这个思路也来自一个传奇故事：

 故事来自一个著名化肥厂，这里曾流传着这样一个顺口溜：“脱硫车间，给个县长也不换”。

    化肥生成的关键产品是氨的合成，需要用氮气和氢气为原料，氮气来自空气。制备氢气的方法是采用煤（碳）与水在高温下还原反应，产生一氧化碳和氢，一氧化碳和水继续反应可产生更多氢，这个车间就是造气车间，由于车间内存在高浓度一氧化碳，一旦泄露容易发生一氧化碳中毒。

 另外由于煤中存在一定水平的硫，就需要一个车间进行脱硫，实际上是进行氢的纯化，这个车间有这样一个特点，比较简单轻松，但也有含硫气体，味道不好。当时由于生产工艺问题，造气车间有可能发生一氧化碳中毒，而且往往是许多人同时出现，这些发生中毒的工人，有的去世了，有的没有问题，有的会出现后遗症（一氧化碳中毒迟发性脑病），对这些出现后遗症的工人患者，由于造气车间工作复杂，劳动强度大，这些患者无法胜任，需要重新安排工作。安排的工作有两类：脱硫车间和机关。经过1年左右时间，竟然出现奇怪的结果：分配到脱硫车间工作的患者大部分恢复正常，但在机关工作的患者却没有这样幸运，大部分没有恢复，有的甚至病情继续恶化。

于是有了这样一个顺口溜。“脱硫车间，给个县长也不换”。

这个故事有一个很强的提示：呼吸含氢气体对那些神经系统损伤，特别是这类脑病患者有很好的治疗效果。

因为这个车间最多的泄露气体是氢，从味道不好可以说肯定有泄露，从其成分组成看，最重要的应该是氢。

        看来科研思路需要到基层去发掘。

Hydrogen as a novel and effective treatment of acute carbon monoxide poisoning.

Meihua Shen, M.D, Ph.D; Jianmei Cai, M.D, Ph.D; Qiang Sun, M.D, Ph.D; Jian He, M.D, PhD；Xuejun Sun, M.D, Ph.D; Zhenglu Huo, M.D, Ph.D.

summary

Hydrogen is a major component of interstellar space and the fuel that sustains the stars. However, it is seldom regarded as a therapeutic gas. A recent study provided evidence that hydrogen inhalation exerted antioxidant and anti-apoptotic effects and protected the brain against ischemia-reperfusion injury by selectively reducing hydroxyl radical and peroxynitrite. It has been known that the mechanisms underlying the brain injury after acute carbon monoxide poisoning are interwoven with multiple factors including oxidative stress, free radicals, and neuronal nitric oxide synthase as well as abnormal inflammatory responses. Studies have shown that free radical scavengers can improve the neural damage. Based on the findings abovementioned, we hypothesize that hydrogen therapy may be an effective, simple, economic and novel strategy in the treatment of acute carbon monoxide poisoning.

Introduction

Hydrogen is the simplest and most essential chemical element, composing nearly 75% of the universe’s elemental matter. It is a colorless, tasteless, odorless, non-irritating and highly flammable diatomic gas which has been used in the fossil fuel processing and ammonia production. Hydrogen is seldom regarded as an important candidate in medicine, especially as a therapeutic gas. However, a recent study showed that hydrogen inhalation exhibited antioxidant and anti-apoptotic activities which protected the brain against ischemia–reperfusion injury by selectively reducing hydroxyl radical (·OH) and peroxynitrite (ONOO－) [1]. This study indicated that hydrogen, a highly diffusible molecular, may be a novel anti-oxidative agent which can specifically target intracellular sources of reactive oxygen species (ROS).

ROS and reactive nitrogen species (RNS) including ·OH, superoxide anion (O2－), hydrogen dioxide (H2O2), nitric oxide (NO), ONOO－, have been confirmed to play critical roles in the cell damage after stroke, myocardial ischemia-reperfusion injury, transplantation injury and other injuries. Many efforts have been conducted to restore the blood flow to the ischemic tissues after stroke or a heart attack. However, it is still difficult to relieve this pathological cascade of oxidative damage after reperfusion injury [2].

Ohsawa and colleagues [1] presented that hydrogen selectively reduces the toxic ·OH to H2O, and has antioxidant and anti-apoptotic properties affording neuroprotection in the setting of ischemia-reperfusion injury. Their findings support a novel hypothesis that hydrogen might act as a gaseous oxygen radical scavenger that prevents neural death. Other researchers have showed that hydrogen can also improve myocardial, hepatic ischemia-reperfusion injury, neonatal hypoxia-ischemia, Parkinson’s disease, oxidative stress induced cognitive decline, etc [3-7].

However, no study has been conducted to investigate the effects of hydrogen in the treatment of acute carbon monoxide (CO) poisoning, in which ROS also play pivotal roles.

Acute carbon monoxide poisoning

Acute CO inhalation is the leading cause of death relevant to gas poisoning in the world since increasing use of carbon-based fuels. Autopsy has revealed that CO poisoning injures several brain regions, including the cerebral cortex, globus pallidus, caudate putamen, hippocampus and striatum [8-10]. Furthermore, neuropsychiatric abnormalities, including parkinsonism and dementia, with abnormal images of those brain regions in computed tomography (CT) and/or magnetic resonance imaging (MRI), have been reported in survivors from acute CO poisoning [11-14]. Delayed neurological syndrome (DNS), typically character of which is the lucid interval before the appearance of neuropsychiatric abnormalities, are commonly observed after acute CO poisoning.

It has still been a barrier for medical person because of poor early detection and disappointing prognosis. The specific mechanisms underlying the brain damage including DNS after CO poisoning are still poorly understood. However, numerous studies have indicated significantly increased production of ROS, which are of crucial relevance in the pathophysiology of CO intoxication [10,15-17]. Although ROS are probably intended to fight against invaded pathogens, they seem to produce substantial collateral damage resulting in DNA strand breaks, and lipid and protein oxidation [18-20]. The brain is highly vulnerable to oxidative stress in comparison with other organs due to high metabolic rate to meet the need of the brain for energy, which leads to the increased production of ROS. Once the defense against these ROS is insufficient, these ROS may inevitably cause oxidation of unsaturated fatty acids resulting in lipid peroxidation [21,22]. Enhancement in the ROS generation following brain insults, including cerebral ischemia/hypoxia, brain trauma, and CO poisoning, may disrupt the balance between ROS generation and the defense system, accelerating the neural injury resulting in extension of the injury or a more severe outcome [23,24,10].

Numerous strategies have been applied in the treatment of CO poisoning including aggressive supportive care, application of free radical scavengers, monoamine oxidase inhibitors, and N-methyl-D-aspartate blockers, as well as hyperbaric oxygen (HBO) therapy. Furthermore, general agreement that HBO therapy can reduce the neurologic morbidity and mortality, and partially ameliorate the impaired neurofunction has also been achieved [25-27]. The main mechanisms underlying the beneficial effects of HBO on acute CO poisoning is by accelerating the dissociation of CO from Hemoglobin. However, there are still controversial over the effectiveness of HBO treatment on severe CO poisoning [28,29]. More attention should be paid to the adverse effects of HBO therapy. Theoretically, the increase availability of oxygen due to oxygen therapy may lead to the augmented formation of oxygen radicals. Studies have reported increased production of ROS in human blood and rat brain after HBO treatment [30,31]. Li et al also found that HBO may result in convulsion through up-regulating nitric oxide synthases (NOS) [32].

Despite a variety of neuroprotective agents have been widely studied in the past decades, no agent is found to meet the criteria of an optimal neuroprotectant. Various researchers have engaged in identifying novel, nontoxic, effective, and convenient compounds to protect against tissue injuries caused by acute CO poisoning.

Hypothesis

Our hypothesis is that hydrogen may be a promising, effective and specific treatment of acute CO poisoning. Our hypothesis is on the ground of the theory that molecular hydrogen can selectively decrease ·OH and ONOO－ [1]. Given ·OH and ONOO－ are much more reactive than other ROS, we have reason to believe that hydrogen will act in response with only the strongest toxic oxidants.

This is beneficial for medical procedures in that molecular hydrogen is so mild that it does not disturb metabolic oxidation-reduction reactions or not disrupt ROS involved in cell signaling [1,2]. In addition, it can penetrate biomembranes and diffuse into the cytosol, mitochondria and nucleus. Therefore, hydrogen may protect nuclear DNA damage and mitochondrial membrane permeabilization. Furthermore, it can react with low density toxic ROS in that its relative concentration is quite high. Also as a potential treatment, hydrogen has distinct advantages over pharmaceutical drugs: it easily diffuses across the blood-brain barrier to reach target tissues, may act via multiple pathways. Last but not least, the tissue compatity of hydrogen is stronger than many other antioxidant because it is an endogenous substance [33].

Since it has been known that the mechanisms underlying the brain injury after acute CO poisoning are interwoven with multiple factors including oxidative stress, free radicals, and neuronal nitric oxide synthase as well as abnormal inflammatory responses, and hydrogen can protect cells from oxidative damage through selectively scavenging ·OH and ONOO－ [1], we hypothesize that hydrogen can be potentially effective for acute CO poisoning. That is to say, hydrogen may be a promising novel neuroprotectants. We believe that in vitro and in vivo work for hydrogen on neuroprotection against acute CO poisoning should commence as soon as possible.

Conflict of interest statement

None declared.

Acknowledgements

We thank Dr. John H Zhang from the Department of Neurosurgery, Loma Linda University, Loma Linda, California, USA and Dr. Wenwu Liu from the Department of Diving Medicine of our university for providing so many helps.

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