| With the continuous development of China’s Marine strategy,various commercial diving activities in underwater engineering are booming.Scientific diving aimed at marine resource exploration and scientific research has also boomed in recent years.With the booming coastal tourism and improvement of people’s living standard,recreational diving is increasing at a rate of 10%～20%per year.When people go underwater for various activities,they must breathe high-pressure gas equal to the pressure in the surrounding water depth to counter hydrostatic pressure and ensure physiological safety.Physiologically inert gases dissolved in the body at high pressure must follow certain rules before they can be safely expelled from the body,or they may form bubbles and cause decompression sickness(DCS).Although the modern diving protocol has been very complete,but because of the complex underwater environment and the diversity of operating conditions and individual differences,the occurrence of DCS is difficult to avoid.In special activities such as submarine escape,there may also be a large number of survivors suffering from serious DCS.Therefore,the treatment of DCS is always the core task of diving medical research.During rapid decompression,the inert gas dissolved in the body evolves into bubbles due to unsafe desaturation,which is the underlying cause of DCS.In addition to causing physical damage to the body,bubbles also trigger a series of biochemical reactions,especially in the development of severe DCS.Circulating and tissue bubbles activate vascular endothelium,initiate inflammatory cascades,activate coagulation and complement system,etc.These biochemical effects do not stop in time even after effective recompression therapy,but continue to lead to a series of symptoms and signs,and even make the disease worse.Targeted on these injuries related to DCS,drugs commonly used include anticoagulants,anti-inflammatory drugs,endothelial protective drugs,perfluorocarbons,lidocaine,steroids,etc.Both aspirin and heparin failed to inhibit platelet aggregation following decompression.Although perfluorocarbon emulsions can promote tissue oxygenation and accelerate the excretion of inert gas from the body,perfluorocarbon emulsions can only be dissolved in water by emulsions.However,the resulting short shelf life,slow metabolism and many side effects limit the clinical application of perfluorocarbons.Steroids have many side effects,such as promoting blood sugar,further aggravating nerve damage,and at the same time,not conducive to the elimination of tissue edema.It has been no longer recommended as a treatment in the U.S.Navy’s diving manual.It can be seen that drugs targeted on DCS therapies are still relatively scarce,it is imperative to explore effective drugs for DCS treatment.Ulinastatin is one glycoprotein extracted from human urine.It is capable of inhibiting generation and release of inflammatory factors,protecting vascular endothelium,improving capillary permeability and tissue perfusion,as well as protecting organs function.Xubijing injection is a traditional Chinese medicine based on the“four certificates and four methods”and the theory of“combined treatment of bacteriosis”.It is extracted from various herbs including Carthamus tinctorius,Paeonia lactiflora pall,Rhizoma chuanxiong,Angelica sinensis and Salvia miltiorrhiza.It can protect vascular endothelium,and regulate blood coagulation and immune function via many mechanisms.Ulinastatin and Xuebijing have been widely used in the clinical treatment of critical diseases,such as sepsis and shock.They are also recommended for the treatment of new coronavirus pneumonia.Considering their properties,which maybe beneficial for DCS treatment,so this project aims to establish a stable rabbit DCS model,explore potential therapeutic effects and mechanisms of Ulinastatin and Xubijing on DCS.Methods:New Zealand white rabbits were subjected to simulated diving in DWC150animal compression chamber using profiles with different exposure time or decompression rates.We evaluated rabbits’limb motor function,and used ultrasonography to assess bubble load in the right ventricles,and take blood samples for routine blood examination.Samples from lung and spinal cord were taken for histological analysis after euthanasia.All these formed into a set of evaluating parameters including the overall behavior,indices of hematology,histopathology and bubble formation.Results:Different hyperbaric exposures produced DCS models with different severity.When compressed to 500 k Pa for 60 min,and decompressed at rate of 200 k Pa/min,the incidence of DCS and severe DCS was 76%and 64%,the mortality rate was 28%.After modeling under this profile,cardiac ultrasonography detected significant amount of bubbles,and we found that rabbits’limb motor function was significantly damaged.Prothrombin time was extended,and contents of fibrinogen increased.Platelets count decreased soon after decompression and then increased dramatically.There were substantial changes including inflammatory response,bleeding and edema in histological sections of lung and spinal cord.Conclusions:By adjusting hyperbaric exposure time and decompression speed,the ideal profile for DCS modeling is successfully achieved and we establish a set of evaluating parameters system considering the overall behavior,histopathology of lung and spinal cord tissues,as well as bubble load.PartⅡExploration of Drug Treatment for Decompression Sickness1.Therapeutic Effects of Ulinastatin on DCS in RabbitsMethods:Eighty-eight rabbits were subjected to simulated diving to 500 k Pa for 60min,decompressed at a rate of 200 k Pa/min.Three doses of UTI(15/7.5/3.75×10~5 U/kg)or saline were intravenously administered immediately following decompression.Circulating bubbles were monitored for 3 h following decompression and DCS signs were evaluated for 24 h.Blood was sampled 8 times during 72 h after decompression for inflammatory(IL-1βand MCP-1),endothelial(ET-1 and ICAM-1),oxidative(MDA and MPO),and routine blood indices.Lung tissues were also sampled for evaluating endothelial function.Another 6 rabbits were used as Normal control.Results:In high dose UTI group,the mortality,general morbidity and incidence of severe DCS was decreased from 31.25%to 9.38%(P=0.030),84.38%to 62.50%(P=0.048)and 46.88%to 21.88%(P=0.035),respectively.High dose of UTI significantly postponed the occurrence of DCS(8.2±0.7 min vs.13.0±2.5 min,P=0.030)and prolonged the survival time(22.9±4.9 min vs.50.7±14.6 min,P=0.009)compared with Saline group.Besides,High dose of UTI significantly ameliorated inflammation responses,endothelial injuries and oxidative damages.The other two doses of UTI showed trends but had no statistical significance.Conclusions:The results strongly suggest the benefits of UTI on DCS by its anti-inflammatory,anti-oxidative and endothelial protective properties,especially for severe cases.UTI may be a potential ideal candidate for the treatment of DCS.2.Therapeutic Effects of Xuebijing on DCS in RabbitsMethods:Twenty-four male New Zealand White rabbits underwent simulated diving to 500 k Pa for 60 min,decompressed at a rate of 200 k Pa/min,and received an intravenous injection of XBJ(5 ml/kg)or the same volume of saline immediately following decompression.DCS signs were monitored for 24 h,and blood was sampled before simulated diving and 1,6,12 h post decompression for determination of inflammatory indices(IL-1βand MCP-1)and blood routine examination.Lung tissues were sampled after euthanasia to evaluate severity of lung injuries.Another 6 rabbits were used as Normal control.Results:XBJ significantly ameliorated lung injuries(lung wet/dry ratio and total protein content in bronchoalveolar lavage fluid),and notably inhibited systemic(serum level of IL-1β)and local(TNF-αin bronchoalveolar lavage fluid)inflammation responses.Conclusion:The results indicate benefits of XBJ on ameliorating DCS lung injuries,which is possibly via inhibiting systemic and local inflammation.XBJ may be a potential candidate for the treatment of decompression-induced lung injuries. |
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