Effects Of Simvastatin On Th1/Th2Balance And MMP-9,TIMP-1in Asthmatic Rats

Objective: To investigate the effects of simvastatin on Th1/Th2balanceand expressions of MMP-9,TIMP-1in asthmatic rats. We established the ratasthma model, and use IFN-γ,1L-4in serum which reflect the level ofTh1/Th2as airway inflammation indicator, and use MMP-9,TIMP-1on lungtissue which reflect airway remodeling as another indicator. Throughobserving the change of IFN-γ,1L-4and MMP-9,TIMP-1after simvastatinintervention to explore the effects of simvastatin on airway inflammation andremodeling in asthma, at the same time we investigate the effects of differentdoses of simvastatin on airway inflammation and remodeling in asthma, andprovide a new way other than glucocorticoids for clinical prevention andtreatment of asthma.Methods: Forty healthy male Sprague-Dawley(SD) rats, six weeks old,were randomly divided into five groups,8in each group: control group,asthma group, simvastatin20mg/kg treat group(S1), simvastatin40mg/kg treatgroup(S2), simvastatin60mg/kg treat group(S3). All rats except control groupwere sensitized with OVA100mg mixed with AL(OH)3100mg (mixed with9g/L sodium chloride2ml)on the first and the8th day by intraperitonealinjection. Then the rats were challenged repeatedly with inhaled aerosolizedOVA in a close tightly box from the15th day,the OVA concentration wasincreased every4times by1%,1.5%,2%,2.5%,3%,30minutes every time,every other day at a time,20times altogether. The control group was given0.9%sodium chloride instead, method is the same as above. Simvastatin20mg/kg treat group,40mg/kg treat group and60mg/kg treat group wererespectively gavaged with20mg/kg,40mg/kg,60mg/kg simvastatin mixedwith odium chloride half an hour before every challenge.24hours later afterthe last challenge, the rats were anaesthetized, the basic expiratory peak and its alteration after injected Ach which reflect airway resistance were measuredby animal lung function meter. Then the rats were sacrificed and the serum,bronchial alveolar lavage fluids (BALF) and lung tissue of each group ratswere taken, total cells number, eosinophils(EOS), lymphocytes(Lym) andneutrophils(Neu) in BALF were detected. The expressions of IFN-γ,1L-4inserum were detected by ELISA. Part of lung tissue histopathology wasanalyzed by H-E, thickness of bronchus tract wall were messured byimage analysis system, part of lung tissue histopathology was used toobserve collagen deposition by Masson, the other was detected the expressionsof MMP-9and TIMP-1on airway by immunohistochemistry.Results: The rat asthma model were successfully established, ascompared with others, lung pathological by HE staining showed the number ofinflammatory cells around the airway and vessel were remarkably increased,bronchial mucosal was damaged, airway wall thickness were increased,masson staining showed much collagen deposition around the airway andvessel in asthma group. Lung function test showed, as concentration of Achincreased, the expiratory peak decreased remarkably in asthma group, that isas concentration of Ach increased, expiratory resistance increased remarkablyin asthma group; the number of total cells, eosinophils, lymphocytes andneutrophils in BALF were increased, the expressions of1L-4increased, IFN-γdecreased in serum, the expressions of MMP-9and TIMP-1increased,MMP-9/TIMP-1decreased on airway in asthma group(P<0.01). As comparedwith asthma group, the infiltration of inflammatory cells around the airwayand vessel, collagen deposition and the alteration of expiratory peak afterinjected Ach were all improved in simvastatin groups, the number ofinflammatory cells in BALF and the level of1L-4in serum were decreased,IFN-γ were increased, the expressions of MMP-9and TIMP-1were decreased,MMP-9/TIMP-1were increased on airway, simvastatin60mg/kg treat groupwere better than simvastatin20mg/kg treat group(P<0.01).The related analysisshowed the level of MMP-9is positive correlation with TIMP-1and1L-4,negative correlation with IFN-γ, the level of TIMP-1is positive correlation with airway wall thickness and collagen deposition, and negative correlationwith basic expiratory peak, the level of MMP-9/TIMP-1is negativecorrelation with airway wall thickness and collagen deposition, and positivecorrelation with basic expiratory peak in asthma group(P <0.01).The level ofMMP-9is positive correlation with1L-4, negative correlation with IFN-γ insimvastatin treat groups(P<0.05).Conclusion: Simvastatin can lessen airway inflammation through raisingthe level of IFN-γ, reducing the level of IL-4, enhancing Th1, inhibiting Th2reaction, regulating the balance of Th1/Th2, which maybe one of themechanisms of simvastatin in treating asthma; simvastatin can prevent andrelieve airway remodeling by regulating the balance of MMP-9/TIMP-1, thisprocess maybe achieved by raising the level of IFN-γ, reducing the level ofIL-4, thereby reducing the expressions of MMP-9, which indirectly affect theexpressions of TIMP-1, it maybe one of the mechanisms of simvastatin onairway remodeling in asthma. The effects of simvastatin on asthma maybedose-dependent. Therefore, simvastatin may become an effective medicineother than glucocorticoids in treating airway inflammation and remodeling.