Therapeutic Effect And Mechanism Of Captopril Against Acute Lung Injury Induced By PFIB Inhalation

Perfluoroisobutylene（PFIB）is also called Octafluoisobutylene because of its structural formula of（CF₃）₂C=CF₂.As the major by-product of fluoroplastics production and processing,PFIB is well known as the most toxic lung damaging agent in that its toxicity is about ten times of phosgene and it can be very easy of filtration mask penetration,which will result in dangerous threat to life.PFIB is enrolled in the schedule 2 toxic chemicals of the Chemical Weapons Convention（CWC）.Low dosage of PFIB exposure can cause headache,cough,substernal pain and dyspnea in the early days.The symptoms will aggravate after 6-8 hours.High dosage of PFIB exposure can cause pulmonary edema,acute lung injury（ALI）,acute respiratory distress syndrome（ARDS）,and even death after 8-48 hours.Accumulated evidences concerning the pathogenesis of PFIB-ALI,by far,involve multi-stage,multi-level,multi-signal transduction pathway and polymolecular regulation complex network,which definitely attribute in a very large part to the lack of effective therapeutic and preventive countermeasures against PFIB inhalation intoxication in clinical practice.OBJECTIVE Enlightened by the fact that the angiotensin-converting enzyme inhibitors（ACEIs）have been proved preferable protective effect on ALI caused by different initiators,e.g.,phosgene inhalation,heptic ischemia-reperfusion injury,etc.,the current research selected captopril and enapril as typical ACEIs and tested the working hypothesis that they can be,to some extent,a way-out against PFIB intoxication.STUDY PLAN（1）Characterizing the changing pattern of the lung coefficient,arterial blood gas analysis,lung morphology,and the total protein and phospholipid of BALF in the pathogenesis of PFIB-ALI.（2）Observing the effects of typical ACEIs,i.e.,captopril and enapril,against PFIB intoxication.（3）Clarifying the possible involvement of the redox system and renin-angiotensin system in the pathogenesis of PFIB-ALI.METHODS（1）Mice were exposed to the lethal dose of dynamic PFIB-inhalation intoxication.Different doses of captopril were used to establish the ACEIs intervention model.The seven-day survival rate of mice after PFIB exposure was observed.（2）Rats were exposed to the median lethal dose of dynamic PFIB-inhalation intoxication.Different doses of captopril and enapril were used to establish the ACEIs intervention model.Data of the lung coefficient,arterial blood gas analysis,the morphology of the lungs,the pathological changes of the lungs,and the total protein and phospholipid of BALF were collected 24h after the PFIB exposure.The lung tissue homogenate and BALF were prepared to evaluate the possible functional changes in the redox system and renin-angiotensin system.The LPO content,MDA content,SOD activity,and Gpx-1 activity in rat lung tissue homogenates were measured.The ACE content in rat BALF was also measured.RESULTS（1）In the PFIB-ALI mouse models,the seven-day survival rate of mice was increased by using different volume of captopril,and the mild moderate dose had a 58.3 percent survival rate whose effect was the best.（2）Captopril and enapril could both improve the degree of rats’lung injury and decrease the protein and phospholipid content of rats’BALF.Captopril could improve the degree of pulmonary edema and decrease the exudates and macrophages in the alveolar space.（3）Captopril could obviously decrease the concentration of LPO in the lung tissue of the PFIB-ALI rat models in a dose-dependent manner.But it had little effect on the concentration of MDA,SOD,and GSH-Px in the lung tissue.And the middle and high doses of captopril could also decrease the concentration of ACE in PFIB-ALI rats’BALF.ACEIs could decrease oxidative damage caused by PFIB and had certain early therapeutic effects in PFIB-ALI.CONCLUSION（1）Typical ACEIs,i.e.,captopril and enapril,can be recommended to the management of PFIB-ALI.It can effectively decrease the degree of lung injury and increase the survival rate.Captopril is remarkably effective and enapril has some preventive effect.（2）Oxidative damage is the key factor of PFIB-ALI.ACEIs can decrease oxidative damage caused by PFIB via decreasing LPO deposition in lung,and so as to achieve the effect of curing ALI.