他克莫司对重症急性胰腺炎大鼠肺损伤的治疗作用

The therapeutic effect of tacrolimus against the lung injuries induced by severe acute pancreatitis in rats

目的观察他克莫司(Tacrolimus,FK506)对重症急性胰腺炎(SAP)大鼠肺损伤的潜在治疗作用并探究其机制。方法健康雌性SD大鼠54只,随机分为对照组(C组)、SAP组(S组)、SAP+Tacrolimus治疗组(ST组)。检测3组大鼠术后3,6,12h血清肿瘤坏死因子α(TNF-α)及基质金属蛋白酶9(MMP-9)水平、支气管肺泡灌洗液(BALF)蛋白含量、肺组织髓过氧化物酶(MPO)活性,并计算存活率,观察肺组织及胰腺组织的病理变化。结果S组血清TNF-α及MMP-9水平和BALF蛋白含量及肺组织髓过氧化物酶(MPO)活性均较对照组显著升高(P<0.01);与S组比较,ST组12h后上述指标均明显降低[TNF-α:(171.31±19.58)vs(243.17±26.19);MMP-9:(1658.32±27.49)vs(2987.34±34.53);MPO:(2.75±0.22)vs(11.27±0.49);BALF:(631.58±57.25)vs(1987.39±158.34)](均P<0.01),ST组存活率高于S组(P<0.01)。组织病理切片提示S组胰腺、肺组织损伤随病情进展而逐渐加重;ST组较S组减较。结论Tacrolimus可有效降低SAP大鼠肺损伤的严重程度,能提高其存活率,对SAP有一定的治疗作用。其机制可能与减少肺脏的毛细血管渗透性、抑制中性粒细胞(PMN)释放MPO和MMP-9及抑制TNF-α等炎症介质的释放有关。

Objective To observe the potential therapeutic effect of tacrolimus against lung injuries induced by severe acute pancreatltis （SAP） in rats and investigate its mechanism. Methods Fifty-four female SD rats were randomly divided into 3 groups ： Control group （ group C ） , SAP group （ group S ） and SAP ± tacrolimus treatment group （group ST ） （n = 18 each group ）. Serum levels of tumor necrosis factor-alpha （TNF-ct） and matrix metaUoproteinase-9 （ MMP-9 ） , myeloperoxidase （ MPO ） activity of lung tissue and the protein content of bronchoalveolar lavage fluids （ BALF ） were evaluated 3,6, and 12 h after operation. The survival rates of 3 groups were also evaluated, and histopathologic changes of lung and pancreas were observed. Results In group S, serum level of TNF-α and MMP-9, MPO activity of lung tissue, and the protein content of BALF were significantly increased than those in group C （all P〈0.01 ）. All the indicators of group ST were significantly decreased 12h after operation as compared with group S [ TNF-α ： （171. 31 ± 19.58） vs（243. 17 ± 26. 19） ; MMP-9 ： （ 1 658.32 ±27.49） vs（2 987.34 ± 34.53 ） ; MPO ： （2.75 ±0.22）vs（11.27 ~0.49）; BALF：（631.58 ±57.25）vs（1 987.39 ±158.34）] （P〈0.01）. Histopathology showed that the lung and pancreas injuries in group S were gradually aggravated with disease progression, and alleviated obviously with tacrolimus treatment. Conclusions Tacrolimus can relieve the severity of lung injuries of pancreatitis rats, increase survival rate, and provide a certain therapeutic effect for SAP rats. The mechanism of tacrolimus effect may be related to the reduction of lung blood capillary permeability, and the inhibition of serum level of TNF-ot and MMP-9, lung MPO, and other inflammatory factors.