洛伐他汀对脓毒症大鼠肺损伤的保护作用及对脂联素表达的影响

Protective effects of lovastatin on lung injury and adiponectin expression in septic rats

目的：观察洛伐他汀对脓毒症大鼠肺损伤的保护作用及对脂联素表达的影响。方法健康雄性清洁级Wistar大鼠54只，体质量250～300 g，采用数字表法随机分为三组：假手术组（Sham组）、脓毒症组（CLP组）、洛伐他汀处理组（LOV组）。 Sham组及LOV组术前1周腹腔注射洛伐他汀4 mg／kg，CLP组则注射等体积的溶剂0．5％缩甲基纤维素钠（CMC）。各组术后4 h、12 h和24 h取支气管肺泡灌洗液（BALF）测定TNF-α及IL-6水平；取肺组织观察组织病理学改变及检测髓过氧化物酶（MPO）及丙二醛当量（MDA）含量；另取血标本检测血清脂联素水平。结果 Sham组4 h、12 h和24 h TNF-α含量分别是（1．80±0.13）pg／mL、（2．04±0．15）pg／mL和（1．93±0．19）pg／mL；IL-6含量分别是（20．56±0．23）pg／mL、（18．35±0．15）pg／mL和（21．23±0．20）pg／mL；MPO含量分别是（2．82±0．14）U／g组织、（2．88±0．07）U／g组织和（2.76±0．18）U／g组织；MDA含量分别是（3．32±0．12）nmol／mg、（3．09±0．11）nmol／mg和（3．21±0．08）nmol／mg；脂联素浓度分别是（2．68±0．14）μg／mL、（2．80±0．07）μg／mL和（2．86±0．18）μg／mL。与Sham组相比：（1）CLP组及LOV组肺损伤形态学改变明显，CLP组BALF中TNF-α含量[4 h、12 h和24 h分别是（4.23±0．18） pg／mL、（5．62±0．24）pg／mL和（5．14±0．10）pg／mL，t＝28．41、30．98、36．62]及IL-6含量[4 h、12 h和24 h分别是（39．12±0．17）pg／mL、（47．25±0．21）pg／mL和（44．69±0．27）pg／mL，t＝158．90、273．40、127．28]增高，肺组织匀浆中MPO水平[4 h、12 h和24 h分别是（4．85±0．13） U／g组织、（6．17±0.08） U／g组织和（7．84±0．10）U／g组织，t＝26．39、79．40、60．43]及MDA水平[4 h、12 h和24 h分别是（6．24±0．06）nmol／mg、（7．56±0.15）nmol／mg和（8．43±0．10）nmol／mg，t＝53．31、58．86、90．06]增高、血清中脂联素水平[4 h、12 h和24 h分别是（1．35±0．10）μg／mL、（1．17±0．07）μg／mL和（1．24±0．11）μg／mL，t＝19．86、12.75、18．81]降低（均P＜0．05）；（2）LOV组BALF中TNF-α含量[4 h、12 h和24 h分别是（2．85±0．17）pg／mL、（3．72±0．13）pg／mL和（3．24±0．09）pg／mL，t＝12．02、20．73、16．68]及IL-6含量[4 h、12 h和24 h分别是（30．75±0．22）pg／mL、（37．52±0．29）pg／mL和（32．43±0．26）pg／mL，t＝78．42、68．29、83．67]增高，肺组织匀浆中MPO水平[4 h、12 h和24 h分别是（3．59±0．05） U／g组织、（4．67±0．11） U／g组织和（5．33±0．05） U／g组织，t＝12．03、33.63、33．70]及MDA水平[4 h、12 h和24 h分别是（4．45±0．10）nmol／mg、（5．01±0.11）nmol／mg和（5．83±0.04）nmol／mg，t＝17．72、30．23、71．75]亦增高、血清中脂联素水平[4 h、12 h和24 h分别是（2．09±0．08）μg／mL、（2.07±0．05）μg／mL和（2．03±0．10）μg／mL，t＝8．96、20．79、6.30]亦降低（均P＜0．05）。而LOV处理组与CLP组比较，肺损伤形态学改变减轻，TNF-α（t＝13．46、17．05、15．43）、IL-6（t＝73．70、64．10、80．12）含量均有下降，MPO（t＝22．16、27．01、32．86）及MDA（t＝37．59、42．72、59．13）水平均降低，同时血清脂联素水平（t＝14．15、8．10、3．19）均显著提高（均P＜0．05）。结论洛伐他汀可降低脓毒症大鼠TNF-α、IL-6等的浓度，减轻炎性反应及氧化应激损伤，减轻脓毒症肺损伤，并能提升脓毒症大鼠血清中脂联素水平。

Objective To observe the protective effects of lovastatin against lung injury and the expression changes of adiponectin in the septic rats.Methods Fifty four male Wistar rats weighting 250-300g were randomly divided into the three groups：sham operation group （group Sham） ,sepsis group （group CLP） and lovastatin interven tion group （group LOV）.Rats were injected with lovastatin （4mg/kg） or 0.5%CMC （vehicle） for five days and then subjected to CLP.At 4h,12h and 24h after operation.BALF was collected to determine the levels of TNF-αand IL-6,lung tissue was obtained to observe histopathological changes,and to detect the content of MPO and MDA,the blood sample was obtained to detect the level of adiponectin.Results In the group Sham,at 4h,12h and 24h time points,the levels of TNF-αwere （1.80 ±0.13）pg/mL,（2.04 ±0.15）pg/mL and （1.930.19）pg/mL;the levels of IL-6 were （20.56 ±0.23）pg/mL,（18.35 ±0.15） pg/mL and （21.23 ±0.20） pg/mL;the contents of MPO were （2.82 ±0.14） U/g tissue,（2.88 ±0.07） U/g tissue and （2.76 ±0.18） U/g tissue;and the levels of MDA were （3.32 ±0.12）nmol/mg,（3.09 ±0.11）nmol/mg and （3.21 ±0.08）nmol/mg;the concentrations of adiponectin were （2.68 ±0.14）μg/mL,（2.80 ±0.07）μg/mL and （2.86 ±0.18）μg/mL.Compared with group Sham,both LOV group and CLP group had increased pulmonary damage：（1）the levels of TNF-α[4h,12h and 24h were （4.23 ± 0.18）pg/mL,（5.62 ±0.24）pg/mL and （5.14 ±0.10）pg/mL,t=28.41,30.98 and 36.62]and IL-6[4h,12h and 24h were （39.12 ±0.17） pg/mL,（47.25 ±0.21） pg/mL and （44.690.27） pg/mL,t =158.90,273.40 and 127.28] of the CLP group in BALF were both increased,and MPO[4h,12h and 24h were （4.85 ±0.13） U/g tissue, （6.17 ±0.08）U/g tissue and （7.84 ±0.10）U/g tissue,t=26.39,79.40 and 60.43]and MDA[4h,12h and 24h were （6.24 ±0.06）nmol/mg,（7.56 ±0.15）nmol/mg and （8.43 ±0.10）nmol/mg,t=53.31,58.86 and 90.06] concentrations in lung homogenate were raised with the decreased expression of serum adiponectin[4h,12h and 24h were （1.35 ±0.10）μg/mL,（1.17 ±0.07）μg/mL and （1.24 ±0.11）μg/mL,t=19.86,12.75 and 18.81]（all P〈0.05）;（2） meanwhile the levels of TNF-α[4h,12h and 24h were （2.85 ±0.17） pg/mL,（3.720.13） pg/mL and （3.240.09）pg/mL,t=12.02、20.73 and 16.68]and IL-6[4h,12h and 24h were （30.75 ±0.22）pg/mL, （37.52 ±0.29）pg/mL and （32.43 ±0.26）pg/mL,t=78.42,68.29 and 83.67]in BALF of the LOV group were all increased,the contents of MPO[4h,12h and 24h were（3.59 ±0.05）U/g tissue,（4.67 ±0.11）U/g tissue and （5.33 ± 0.05）U/g tissue,t=12.03,33.63 and 33.70]and MDA[4h,12h and 24h were （4.45 ±0.10）nmol/mg,（5.01 ± 0.11）nmol/mg and （5.83 ±0.04） nmol/mg,t =17.72,30.23 and 71.75] were also increased with the serum adiponectin concentrations[4h,12h and 24h were （2.09 ±0.08）μg/mL,（2.07 ±0.05）μg/mL and （2.03 ± 0.10）μg/mL,t=8.96,20.79 and 6.30]dicreased（all P〈0.05）.There were less histopathological changes in the LOV group,and the levels of TNF-α（t=13.46,17.05 and 15.43）,IL-6（t=73.70,64.10 and 80.12）,MPO（t=22.16,27.01and 32.86） and MDA（t=37.59,42.72 and 59.13） were lower than those in CLP group,also the level of adiponectin（t=14.15,8.10 and 3.19） increased siginificantly（all P〈0.05）.Conclusion Administration of lovastatin could attenuate lung injury of the sepsis by down-regulate the level of TNF-αand IL-6,with reduced inflam-matory response and oxidative stress,and could upregulate the level of adiponectin in serums of rats with sepsis.