts opposing functions in these obesity-associated metabolic phenotypes. In this review, recent evidence elucidating functional implications of adipocyte HIFs in obesity and, more importantly, how these regulate obesity-associated inflammation, fibrosis, and insulin resistance will be discussed. Further, we propose that modulation of HIF-1 could be a potential novel therapeutic strategy for antidiabetic treatment.

在肥胖中，代谢失调和脂肪组织的异常扩张导致组织缺氧的发展，这在肥胖相关的代谢紊乱中起着重要作用。最近利用脂肪细胞特异性缺氧诱导因子-α (HIF-α)获得或丧失功能的动物模型的研究强调了缺氧反应在肥胖相关炎症和胰岛素抵抗的发病机制中的关键作用。HIF-1α是一种主要的氧稳态转录因子，在肥胖中诱导炎症和胰岛素抵抗，而其同型异构体HIF-2α在这些肥胖相关的代谢表型中发挥相反的功能。在这篇综述中，最近的证据阐明脂肪细胞hif在肥胖中的功能意义，更重要的是，这些如何调节肥胖相关的炎症、纤维化和胰岛素抵抗将被讨论。此外，我们提出调节HIF-1可能是一种潜在的抗糖尿病治疗新策略。

引用次数: 42

Effects of copper sulfate-oxidized or myeloperoxidase-modified LDL on lipid loading and programmed cell death in macrophages under hypoxia. 硫酸铜氧化或髓过氧化物酶修饰的低密度脂蛋白对缺氧条件下巨噬细胞脂质负荷和程序性细胞死亡的影响

Hypoxia (Auckland, N.Z.)

Pub Date : 2014-09-23 eCollection Date: 2014-01-01 DOI: 10.2147/HP.S65242

Benoit Vlaminck, Damien Calay, Marie Genin, Aude Sauvage, Noelle Ninane, Karim Zouaoui Boudjeltia, Martine Raes, Carine Michiels

Atheromatous plaques contain heavily lipid-loaded macrophages that die, hence generating the necrotic core of these plaques. Since plaque instability and rupture is often correlated with a large necrotic core, it is important to understand the mechanisms underlying foam cell death. Furthermore, macrophages within the plaque are associated with hypoxic areas but little is known about the effect of low oxygen partial pressure on macrophage death. The aim of this work was to unravel macrophage death mechanisms induced by oxidized low-density lipoproteins (LDL) both under normoxia and hypoxia. Differentiated macrophages were incubated in the presence of native, copper sulfate-oxidized, or myeloperoxidase-modified LDL. The unfolded protein response, apoptosis, and autophagy were then investigated. The unfolded protein response and autophagy were triggered by myeloperoxidase-modified LDL and, to a larger extent, by copper sulfate-oxidized LDL. Electron microscopy observations showed that oxidized LDL induced excessive autophagy and apoptosis under normoxia, which were less marked under hypoxia. Myeloperoxidase-modified LDL were more toxic and induced a higher level of apoptosis. Hypoxia markedly decreased apoptosis and cell death, as marked by caspase activation. In conclusion, the cell death pathways induced by copper sulfate-oxidized and myeloperoxidase-modified LDL are different and are differentially modulated by hypoxia.

动脉粥样斑块含有大量脂质的巨噬细胞，这些巨噬细胞会死亡，从而产生这些斑块的坏死核心。由于斑块的不稳定性和破裂往往与大面积坏死核心有关，因此了解泡沫细胞死亡的内在机制非常重要。此外，斑块内的巨噬细胞与低氧区域有关，但人们对低氧分压对巨噬细胞死亡的影响知之甚少。这项研究旨在揭示氧化低密度脂蛋白（LDL）在常氧和低氧条件下诱导巨噬细胞死亡的机制。分化的巨噬细胞在原生、硫酸铜氧化或髓过氧化物酶修饰的低密度脂蛋白存在下进行培养。然后对未折叠蛋白反应、细胞凋亡和自噬进行了研究。髓过氧化物酶修饰的低密度脂蛋白触发了未折叠蛋白反应和自噬，而硫酸铜氧化的低密度脂蛋白在更大程度上触发了未折叠蛋白反应和自噬。电子显微镜观察显示，氧化低密度脂蛋白在常氧条件下诱导过度自噬和细胞凋亡，而在缺氧条件下则不那么明显。髓过氧化物酶修饰的低密度脂蛋白毒性更强，诱导的细胞凋亡水平更高。缺氧明显降低了细胞凋亡和细胞死亡，以 caspase 激活为标志。总之，硫酸铜氧化的低密度脂蛋白和髓过氧化物酶修饰的低密度脂蛋白诱导的细胞死亡途径不同，而且受缺氧的调节也不同。

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引用次数: 0

Arginine-vasopressin marker copeptin is a sensitive plasma surrogate of hypoxic exposure 精氨酸-抗利尿激素标志物copeptin是缺氧暴露的敏感血浆替代物

Hypoxia (Auckland, N.Z.)

Pub Date : 2014-09-11 DOI: 10.2147/HP.S57894

L. Ostergaard, A. Rudiger, S. Wellmann, Elena Gammella, B. Beck-Schimmer, J. Struck, M. Maggiorini, M. Gassmann

Background A reduced oxygen supply puts patients at risk of tissue hypoxia, organ damage, and even death. In response, several changes are activated that allow for at least partial adaptation, thereby increasing the chances of survival. We aimed to investigate whether the arginine vasopressin marker, copeptin, can be used as a marker of the degree of acclimatization/adaptation in rats exposed to hypoxia. Methods Sprague-Dawley rats were exposed to 10% oxygen for up to 48 hours. Arterial and right ventricular pressures were measured, and blood gas analysis was performed at set time points. Pulmonary changes were investigated by bronchoalveolar lavage, wet and dry weight measurements, and lung histology. Using a newly developed specific rat copeptin luminescence immunoassay, the regulation of vasopressin in response to hypoxia was studied, as was atrial natriuretic peptide (ANP) by detecting mid-regional proANP. Results With a decreasing oxygen supply, the rats rapidly became cyanotic and inactive. Despite continued exposure to 10% oxygen, all animals recuperated within 16 hours and ultimately survived. Their systemic blood pressure fell with acute (5 minutes) hypoxia but was partially recovered over time. In contrast, right ventricular pressures increased with acute (5 minutes) hypoxia and normalized after 16 hours. No signs of pulmonary inflammation or edema were found despite prolonged hypoxia. Whereas copeptin levels increased significantly after acute (5 minutes) hypoxia and then returned to near baseline after 16 hours, mid-regional proANP levels were even further increased after 16 hours of exposure to hypoxia. Conclusion Plasma copeptin is a sensitive marker of acute (5 minutes) exposure to severe hypoxia, and subsequent regulation can indicate recovery. Copeptin levels can therefore reflect clinical and physiological changes in response to hypoxia and indicate recovery from ongoing hypoxic exposure.

研究背景供氧减少使患者面临组织缺氧、器官损伤甚至死亡的危险。作为回应，一些变化被激活，允许至少部分适应，从而增加生存的机会。我们的目的是研究精氨酸抗利尿激素标志物copeptin是否可以作为大鼠缺氧环境适应程度的标志。方法将Sprague-Dawley大鼠暴露于10%氧气环境48小时。测量动脉和右心室压力，并在设定的时间点进行血气分析。通过支气管肺泡灌洗、干湿体重测量和肺组织学检查肺部变化。采用新开发的特异性大鼠copeptin发光免疫分析法，研究了抗利尿素对缺氧反应的调节，并通过检测心房钠素(ANP)中部区域的proANP来研究心房钠素(ANP)。结果随着供氧量的减少，大鼠迅速变成紫绀型和失活型。尽管持续暴露在10%的氧气中，所有动物都在16小时内恢复并最终存活下来。他们的全身血压在急性(5分钟)缺氧时下降，但随着时间的推移部分恢复。相反，右心室压力在急性(5分钟)缺氧时升高，16小时后恢复正常。尽管长期缺氧，但未发现肺部炎症或水肿的迹象。急性缺氧(5分钟)后copeptin水平显著升高，16小时后恢复到接近基线水平，缺氧16小时后中部proANP水平进一步升高。结论血浆copeptin是急性(5分钟)严重缺氧暴露的敏感标志物，随后的调节可提示恢复。Copeptin水平因此可以反映临床和生理变化对缺氧的反应，并表明从持续的缺氧暴露恢复。

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引用次数: 14

Prolyl hydroxylase domain enzymes: important regulators of cancer metabolism 脯氨酸羟化酶结构域酶:肿瘤代谢的重要调节因子

Hypoxia (Auckland, N.Z.)

Pub Date : 2014-08-30 DOI: 10.2147/HP.S47968

Ming Yang, Huizhong Su, T. Soga, Kamil R. Kranc, Patrick J. Pollard

The hypoxia-inducible factor (HIF) prolyl hydroxylase domain enzymes (PHDs) regulate the stability of HIF protein by post-translational hydroxylation of two conserved prolyl residues in its α subunit in an oxygen-dependent manner. Trans-4-prolyl hydroxylation of HIFα under normal oxygen (O2) availability enables its association with the von Hippel-Lindau (VHL) tumor suppressor pVHL E3 ligase complex, leading to the degradation of HIFα via the ubiquitin-proteasome pathway. Due to the obligatory requirement of molecular O2 as a co-substrate, the activity of PHDs is inhibited under hypoxic conditions, resulting in stabilized HIFα, which dimerizes with HIFβ and, together with transcriptional co-activators CBP/p300, activates the transcription of its target genes. As a key molecular regulator of adaptive response to hypoxia, HIF plays important roles in multiple cellular processes and its overexpression has been detected in various cancers. The HIF1α isoform in particular has a strong impact on cellular metabolism, most notably by promoting anaerobic, whilst inhibiting O2-dependent, metabolism of glucose. The PHD enzymes also seem to have HIF-independent functions and are subject to regulation by factors other than O2, such as by metabolic status, oxidative stress, and abnormal levels of endogenous metabolites (oncometabolites) that have been observed in some types of cancers. In this review, we aim to summarize current understandings of the function and regulation of PHDs in cancer with an emphasis on their roles in metabolism.

低氧诱导因子(HIF)脯氨酸羟化酶结构域酶(PHDs)以氧依赖的方式通过翻译后α亚基上两个保守脯氨酸残基的羟基化来调节HIF蛋白的稳定性。在正常氧(O2)可用性下，HIFα的反式-4-脯氨酰羟基化使其与von Hippel-Lindau (VHL)肿瘤抑制因子pVHL E3连接酶复合物结合，通过泛素-蛋白酶体途径导致HIFα降解。由于氧分子作为共底物的强制性要求，ph在缺氧条件下的活性被抑制，导致HIFα稳定，HIFα与HIFβ二聚，并与转录共激活因子CBP/p300一起激活其靶基因的转录。HIF作为低氧适应性反应的关键分子调控因子，在多种细胞过程中发挥重要作用，其过表达已在多种癌症中被检测到。特别是HIF1α亚型对细胞代谢有强烈的影响，最显著的是促进无氧代谢，同时抑制o2依赖性的葡萄糖代谢。PHD酶似乎也具有与hif无关的功能，并且受除O2以外的其他因素的调节，例如代谢状态、氧化应激和在某些类型的癌症中观察到的内源性代谢物(肿瘤代谢物)的异常水平。在这篇综述中，我们旨在总结目前对博士在癌症中的功能和调控的理解，重点是它们在代谢中的作用。

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引用次数: 38

Modulation of hydrogen sulfide by vascular hypoxia 血管缺氧对硫化氢的调节

Hypoxia (Auckland, N.Z.)

Pub Date : 2014-08-25 DOI: 10.2147/HP.S51589

J. Osmond, N. Kanagy

Hydrogen sulfide (H2S) has emerged as a key regulator of cardiovascular function. This gasotransmitter is produced in the vasculature and is involved in numerous processes that promote vascular homeostasis, including vasodilation and endothelial cell proliferation. Although H2S plays a role under physiological conditions, it has become clear in recent years that hypoxia modulates the production and action of H2S. Furthermore, there is growing evidence that H2S is cytoprotective in the face of hypoxic insults. This review focuses on the synthesis and signaling of H2S in hypoxic conditions in the vasculature, and highlights recent studies providing evidence that H2S is a potential therapy for preventing tissue damage in hypoxic conditions.

硫化氢(H2S)已成为心血管功能的关键调节因子。这种气体递质在脉管系统中产生，参与许多促进血管稳态的过程，包括血管舒张和内皮细胞增殖。虽然H2S在生理条件下发挥作用，但近年来已经清楚缺氧调节H2S的产生和作用。此外，越来越多的证据表明H2S在面对缺氧损伤时具有细胞保护作用。本文综述了H2S在缺氧条件下在血管中的合成和信号传导，并重点介绍了最近的研究，这些研究提供了H2S在缺氧条件下预防组织损伤的潜在治疗方法。

引用次数: 7

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