L-arginine In The Treatment Of Phosgene Poisoning And The Effects On Pulmonary Function

Research background:Phosgene,with its chemical formula COCl₂,molecular weight 98.92 and chemical name dichloro carbon acyl,is colorless and rotten straw-or rotten fruit-like smell gas under normal temperature.Its boiling point is 8.2 ?with a freezing point of-124 ?.Its vapor specific gravity is 3.5 that is more heavier than the air.When in the air,phosgene concentration of 0.005 mg/L?namely 5 mg/m3,1.235 parts per million?PPM??,can be smelled out.Phosgene is one of the four kinds of lethal poisonous agents in the main categories of foreign armament of chemical weapons.It is also a important material widely used in industry,research and pharmaceutical production.It is a significant intermediate material in the industrial and agricultural productions such as the agricultural chemicals,polymer materials,printing and dyeing,pesticides,plastics and pharmaceutical products.Phosgene is volatile at 7.9 ?,and its volatility is 6340 mg/L at the temperature of 20 ?.Upon releasing,it can quickly disperse and form poisonous concentration in the state of vapor.It can cause phosgene poisoning on people due to improper protection or accidental release.Phosgene can directly target the respiratory tract and thus resulting in lung tissue structure change and pulmonary edema.It can finally cause pulmonary gas exchange dysfunction so as to result in asphyxia.Therefore,it is also called a asphyxiant agents or lung damaging agents.When people are exposed to high doses of phosgene,they may readily catch a phosgene poisoning and then will develop acute lung injury and pulmonary edema.A serious case may develop acute respiratory distress syndrome?ARDS?and even to death.In the event of phosgene poisoning,the contaminated clothing should be quickly removed and body surface be washed.Then,according to the condition clinical manifestation,the main treatment is to counteract hypoxia,control infection,and prevent and treat pulmonary edema.The pathogenesis of acute lung injury due to phosgene inhalation is complex,which has not been fully revealed so far.Carbonyl group?C=O?in the molecules of phosgene has a very active nature,and it can easily get into acylation with molecules containing sulphur,amino and hydroxyl groups.Amino acids,proteins and enzymes are the chemical compositions in the lung tissue,which richly contain groups mentioned above,so it is easy to be acylated by phosgene and cause lung damage.When these ingredients in the alveolar walls and capillary wall are damaged,it will lead to cell structural and functional disorder.Also,the structure integrity of alveolar tissue will be damaged.The lung permeability is increased,in turn,the plasma will exudate to pulmonary interstitial and alveolar cavities,gradually forming pulmonary edema.Studies have found that in the process of phosgene poisoning,reactive oxygen species?ROS?in the lung tissue increased.The acute phosgene inhalation can cause malondialdehyde?MDA?increase in the serum,liver and lung,which shows that the whole body ROS level changes in the process of acute phosgene injury.Oxidative stress plays an important role in the acute lung injury?ALI?course caused by phosgene inhalation.Dexamethasone is a kind of glucocorticoid,and is widely used in the treatment of pulmonary edema,acute lung injury and acute respiratory distress syndrome caused by many reasons.At the same time,it has a protective effect on acute lung injury due to phosgene inhalation.It has been reported in the literature that NO levels of phosgene-poisoned rat serum and liver were significantly reduced with iNOS levels increased.L-arginine?L-Arg?is a kind of polar ?-amino which is alkaline,guanidine-containing of aliphatic series.It has been reported that L-arginine has a therapeutic effect on lipopolysaccharide-induced acute lung injury and high altitude pulmonary edema.Therefore,this study will use dexamethasone as a positive control drug to investigate the protective effect on lung function from L-arginine to phosgene-inhalated rats with acute lung injury model,and to explore its possible mechanism in order to provide new ideas for treatment on lung injury caused by phosgene inhalation clinically.MethodsTotal 48 rats were randomly divided into normal control group,L-arginine-controlled group,phosgene poisoning group,L-arginine low dose treatment group,L-arginine medium dose treatment group,L-arginine high dose treatment group,dexamethasone treatment group and L-arginine plus dexamethasone treatment group.There are 6 rats in each group?n=6?.Except for the normal control group and the arginine control group,the other groups of animals are exposed to 0.45 g solid triphosgene-produced phosgene gas in a cabin and the animals are exposed to the poison for 5 minutes.After being poisoned,they will be injected with L-arginine,dexamethasone and physiological saline.After 2,4 and 6 h of poisoning,lung function monitoring instrument for small animal was used to test the lung function index of animals in each group.The animals will sacrificed 6 h after poisoning.The wet-to-dry ratio of lung tissue,the content of plasma glutathione?GSH?and malondialdehyde?MDA?were measured by radioimmunoassay?RIA?,activities of superoxide dismutase?SOD?and inducible nitric oxide synthase?iNOS?were examined.Pulmonary pathology was observed under light microscopy as well.Results1.Compared with the normal control group,after the exposure to phosgene,the levels of f,TV,MV,PIF,PEF,PAU and Penh of the 2,4 and 6 h animals were increased,with levels of Ti,Te and Tr decreased to some extent.And the change of most parameters was statistically significant?P <0.05 or P <0.01?.And among those poisoning group,the Penh index at 2,4 and 6 h are 5.88±2.9,4.64±2.98,5.9±3.35,which correspondingly indicate a increase of 157%?P <0.01?,151%?P <0.05?and 281%?P<0.01?separately compared with normal control group at the same time point.Although the differences are not statistically significant?P> 0.05?in each treatment group at each time point compared with phosgene poisoning group,it shows a trend of increase at 2 h and decrease at 6 h after poisoning.The Penh index at 2,4 and 6h in high dose arginine group increased 18.9% and decreased 19.8% and 39.7% respectively compared with the poisoning group at the same time point.2.The lung wet-dry ratio increased significantly after phosgene poisoning.Except for dexamethasone and arginine treatment group,the other groups showed statistically significant increase.As the arginine dose increased,wet/dry ratio decreased.Compared with phosgene poisoning group,wet/dry ratio decreased greatly in high dose of arginine and was significantly lower than dexamethasone treatment group.3.In the arginine treatment group,there was no obvious exudation in the alveolar cavities,while a small amount of red blood cells and less degree of thickening in the alveolar wall could be seen.These changes were similar to that of dexamethasone treatmnet group.There was no exudate in the alveolar cavity in arginine plus dexamethasone treatment,showing a small amount of red blood cells with a thin alveolar wall,suggesting a synergistic effect when the drugs were used in combination.4.Compared with the positive control drug of dexamethasone treatment,arginine treatment can significantly improve the content of GSH in phosgene-poisoned animals,while reducing MDA content,increasing SOD activity and reducing iNOS activity.dexamethasone and arginine show synergistic effect in the treatment of lung injury.ConclusionsLung function and pathological changes are significantly reduced after L-arginine treatment.L-arginine can reduce lung tissue oxidative stress response and improve the anti-oxidative capacity.It is confirmed from experiments that L-arginine and dexamethasone have comparable protective effect on phosgene-induced lung injury,and a synergistic effect when used in combination.