慢性氧中毒即使一种研究氧气慢性毒性的模型，也是一种比较理想的研究慢性肺损伤的模型。慢性氧中毒模型是一种非常好的动物模型，因为可以根据需要调整氧气的浓度、暴露时间和暴露压力，能制备出不同程度的肺损伤模型。

慢性氧中毒是患者呼吸高分压氧（60%）时发生的一种疾病。当患者因肺功能障碍需要通过呼吸高浓度氧来维持血氧饱和度时，就会出现非常令人尴尬的局面：如果不提高呼吸气体的氧浓度，患者会发生缺氧，如果提高呼吸气体的氧浓度，氧气本身会增加肺损伤。一旦患者到了这个处境，也意味着到了绝境。这种情况在医院的ICU是经常遇到的。

慢性氧中毒的主要原因是呼吸高分压氧增加了肺组织内的活性氧，后者导致肺组织发生氧化损伤，最有效的方法是降低氧分压。当患者需要呼吸氧气的时候，必须采取间隔呼吸氧气的方法，这样才可以有效降低氧气的毒性（高压氧治疗采用间歇呼吸氧气也有这个考虑）。慢性氧中毒早期改变类似于支气管肺炎的改变，如果不能及时降低氧分压，患者将会出现炎症加重，并最终导致肺纤维化，这个过程非常类似于病毒性肺炎（非典型肺炎），在非典期间，我曾经建议采用这个模型来研究药物，特别是非抗病毒性药物。

氢气抗氧化的发现后，结合我们过去有许多研究慢性氧中毒的经验，我们早就开始了用氢气治疗这个疾病的研究（同时开展对急性氧中毒的研究，发现没有治疗效果）。数月前，我们已经用2个大气压短时间（6小时）暴露的慢性氧中毒模型证明了氢气对慢性氧中毒的效果，文章发表在Undersea and Hyperbaic medicine上。由于考虑到慢性氧中毒更多发生在常压呼吸氧气的情况，我们现在又采用常压吸氧48小时的模型重复了该研究，并通过炎症因子测定，抗氧化酶测定和细胞凋亡检测进行相对深入的研究。这个研究论文被J Surgical Res接受(全文pdf offprint）。

在投稿过程中，有一个小插曲，我们与美国匹兹保大学Nakao教授就这个课题多次交换过意见，他们也进行了相关研究，我们开始希望他做共同作者，他没有接受我们的建议。而且由于我们的文章写的比较早，他们提出让我们推迟投稿3个月，等他们的文章出来大家一起投稿。我虽然觉得他有一些过分，因为这个研究是我们独立完成的。但考虑到大家将来的合作，也不太懂这方面的情况到底如何处理，我们最后还是把这个文章就延迟了几个月才投稿。

该文章第一作者我们博士研究生，这是他以第一作者发表的第4篇SCI论文，今天上午正好去美国美国匹兹保大学器官移植中心Nakao教授从事合作研究。写下此文以做留念，并祝愿他在美国的工作生活顺利，在Nakao教授的指导下，做出更加精彩的研究。

 

Hydrogen-Rich Saline Provides Protection Against Hyperoxic Lung Injury

Qiang Sun.*, Jianmei Cai†, Shulin Liu*, Yun Liu*, Weigang Xu*, Hengyi Tao*, , , and Xuejun Sun Ph.D., M.D.*,

† Department of Neurology, Changhai Hospital, 174 Changhai Road, Shanghai, PR China

* Department of Diving Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai, PR China

Received 21 August 2010. 

Available online 15 October 2010.

 

Background

Hydrogen has been proven to be a novel antioxidant through its selectively reducing of the hydroxyl radical. In this study, we investigated the effects of hydrogen-rich saline on the prevention of acute lung injury induced by hyperoxia (HALI) in rats.

Materials and Methods

Physiologic saline, hydrogen-rich saline, or nitrogen- rich saline was administered through intraperitoneal (i.p.) injection during exposure to hyperoxia (10 mL/Kg), respectively.

Results

Severity of HALI was assessed by the volume of pleural effusion, wet-to-dry weight ratio (W/D), and histologic analysis. Apoptosis in lung cells was determined with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive staining. The content of pro-inflammatory cytokine interleukin IL-1b and TNF-a in the lung tissues were detected by enzyme-linked immunosorbent assay (ELISA). Hydrogen-rich saline treatment provides protection against HALI by inhibiting lipid, DNA oxidation, and tissue edema. Moreover, hydrogen-rich saline treatment could inhibit apoptosis and inflammation while no significant reduction was observed in nitrogen- rich saline treated animals.

Conclusion

The results of this study demonstrate that hydrogen-rich saline ameliorated hyperoxia-induced acute lung injury by reducing oxidative stress and inflammatory cascades in lung tissue.

Key Words: hydrogen ; acute lung injury ; oxidative stress; inflammation; apoptosis

Introduction

Hyperoxic acute lung injury (HALI), caused by prolonged supplement of very high concentrations of oxygen (fractional concentrations of oxygen > 50%), is a clinical syndrome characterized by endothelial and epithelial injury and enhanced alveolar capillary protein leak [1], [2], [3], [4], [5] and [6]. It is generally accepted that increased generation of reactive oxygen species (ROS) plays an important role in lung injury during exposure to hyperoxia [7], [8] and [9]. To evaluate antioxidant defenses, a principal focus of prior studies has been on antioxidant enzymes such as superoxide dismutase (SOD) [10] and [11], GSH peroxidase (GPx) [12] and [13], and peroxiredoxin 6 [14] and [15] utilizing both overexpression and suppression of activity. In addition, subsequent reports indicated that IL-1, tumor necrosis factor (TNF)-a and IL-6 induce tolerance [1] and [16]. As yet, there are no specific treatments for HALI available and new effective treatment are needed for clinical settings.

Hydrogen is a gaseous molecule without known toxicity, which could react with hydroxyl radical, has been considered as a novel antioxidant [17]. Both in vivo and in vitro studies support the protective effect of hydrogen on ischemia-reperfusion injuries caused by oxidative stress in brain [18], liver [19], heart [20], [21] and [22], and intestine [23], as well as anti-inflammatory effect on acute pancreatitis [24], colon inflammation [25], liver inflammation [26].

Our previous study has demonstrated that hydrogen-rich saline could reduce lung injury induced by intestinal ischemia/reperfusion in rats [27]. This raises the possibility that the hydrogen-rich saline might lead to protection against HALI. Therefore, the present study investigated the possible therapeutic effects of hydrogen-rich saline on lung injury induced by hyperoxia in rats.

 

本研究可以结合最近一个会议的报道。估计这个论文1年内也会正式发表。

Inhaling Hydrogen May Help Reduce Lung Damage in Critically Ill Patients, Animal Study Suggests
高浓度吸氧可以导致肺损伤，这对晚期的肺功能障碍患者是一个非常致命的问题，不吸氧无法维持正常的血氧浓度，会发生肺功能障碍，呼吸氧气可以纠正血氧浓度，但如果长时间，例如呼吸100%氧气超过24小时，氧气本身可以造成肺的损伤。继续吸氧，肺功能更差，这样必然导致恶性循环，最终导致无法挽回的局面。
最近有人报道可以呼吸氢气解决这个令人棘手的问题。特别是提出氢气可以促进HO-1的表达，如何理解和解释这个现象是值得我们深入思考的问题。
ScienceDaily (May 16, 2011)— Inhaling small amounts of hydrogen in addition to concentrated oxygen may help stem the damage to lung tissue that can occur when critically ill patients are given oxygen for long periods of time, according to a rat model study conducted by researchers in Pittsburgh. The study also found hydrogen initiates activation of heme-oxygenase (HO-1), an enzyme that protects lung cells. The results will be presented at the ATS 2011 International Conference in Denver.
"We found that inhalation of hydrogen can reduce hyperoxic lung injury that occurs as the result of exposure to concentrated oxygen for prolonged periods, an important problem in critically ill, ventilated patients," said Tomohiro Kawamura, MD, research fellow at the University of Pittsburgh's Thomas E. Starzl Transplantation Institute. "Administering hydrogen treatment by providing gas for the patient to inhale is a new approach and may be feasible in clinical practice." Highly concentrated oxygen is routinely administered to critically ill patients who cannot breathe efficiently, such as patients with severe heart or lung disease. Given over a prolonged period, oxygen toxicity can occur, causing severe lung injury which can lead to respiratory failure. In this study, the researchers hypothesized that the addition of hydrogen, which has potent antioxidant and anti-inflammatory effects, might help mitigate the damage caused by prolonged exposure to concentrated oxygen. To find out, the researchers assigned male rats assigned to four experimental groups: rats exposed to high concentrations of oxygen and either 2 percent nitrogen or 2 percent hydrogen, and rats given normal levels of oxygen and either 2 percent nitrogen or 2 percent hydrogen. Exposure periods for all groups were 60 hours. Lung function was evaluated by blood gas analysis of the arterial blood, and body weight, lung fluid volume, inflammatory cell count in lung fluids and HO-1 levels were measured. Comparing oxygen exposure groups to controls, the researchers found exposure to 2 percent nitrogen with 98 percent oxygen for 60 hours markedly impaired lung function and caused inflammation and a build-up of fluid in the lung. In contrast, rats exposed to 2 percent hydrogen with 98 percent oxygen had less swelling and improved lung function, as well as significant reductions in inflammation compared to controls. In addition, levels of HO-1 were elevated in rats exposed to hydrogen. "Hydrogen-induced hemeoxygenase-1 is a protein that protects the cells and has antioxidant and anti-inflammatory activities," Dr. Kawamura noted. "HO-1 induction protects against harmful stimuli, including hyperoxia. "HO-1 induction in the lung may be one of the mechanisms underlying the protective effects of hydrogen," he added. "Our study is the first to show induction of HO-1 by hydrogen, and our results suggest that hydrogen functions by inducing protective proteins such as HO-1."
Dr. Kawamura said he and his colleagues have conducted extensive research on the beneficial effects of hydrogen in lung injuries. "In one recent mouse study, we showed that inhaled hydrogen could prevent acute lung injury induced by mechanical ventilation, and we also showed that inhaled hydrogen gas therapy for lung transplant donors and recipients reduced some transplant-associated injuries in a rat model study," he said. The results of this study indicate hydrogen inhalation therapy may have applications in other lung injuries, he added. "Hydrogen has a therapeutic potential not only in treating acute lung injury, but also in treating chronic lung diseases such as chronic obstructive pulmonary disease (COPD), which is the fourth leading cause of death in the U.S.," he said. "Hydrogen may help prevent progression of COPD, which could have a huge impact on treatment. "Administering hydrogen treatment by providing gas for the patients to inhale is straightforward and may be feasible in clinical practice in the future," Dr. Kawamura added. Future research should focus on establishing efficacy and safety profiles of hydrogen inhalation therapy in animal models, prior to its possible use in a clinical setting, he said.

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