| Oxygen is a common adjunct to clinical treatment of various diseases,widely used in the medical field,especially hyperbaric oxygen therapy,hyperbaric oxygen therapy can increase the amount of dissolved oxygen in the plasma,thereby increasing the blood oxygen partial pressure,improve tissue oxygen supply.However,prolonged inhalation of high concentrations of oxygen(oxygen partial pressure of more than 50%)can lead to chronic oxygen toxic(COT).Studies have shown that the mechanism is mainly: high concentrations of oxygen into the body,causing the body to produce a large number of reactive oxygen species(ROS),excessive reactive oxygen species can lead to extensive pulmonary inflammatory response and oxidative stress injury,So that the capillary endothelial cells and alveolar epithelial cells necrosis,apoptosis,and ultimately cause lung tissue lesions and pulmonary dysfunction.Studies have shown that the mitogen-activated protein kinase(MAPK)signaling pathway plays an important role in lung injury caused by chronic oxygen toxic.Apoptosis signal-regulated kinase 1,ASK1),a member of the family of mitogen-activited protein kinase kinase(MAPKKK),is a key molecule linking ROS and MAPKs pathway and is activated in chronic oxygen toxic by MKK3 / 6 and MKK7 activates downstream P38 and JNK protein kinases to induce apoptosis,leading to a variety of stress injury and proinflammatory cytokine releases,thus involved in pathophysiological processes.It has been reported that,in addition to ROS,intracellular calcium concentration,endoplasmic reticulum stress,tumor necrosis factor can induce ASK1 expression.Recent studies have shown that ASK1 inhibitors have protective effects on the lung injury of oxygen poisoning.After ASK1 knockdown,the release of IL-1β,IL-6 and TNF-α is decreased and the inflammatory response is weakened.In clinical treatment,if patients with chronic oxygenosis will face a very embarrassing situation: If you do not improve the oxygen concentration of respiratory gas will lead to hypoxia,but oxygen itself will have a damaging effect on the lung,if increasing the oxygen concentration will lead to further deterioration of lung function,so once the patient encountered such a contradictory situation,often can not save lives.The study found that in the treatment of acute respiratory failure patients and premature children,often need long-term oxygen,resulting in oxygen poisoning lung injury,some babies will occur bronchial dysplasia,pulmonary interstitial fibrosis,pulmonary inflammation and other pathological phenomena.Severe cases can even lead to severe pulmonary dysfunction,so clinical oxygen has been a certain degree of restrictions.In addition,in the field of diving operations,in order to avoid the occurrence of oxygen poisoning phenomenon,must strictly limit the oxygen inhaled gas and continuous oxygen time,but also seriously affected the operating efficiency.Therefore,it is of great clinical and military significance to study the prevention and treatment of chronic oxygenosis and its protective mechanism.About the prevention of chronic oxygen toxic is mainly the prevention of it.Patients with regular hyperbaric oxygen therapy need to use free radical scavenger adjuvant therapy,and in the course of treatment need to use intermittent oxygen way to prevent the occurrence of oxygen poisoning,but so far in the treatment of oxygen poisoning is still no effective means.In recent years,the mechanism of hydrogen is rapidly developing in research field,and is expected to become a new gas signal molecules playing a wide range of biological effects.In 2007,it is reported that inhalation of 2% of hydrogen can be effective for cerebral ischemia-reperfusion injury.In the treatment of lung disease,it has been reported that hydrogen can significantly reduce lung injury after burns,while the mechanical ventilation caused by lung injury and lung ischemia-reperfusion injury has a significant therapeutic effect.The preliminary study of my research group found: Hydrogen saturated saline can reduce the oxidative stress caused by hyperbaric oxygen exposure and reduce the damage of chronic oxygen poisoning lung function.This study is based on the preliminary work to further explore the protective effect of hydrogen on oxygen poisoning from apoptosis and its mechanisms of signal transduction pathway.This study first clarified the protective effect of hydrogen on chronic oxygen toxic.We first established rat chronic oxygen toxic model(oxygen chamber continued exposure for 60 hours,98% pure oxygen inhalation,animals into the compartment get intraperitoneal injection of saline,hydrogen saturated saline(10ml / kg)every 12 hours with a total of 4 times,and the time point is 12 hours,24 hours,36 hours,48 hours after exposure,the animals out of the cabin after 60 hours).Inhalation of normoxic air group as a control,efficacy indicators using lung wet and dry ratio and pleural effusion content determination.The arterial oxygen saturation was measured by blood gas analysis.The pathological changes of lung were observed by HE staining.The apoptosis of lung tissue was observed by TUNEL staining.On the basis of successful establishment of chronic oxygen toxic model,we found that hydrogen therapy can significantly reduce the degree of pulmonary edema and inflammatory exudation after oxygen poisoning in rats,and hydrogen can effectively reduce the oxygen level caused by oxygen poisoning.The morphological damage of lung caused by oxygen poisoning in the treatment group was significantly reduced and the apoptosis was significantly inhibited.The results suggest that hydrogen saturated saline has a protective effect on chronic oxygenosis.Secondly,we study the protection mechanism,we choose ASK1 as the starting point,exploring the mechanism of hydrogen protection of chronic oxygen poisoning.After the establishment of rat chronic oxygenosis model,using proper way to deal with samples.The expression of ASK1 m RNA and protein was detected by Real time PCR and Western Blot respectively.The results showed that compared with the normal saline group,ASK1 m RNA level and protein level in the intervention group were significantly decreased.The results showed that hydrogen could protect the oxidative effects of chronic oxygen toxic by inhibiting the gene expression and protein level of ASK1 in lung poisoning rats.Finally,we further study the expression of JNK and P38 in ASK1 downstream signaling pathway,and deeply study the molecular mechanism of hydrogen protection.We extracted the total RNA and protein of lung tissue,using Real time PCR and Western Blot detection of JNK and P38 m RNA and protein expression levels,respectively.The results showed that the expression of JNK and P38 was significantly up-regulated after oxygen poisoning.Compared with the saline group,the expression of JNK m RNA was inhibited in the hydrogen intervention group,and the level of p JNK protein was significantly decreased.For P38,There was no significant difference in the m RNA and protein levels of p P38 between the two groups.The results suggest that hydrogen inhibits the expression of ASK1,thereby inhibiting JNK pathway rather than p38 MAPK pathway to play a role in chronic oxygen toxic.In summary,hydrogen molecules have electrical neutrality,molecular weight and other characteristics,easy to penetrate the cell membrane into the intracellular and mitochondria.We explained through a series of experiments,hydrogen can significantly reduce lung injury causing by chronic oxygen toxic,and the mechanism may be closely related to the inhibition of ASK1-JNK signaling pathway.The molecular mechanism of hydrogen protection effect is preliminarily revealed,which provides a new theoretical basis for the clinical application of hydrogen. |
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