As a treatment method, oxygen breathing, with a history of over a hundred years, was initially used for the treatment of such diseases as pneumonia, atelectasis, tuberculosis, asthma and so on. Now, oxygen breathing is also a routine treatment method used more and more extensively in emergency care of trauma or casualty patients, and surgical patients as well during perioperative period. By depending on the concentration of oxygen, oxygen breathing could further be divided into low or pure oxygen breathing, as well as atmospheric and hyperbaric oxygen breathing. Research reveals that HBO could increase oxygen level in blood and tissues, enhance oxygen diffusion, and it can produce better therapeutic effects than atmospheric oxygen. The distance and velocity of oxygen diffusion depend largely on the partial pressure of oxygen. In the patients with inflammation, trauma and burns, edema will develop in pulmonary interstitum and tissues, thus extending oxygen diffusion distance, consequently conventional oxygen breathing could not meet oxygen demand of cells, and in this case, HBO will help to solve the problem encountered. HBO therapy is now extensively used in clinical treatment of ischemia-reperfusion injury, shock, sepsis, multi-organ functional disorder, and various cardio-pulmonary vascular diseases. Studies by Jindal have demonstrated that patients with hepatic and pulmonary disorders or cardio-cerebral vascular diseases, periodic oxygen breathing could decrease frequency of sickness onset, improve functions of internal organs and enhance resistance to diseases. Prolonged and or persistent oxygen therapy has been extensively applied to disease recovery and proves to be highly beneficial to complete recovery of diseases. Oxygen therapy could also prevent complications caused by hypoxia, such as anoxic mental symptoms, encephalopathy, arrhythmia, lactic acidosis, tissue necrosis and so on. Medical research has also revealed that there exist such adverse reactions as oxygen toxicity, which may result in acute lung injury, with similar symptoms as acute respiratory distress syndrome (ARDS), and affect central nervous system with such symptoms as syncope and visual blurring due to retinal damage. In addition, excessive oxygen concentration and over-exposure to oxygen could also damage pulmonary and central nervous systems and retina. At present, the mechanism of oxygen toxicity remains largely unknown, and there are several syntheses, among which the synthesis of reactive oxygen species (ROS) or oxygen radical is the most acceptable.
Cells obtain oxygen from blood, and the glucose in the cell reacts with triglyceride to trigger oxidation reduction reaction and form energy required for the body. However, there is still a small amount of oxygen that is converted into ROS or free radicals. Under homeostatic conditions, ROS will not damage normal cells, which is attributed to the existence of a large amount of antioxidase in cells, and a balance is maintained between ROS and antioxidase within the body. However, when the tissue is in a state of hypoxia, disorder of energy metabolism will occur in cells, and oxygen will not be able to be covered into water by cytochrome oxydase, and the normally harmless oxygen will be converted into cytotoxic ROS. The main trouble of ROS is to cause damage to the structure and function of cells, mitochondrion, cut off energy supply to cells and destruct lysosome, resulting in cell disruption. At the same time, it will also destruct vascular endotheliocyte and vascular walls, and consequently blood cell and serum leakage might be brought about, causing edema and cyanosis of surrounding tissues. On the contrary, excessively high partial pressure of oxygen will also cause damage to cells, the mechanism of which might be associated with the production of ROS[23, 24].
The generation of ROS might be associated with oxygen partial pressure in cells. Either excessively high or low oxygen partial pressure will generate the production of large quantities of ROS, and the amount of its production is closely related with the persistence of the state. It is held that oxygen therapy could recover the function of ischemic cells, enhance oxidation reduction reaction (ORR) and activity of endogenous SOD and increase the capacity of SOD to eliminate ROS. Proper oxygen breathing could decrease the production of inflammatory factors and alleviate tissue damage. However, excessively high oxygen concentration and excessive oxygen exposure will increase ROS level in the body, causing severer tissue damage. Prolonged and high concentration of oxygen intake will result in excessive production of ROS, which will activate the expression of NF-κB, causing release of TNF-α, IL-1β and IL-6, and serious inflammatory reaction will be resulted. On the contrary, proper oxygen therapy could decrease the level of inflammatory factors, which will alleviate damage to tissues. Our experiment has also revealed that HBO therapy could decrease the expression of inflammatory factors in rats and alleviate pulmonary lesion, demonstrating that HBO could produce positive effects on ALI, HBO could not only be applied to the treatment of ALI, but was extensively used in the treatment of serious trauma injuries. Following research on the mechanism of HBO in serious trauma injury, Sourabh held that HBO could promote such synergistic effects as vascular contraction, fibroblast and capillary proliferation, toxin inhibition, as well as the synergistic effect with antibiotics. These effects are obviously beneficial to tissue edema after injury, recovery of tissue damage. In addition, combined use with antibiotics could reduce the occurrence of sepsis. Therefore, HBO could produce positive effects on serious lung injury. Our experiment has also indicated that HBO could alleviate inflammatory reactions after lung injury and reduce cell apoptosis.
Ohsawa et al reported that inhalation of 2% hydrogen could effectively scavenger hydroxyl radicals (-OH) and peroxyritrite (ONOO-), obviously improve injury induced by ischemia reperfusion, and hydrogen dissolved in fluid could selectively neutralize or compromise the most important substance that cause cell oxidative damage. Hydrogen is an active, highly inflammable and explosive gas, which makes it difficult for clinical application. Hydrogen-rich saline, or simply called hydrogenised water, is a saturated, safe and effective agent dissolved in physiological saline. Hydrogen-rich saline with the hydrogen concentration as high as 0.6 mmol/L could be injected into body safely and effectively. It could alleviate inflammatory reaction induced by acute injury of organs, inhibit cell apoptosis, decrease damage to target organs by oxygen radicals, and could produce good therapeutic effects on inflammatory diseases, neural retrograde degeneration and lesions induced by organ ischemia reperfusion as well, the mechanism of which might be mainly attributed to the selective anti-oxidation of hydrogen, which selectively compromise –OH and ONOO- and thus the stability of biological membrane is maintained.
Hydrogen can change signal conduction or transmission within cells, and reduce the generation of inflammatory mediators through controlled release of NF-κB. Our experiment has revealed that the levels of TNF-α and IL-1β in the hydrogen-rich saline group were significantly lower than those of the control group, and the number of apoptosis cells in the HRS group was also reduced to some extent, while the number of apoptosis cells in the control group was the highest. Statistical analysis indicated that the number of apoptosis cells in the LPS + HRS group was significantly less than that of the LPS group, implying that HRS could inhibit cell apoptosis (P < 0.001). The mechanism involved with cell apoptosis might be associated with the blockage of cytochrome C to activate proCaspase-9, further inducing casecade reaction. Other experiments also demonstrated that HRS could obviously decrease apoptosis index and the expression of caspase-3 in the damaged brain tissue. In cell apoptosis detection, it is found that HRS and HBO could decrease cell apoptosis, and there is also difference in the rate of cell apoptosis between the hydrogen-rich saline combined with HBO and simple HRS treatment, indicating that combined treatment could produce a certain synergistic effect and decrease cell apoptosis. This might provide us a new approach to an in-depth research on the mechanism of combined treatment with hydrogen and oxygen for acute lung injury.
Our experiment has further revealed that HBO and the hydrogen-rich saline are all effective in the treatment of lung injury induced by LPS. Through reduced generation of ROS, HBO could decrease the expression level of NF-κB, and further decrease the release of TNF-α, IL-1β and IL-6, thus reducing inflammatory reaction and cell apoptosis. Through inactivation of ROS, the maintenance of cell membrane could be attained and the controlled release of NF-κB, the hydrogen-rich saline could reduce the generation of inflammatory factors. Therefore, HRS and HBO in the treatment of lung injury induced by LPS could decrease inflammatory reactions, reduce the release of inflammatory factors and decrease the levels of inflammatory products. In addition, through decreased expression of NF-κB, HBO and HRS could alleviate cell apoptosis. The target organs of HBO and the HRS are the same, the mechanism of which might be overlapping, as there is no significant difference in efficacy between HBO combined with HRS and simple HBO therapy or simple HRS in the treatment of lung injury induced by LPS.
To sum up, the combined use of HBO and HRS produces a synergistic effect on the decrease of cell apoptosis in the treatment of ALI. In the expression of inflammatory factors and the generation of inflammatory products, the combined treatment of HBO and HRS showed a decreasing trend, as compared with single treatment. Hydrogen and oxygen, being low in price and having with anti-inflammatory, anti-oxidative and cell apoptosis inhibition effects as well as accurate therapeutic effects, are suitable for the treatment of patients with serious ALI. However, the mechanism involved remains further in-depth research, and we are sure that the combined use of HBO and HRS promises a good future in its clinical application.