虽然氢气生物学效应的研究表面上轰轰烈烈，但经过近5年的研究，对氢气生物学效应的分子本质并没有实质性进展，这也成为该领域所面临的最重要困境。不仅这样，一些最基本的学术问题也没有很明确的答案。

关于氢气的效应存在两个主要问题或谜团，一是缺乏相对准确的剂量效应关系。无论是动物试验，还是临床观察，通过饮用氢气水（呼吸和注射没说？）摄取的氢气都是很小量的，但产生的效应又是显著的。二是人类和动物肠道细菌可以产生大量氢气，但是增加小量为何仍会产生如此显著的效应。此外，关于氢气生物效应的分子基础，以及针对不同疾病使用氢气的最佳方法、剂量和频率等问题仍需要更多研究来阐述。

一、氢气生物学效应机制的几种假说

氢气在多种疾病中的治疗作用机制目前尚不十分清楚，目前国际学术界比较认可可能存在三种分子机制假说。一是经典的说法，就是氢气的选择性抗氧化作用，氢气在不影响具有信号作用的自由基基础上，可选择性中和强毒性活性氧羟基自由基和亚硝酸阴离子（抗炎症和抗凋亡都属于广义的抗氧化）；二是氢气可调节基因表达；三是氢气具有信号调节作用。上述三种机制并不矛盾，而且相互之间存在一定联系。氢气中和羟基自由基和亚硝酸阴离子的效应，从化学反应原理中可以推测，因此从理论上并没有特别的创新性。

2007年Ohsawa等采用化学反应溶液直接检测上述两种自由基，证明氢气在溶液中具有直接中和羟基自由基和亚硝酸阴离子的效应。实际上，自由基生物学领域认可采用一些氧化损伤产物可以间接反应机体内羟基自由基和亚硝酸阴离子的水平。例如可以用8-OHdG、4-HNE、MDA、TBARS作为指标，间接反应动物和人体的氧化应激水平。由于氢气非常容易通过呼吸释放到身体外，通过饮用饱和氢气水动物和人体内氢气有效存留时间不超过10分钟。尽管有学者认为，肝脏内糖原可以结合氢气，在一定程度上可以延缓氢气的释放，是氢气在肝脏等器官有明显治疗效果的重要原因，其实这个说法很荒谬，并不只是糖原，各种大分子都具备这个特征，这是气体在复杂液体环境中的共有现象。真正的问题是，人体和动物如何持续利用氢气来中和健康和疾病状态下羟基自由基的持续释放。氢气中和亚硝酸阴离子的效应具有更广泛的意义，尽管氢气中和亚硝酸阴离子的能力远低于羟基自由基（这本质上决定于羟基自由基的氧化性大大超过亚硝酸阴离子），由于亚硝酸阴离子不仅毒性强，同时也是一种信号分子，具有非常广泛的生物学作用。许多研究发现，氢气可以减少动物NO诱导的硝基酪氨酸水平增加。NO是一种著名的气体信号分子，具有扩张血管、抑制血小板聚集等多种生理和病理生理学效应，当NO浓度过度增加时，也会表现出毒性。因为NO可以通过亚硝酸阴离子间接引起蛋白质残基酪氨酸硝基化，产生硝基酪氨酸，并干扰蛋白质功能。推测氢气的一些生物学效应可能与降低硝基酪氨酸的产生有关。

采用基因表达谱研究发现，氢气长期使用可引起正常大鼠肝脏基因表达的小幅度改变。对这些基因的功能进行分析发现，许多受到氢气影响表达上调（十分关键）的基因和氧化还原反应关系密切，而氧化还原是能量代谢的最重要基础，可能提示氢气和能量代谢之间存在密切联系，另外氧化还原也是氧化应激产生的根本，也许氢气抗氧化作用的原因是通过调节这些基因表达实现的。在啮齿类动物疾病模型中，一些研究对部分基因和蛋白的表达水平进行了分析。许多疾病模型中，氢气可以下调炎症因子的基因表达，例如肿瘤坏死因子a、白细胞介素1、白细胞介素6、白细胞介素12、干扰素g和高迁移率组蛋白1（HMGB1)等。氢气也可以下调一些细胞核因子包括NfkB、JNK和细胞增殖核抗原(PCNA)。氢气治疗时，Caspase也往往下调。另外一些有意思的分子如VEGF、MMP2、MMP9、脑钠肽、细胞黏附分子1（ICAM-1）、MPO、Bcl2、Bax、MMP3、MMP13、COX-2、nNOS、缝隙连接蛋白（connexins）30 、connexins 43、离子钙接头蛋白Iba1和成纤维细胞生长因子21 FGF21等。显然，大部分分子变化应该属于继发于氢气治疗疾病中的伴随现象，也许部分分子属于氢气的直接效应，但什么分子如何作用等问题都需要将来更多研究来确定。

使用RBL-2H3浆细胞，Ohno等证明氢气可以降低FceRI（IgE高亲和力受体）Fc eRI相关Lyn磷酸化（注：FceRI与PTK（蛋白酪氨酸激酶）如Lyn、Syk相连，当Fc eRI因为IgE结合发生交联后，引起Lyn和Syk的自我磷酸化，再激活了磷脂酶C（PLC）和Src激酶。PLC激活后产生效应分子，如甘油二酯（DG），继而激活蛋白激酶C（PKC），再经过Btk的PH结构域介导与Btk相互作用），因为Lyn磷酸化可以被下游信号分子再次磷酸化，而形成一个信号传导环路。尽管不清楚氢气是如何具体发挥调节作用的，但研究证明氢气可抑制快速过敏反应，该效应与抗氧化作用无关，反而与氢气调节信号分子的作用关系更为密切。同一课题组进一步使用鼠RAW264巨噬细胞系的研究发现，氢气可以减少LPS/ IFNg诱导的巨噬细胞NO释放增加。氢气可以抑制ASK1磷酸化（细胞内抗氧化物质硫氧化还原蛋白是其内源性阻断剂，微量元素硒也有该作用，氢气如有此效应，真正很神勇！），并可以阻断其下游信号传导通路，例如p38、JNK、IkBa，同时不影响NADPH氧化酶活性（不影响更上游，说明调节位置在ASK1附近，是否就是硫氧化还原蛋白？？？）。上述两项研究提示，氢气也是一种气体信号分子。因为氢气本身不是可以调节的内源性分子，因此这样的说法不够严谨全面，而且需要更多细胞和动物试验来证实。

二、氢气生物学效应的谜团

氢气效应研究中明显存在两个无法解释的谜团。首先，没有发现氢气的剂量效应关系。在多种不同的研究中，摄取氢气的方式有呼吸、饮氢气水、注射氢气生理盐水、点滴和透析液中溶解氢气等。假设60公斤体重的成人每天饮1000 ml氢气饱和水（1.6 ppm or 0.8 mM），即使氢气通过胃肠道被全部吸收，也只有0.8 毫摩尔，考虑到身体内的液体比例，那么体内可以达到的最大浓度为0.022 mM。2.8%的饱和浓度就是0.022 mM，这相当于通过呼吸2.8%氢气达到完全饱和的浓度。又由于身体释放氢气的速度非常快，大约只有10分钟，那么身体内达到这一浓度的时间只有10分钟。就是说氢气的作用时间非常短暂。如果让一个人呼吸2%氢气混合气，身体内达到的氢气浓度可以达到0.016 mM，即使我们认为饮水可以把氢气作用的持续时间全部计算为10分钟，连续呼吸24小时2%氢气混合气的作用剂量也超过饮水摄取氢气的100倍。另外，动物和人往往不是饮用100%的饱和氢气水，考虑到这个因素，饮用氢气水被摄取的氢气量是非常微量的。但是氢气水仍然具有明显的治疗效果，有时候甚至比呼吸氢气的效果更理想，而且饮用氢气水首先被胃肠道吸收然后经过肝脏心脏和肺释放一部分后才能进入其他器官发挥作用，而在脑、脊髓、肾、胰腺、肌肉和软骨的效应又非常明显，那么是否身体内存在携带氢气的机制？（其实动物因体积小，心肺活动剧烈，氢气被释放的比例更高，事态更严重）。

关于氢气生物学效应的第二个谜团是人类和许多动物的胃肠道本身可以产生氢气，尽管高等动物细胞本身是否可以产生目前尚不明确，但在胃肠道和口腔等部分的大量正常菌群，有一大部分是可以产生氢气的，而这些氢气同样可以被机体吸收，而且也可以通过呼吸气体检测到氢气的浓度。人类肠道每天产生的氢气总量可以达到12升（不太靠谱），而通过呼吸或饮用或注射摄取的氢气远远低于胃肠道的氢气产量，但补充氢气又发现具有明显的保护效应。而且更让人无法理解的是，通过诱导胃肠道产生更多氢气，可以治疗一些疾病，例如Kajiya等通过给动物补充可产生氢气的细菌，诱导胃肠道产生更多氢气对Concanavalin A诱导的肝炎具有治疗作用，而用抗生素杀灭细菌，这种效应则完全消失。这也是目前唯一一项关于胃肠道内细菌产生氢气效应的报道。该研究作者也认为通过饮用氢气水可以获得比诱导胃肠道产生氢气更有效的治疗效果。如果通过诱导胃肠道细菌产生氢气可以获得同样的治疗效果，我们将有许多更容易的提高氢气的手段，例如通过阿卡波糖、咖喱原料姜黄素、非吸收合成糖、乳果糖等都可以诱导身体内胃肠道细菌产生更多氢气。关于胃肠道氢气效应的这个谜团也需要将来更多研究来探索和解释。

关于肠道氢气的效应问题，最近的研究给出了一种解释，那就是持续高浓度的氢气会掩盖氢气的生物学效应，而间歇性给于氢气才可以发挥理想的效应。不过这种说法目前并没有被其他学者的研究证实（详见第二章）。

尽管有63个动物疾病模型和6种人类疾病可证明氢气治疗疾病的作用，但只有两种疾病包括脑梗死和代谢综合症同时有动物和临床观察的研究。由于氢气没有任何副作用，这对开展临床研究是显著的优势，即使没有动物试验，仍可以进行一些临床研究的观察。一些人类疾病，包括巴金森病目前正在开展临床研究，并取得了一些良好的结果，相信氢气会对更多人类疾病有一定治疗价值。当然，深入探索氢气的作用机制也是一项非常值得期待但可能充满艰辛的科学方向。

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