实验性急性胰腺炎肺损伤中Nrf2/ARE分子的作用及BML-111对肺损伤的影响
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摘要
[目的]探讨内源性抗氧化信号通路Nrf2/ARE在小鼠急性胰腺炎肺损伤中的动态表达情况以及其作用。
[方法]96只健康雄性Babl/c小鼠,SPF级,随机分为正常对照组(CON组)、生理盐水组(NS组)和重症急性胰腺炎组(SAP组),每组又随机分为3h、6h、12h和24h共4个亚组,每个亚组8只小鼠。各组小鼠禁食12h,不禁水。CON组不做任何处理；NS组腹腔内注射生理盐水10mL/kg/次,间隔1h一次,共七次,最后一次生理盐水加倍。SAP通过腹腔内注射蛙皮素50μg/kg/次(浓度为5mg/L,10mL/kg),间隔1h一次,共七次,最后一次同时注射脂多糖10mg/kg(浓度为0.1g/L,10mL/kg)诱导。于最后一次注射后3h、6h、12h及24h处死小鼠分别采集标本,采用对-硝基苯麦芽七糖苷法检测血清淀粉酶(AMY)水平,双抗体夹心ELISA法检测血清C反应蛋白(CRP),测量肺组织水含量并计算肺脏组织湿干重比率(W/D),胰腺及肺组织行苏木素-伊红染色(H-E染色)并行病理学评分,透射电镜检查肺脏超微结构变化,实时荧光定量PCR (Real-time PCR)检测肺脏组织Nrf2、HO-1、NQO1mRNA表达,Western blot法检测肺脏组织Nrf2、HO-1、NQO1蛋白的表达。
[结果]CON组与NS组各对应时相点比较,血清AMY、CRP、胰腺及肺脏病理学评分、肺脏干湿重比率均无明显差异,胰腺及肺脏组织病理学检查均未见明显异常。SAP组血清淀粉酶、CRP、胰腺及肺脏病理学评分、肺脏干湿重比率均较CON组及NS组增高(P<0.05)。SAP组胰腺H-E染色于3h时即可见胰腺组织结构轻度紊乱,间质水肿,血管周围和胰腺间质可见少量炎性细胞浸润,但小叶结构尚清晰；6h时上述改变更趋明显；12h及24h组小鼠胰腺组织结构更加紊乱,甚至消失,小叶结构模糊,腺泡细胞大部分坏死,可见孤岛状腺泡结构,坏死胰腺组织周围可见大量炎性细胞浸润及片状出血灶；部分血管坏死、弹力纤维崩解,可见血栓形成,还可见小脓肿形成。SAP组肺脏H-E染色于3h时即可见肺泡间隔增宽、间质毛细血管高度充血、肺泡水肿、部分肺泡腔缩小及少量炎性细胞浸润,但肺泡结构尚完整。6h时肺泡间隔明显增宽,肺组织水肿更加明显,血管和小支气管周围间质内大量中性粒细胞浸润。12h与24h时除上述表现外,部分肺泡腔内可见大量红细胞,部分肺泡萎陷,肺泡破裂融合成肺大泡。肺脏电镜检查示：CON组与NS组超微结构均未见明显异常：SAP组各时相点可见不同程度的肺泡隔及毛细血管内炎症细胞附壁,肺泡扩张融合,红细胞和活性物质泄漏到肺泡腔,Ⅱ型肺泡上皮细胞线粒体肿胀,线粒体膜模糊不清,线粒体嵴消失；胞浆内板层小体数量减少及空泡变性,上述表现在12h及24h更加明显。不论是在mRNA还是蛋白水平,SAP组小鼠肺组织中Nrf2、HO-1及NQO1的表达在诱导SAP后3h和6h与CON组及NS组相比均略有上升,在12h和24h时均表现出下降的趋势,但所有差异均无统计学意义。
[结论]内源性抗氧化信号通路Nrf2/ARE在重症急性胰腺炎相关肺损伤中虽然可以被激活,但Nrf2及其下游抗氧化基因HO-1、NQO1的表达并没有明显增加,也没有维持足够的时长。
[目的]探讨脂氧素受体激动剂BML-111对小鼠重症急性胰腺炎相关肺损伤的影响与可能的分子机制。
[方法]128只健康雄性Babl/c小鼠,SPF级,随机分为4组,即①生理盐水对照组(NS组),②BML-111对照组(BML组)；③重症急性胰腺炎组(SAP组)；④BML-111治疗组(SAP+BML组),每组又分为3h、6h、12h及24h共4个亚组,每组8只小鼠；各组小鼠禁食24h,不禁水。NS组及BML组小鼠经腹腔内注射生理盐水10mL/kg/次,间隔1h一次,共七次,最后一次生理盐水加倍。SAP组通过腹腔内注射蛙皮素50μg/kg/次(5mg/L,10mL/kg),间隔1h一次,共七次,最后一次同时注射脂多糖10mg/kg (0.1g/L,10mL/kg); SAP+BML组于诱导SAP之前1h经腹腔注射BML-111(1mg/kg即10mL/kg),BML组于第一次注射生理盐水前1h经腹腔注射BML-111(1mg/kg即10mL/kg), NS组及SAP组于第一次注射生理盐水或蛙皮素之前1h经腹腔注射BML-111的溶媒(0.4%DMSO溶液,10mL/kg)。分别于最后一次注射后3h、6h、12h、24h处死小鼠采集标本,采用对-硝基苯麦芽七糖苷法检测血清AMY水平；双抗体夹心ELISA法检测血清IL-10、TNF-α、IL-β含量；比色法检测肺脏组织SOD、 MPO、MDA含量；胰腺及肺组织行苏木素-伊红染色(H-E染色)并行病理学评分；透射电镜观察肺脏超微结构；测量肺组织水含量并计算肺脏组织湿干重比率(W/D)；采用real-time PCR法检测肺脏组织Nrf2、HO-1、 NQO1mRNA水平；Western blot法检测肺脏Nrf2、HO-1、NQO1蛋白。
[结果]与NS组及BML组各对应时相点比较,SAP组小鼠血清淀粉酶、TNF-α、IL-1β及肺组织MPO、MDA水平、肺组织湿干重比率均显著增加(P<0.05)；血清IL-10及肺组织SOD水平均下降(P<0.05)；胰腺及肺脏H-E染色均符合上述SAP及相关肺损伤的表现；胰腺和肺组织的病理学损伤评分亦均显著增高(P<0.05)；肺脏透射电镜检查亦符合肺损伤的病理诊断。与SAP组各对应时相点比较,SAP+BML组小鼠血清淀粉酶、TNF-α、IL-1β及肺组织MPO、MDA、肺组织湿干重比率、胰腺及肺的病理学损伤评分均明显降低(P<0.05)；血清IL-10及肺组织SOD水平则增高(P<0.05)；肺组织中Nrf2、 HO-1及NQO1的表达均显着增加(P<0.05)；胰腺及肺组织病理学改变亦较SAP组有所改善。
[结论]BML-111预处理对蛙皮素诱导的胰腺炎相关肺损伤具有一定的保护作用,这种作用除归因于BML-111通过激活Nrf2/ARE信号转导通路,诱导下游抗氧化酶HO-1及NQO1的表达所发挥的抗氧化作用外,还可能与BML-111对促炎因子TNF-α、IL-1β及抗炎因子IL-10的调节有关。
Objective:To investigate the role of endogenous antioxidant signaling pathway Nrf2/ARE in acute pancreatitis associated lung injury (APALI) induced by cerulein with subsequent LPS administration in mice.
Methods:Ninety-six Babl/c mice were randomly allocated to three experimental groups:the normal control group (CON group), the normal saline group (NS group) and the severe acute pancreatitis group (SAP group). Each group was randomly divided into4time units (3,6,12,24h) with8mice in each time unit. Twenty-four hours before the start of the experiment, the mice were deprived of food but allowed access to water. The CON group mice received no treatment. In the NS group, mice were injected intraperitoneally (i. p.)10mL/kg BW normal saline repeatedly every1h (7injections in total) and the injection dosage were doubled at the last time. In the SAP group, mice were injected intraperitoneally50μg/kg BW cerulein (10mL/kg of BW) repeatedly every1h (7injections in total) and10mg/kg of BW LPS (10mL/kg of BW, i. p.) after the last dose of cerulein immediately. Eight mice of each group were anesthetized with sodium pentobarbital (90mg/kg BW, i.m.), then were executed at3,6,12and24h after the last injection. Serum amylase was assayed by P-nitrophenyl malt seven glycoside method, C-reactive protein (CRP) were measured by enzyme linked immunosorbent assay (Elisa), histological score of the pancreas and lung and the wet-to-dry weight ratio of lung were evaluated. The severity of lesions was evaluated by pancreatic and lung histology. Expression of Nrf2, HO-1, and NQO1in lung tissue was evaluated by real-time PCR and western blot analysis, respectively.
Results:Compared with CON and NS group, the serum amylase, CRP, histological score of the pancreas and lung and the wet-to-dry weight ratio of lung increased significantly in SAP group(P<0.05). In SAP group mice, the pathology of pancreas showed interstitial edema, minor inflammatory cells infiltration both around vessels and in the pancreatic mesenchyme at3h while lobules of it were still clear to observe. All the changes above were more obvious at6h. The organizational structure of the pancreas was more disturbed at12h and24h as there was no discernable normal lobular architecture, and massive acinar cell necrosis, hemorrhage, vascular necrosis, elastic fiber disintegration, thrombosis, together with microabscess could be seen in the necrotic pancreas; The pathology of lung showed edema, congestion, widened alveolar septa at3h and6h. Besides, RBC exudation, severe inflammatory cell infiltration, severe hemorrhage and alveolar collapse were observed at12h and24h. Ultrastructure of lung tissue showed complete mitochondrial outer membrane and distinct mitochondrial cristae in type II alveolar epithelial cells, and there was no evacuation phenomenon in laminated bodies in the control and NS group. In the SAP group, mitochondria in type II alveolar epithelial cells swelled with membranes indiscernible and most of mitochondrial cristae disappeared at3h and6h; At12h and24h, alveoli were clearly dilated and merged, a large number of red blood cells and active substance leaked into the alveolar space, vacuolar degeneration could be seen in lamellar bodies in type II alveolar epithelial cells. In SAP group mice, mRNA expression of Nrf2, HO-1and NQO1was slightly increased at3and6h compared with it of the CON group mice at the corresponding time point, however, it decreased somewhat at12and24h, but there were all no statistical significance. The expression of protein in the SAP group mice had a similar trend as its mRNA.
Conclusion:The endogenous antioxidant signaling pathway Nrf2/ARE can be activated in SAP, but expression of Nrf2and its downstream antioxidant gene HO-1and NQO1were not increased significantly and cannot maintain adequate time.
Objective:To investigate the effects of BML-111on acute pancreatitis associated lung injury (APALI) induced by cerulein with subsequent LPS administration in mice and its possible mechanisms.
Methods:One hundred twenty-eight mice were randomly allocated to four experimental groups:the SAP group (SAP group), the BML-111pretreatment group (SAP+BML group), the BM-111control group (BML group) and the normal saline group (NS group). Each group was randomly divided into4time units (3,6,12,24h) with8mice in each time unit. Twenty-four hours before the start of the experiment, the mice were deprived of food but allowed access to water. In the NS and BML group, mice were injected intraperitoneally (i. p.)10mL/kg BW normal saline repeatedly every1h (7injections in total) and the injection dosage were doubled at the last time. In the SAP group, mice were injected intraperitoneally50μg/kg BW cerulein (10mL/kg of BW) repeatedly every1h (7injections in total) and10mg/kg of BW LPS (10mL/kg of BW, i. p.) after the last dose of cerulein immediately, and one hour before the first injection of cerulein, the mice received intraperitoneal injections of0.4%DMSO (the menstruum for BML-111,10mL/kg BW). In the BML-111pretreatment group, the mice were administered BML-111(dissolved in0.4%DMSO solution,1mg/kg,10mL/kg BW) one hour before the first cerulein administration instead of0.4%DMSO, and the other was same as the SAP group. In the BML-111control group, identical to the BML-111pretreatment group were performed, except that the normal saline was administered instead of cerulein and LPS. In the NS group, identical to the SAP group except that the normal saline was administered instead of cerulein and LPS. Eight mice of each group were anesthetized with sodium pentobarbital (90mg/kg BW, i.m.), then were executed at3,6,12and24h after the last injection. Serum levels of amylase was assayed by P-nitrophenyl malt seven glycoside method, and TNF-a, IL-1β and IL-10were measured by enzyme linked immunosorbent assay (Elisa). Histological score of the pancreas and lung and the wet-to-dry weight ratio of lung were evaluated. Myeloperoxidase (MPO), malondialdehyde (MDA) and superoxide dismutase (SOD) of lung tissue were assayed by colorimetric analysis. Expression of Nrf2, HO-1and NQOl in lung tissue was evaluated by real-time PCR and western blot analysis, respectively.
Results:The findings revealed that injury of pancreas and lung was typically induced by cerulein. BML-11pretreatment significantly reduced the levels of serum amylase, TNF-a, IL-1β, lung MPO and MDA, the wet-to-dry weight ratio and the pathology injury scores of the lung, which increased in the SAP group. The expressions of Nrf2, HO-1, NQ01and activity of SOD in lung tissue increased in the SAP+BML group compared with those in the SAP group, and the serum levels of IL-10were markedly increased.
Conclusion:BML-111may play a critical protective role on APALI induced by cerulein. The underlying mechanisms of protective role may be attributable to its antioxidant and anti-inflammatory effects through activation of Nrf2/ARE pathway. BML-111pretreatment protected APALI induced by cerulein and these effects may attribute to the antioxidant effect of the antioxidant enzymes that were induced by activation of Nrf2/ARE signaling pathways. In addition, anti-inflammatory effect of BML-111may also be one of the reasons for these protective effects on APALI.
[方法]96只健康雄性Babl/c小鼠,SPF级,随机分为正常对照组(CON组)、生理盐水组(NS组)和重症急性胰腺炎组(SAP组),每组又随机分为3h、6h、12h和24h共4个亚组,每个亚组8只小鼠。各组小鼠禁食12h,不禁水。CON组不做任何处理；NS组腹腔内注射生理盐水10mL/kg/次,间隔1h一次,共七次,最后一次生理盐水加倍。SAP通过腹腔内注射蛙皮素50μg/kg/次(浓度为5mg/L,10mL/kg),间隔1h一次,共七次,最后一次同时注射脂多糖10mg/kg(浓度为0.1g/L,10mL/kg)诱导。于最后一次注射后3h、6h、12h及24h处死小鼠分别采集标本,采用对-硝基苯麦芽七糖苷法检测血清淀粉酶(AMY)水平,双抗体夹心ELISA法检测血清C反应蛋白(CRP),测量肺组织水含量并计算肺脏组织湿干重比率(W/D),胰腺及肺组织行苏木素-伊红染色(H-E染色)并行病理学评分,透射电镜检查肺脏超微结构变化,实时荧光定量PCR (Real-time PCR)检测肺脏组织Nrf2、HO-1、NQO1mRNA表达,Western blot法检测肺脏组织Nrf2、HO-1、NQO1蛋白的表达。
[结果]CON组与NS组各对应时相点比较,血清AMY、CRP、胰腺及肺脏病理学评分、肺脏干湿重比率均无明显差异,胰腺及肺脏组织病理学检查均未见明显异常。SAP组血清淀粉酶、CRP、胰腺及肺脏病理学评分、肺脏干湿重比率均较CON组及NS组增高(P<0.05)。SAP组胰腺H-E染色于3h时即可见胰腺组织结构轻度紊乱,间质水肿,血管周围和胰腺间质可见少量炎性细胞浸润,但小叶结构尚清晰；6h时上述改变更趋明显；12h及24h组小鼠胰腺组织结构更加紊乱,甚至消失,小叶结构模糊,腺泡细胞大部分坏死,可见孤岛状腺泡结构,坏死胰腺组织周围可见大量炎性细胞浸润及片状出血灶；部分血管坏死、弹力纤维崩解,可见血栓形成,还可见小脓肿形成。SAP组肺脏H-E染色于3h时即可见肺泡间隔增宽、间质毛细血管高度充血、肺泡水肿、部分肺泡腔缩小及少量炎性细胞浸润,但肺泡结构尚完整。6h时肺泡间隔明显增宽,肺组织水肿更加明显,血管和小支气管周围间质内大量中性粒细胞浸润。12h与24h时除上述表现外,部分肺泡腔内可见大量红细胞,部分肺泡萎陷,肺泡破裂融合成肺大泡。肺脏电镜检查示：CON组与NS组超微结构均未见明显异常：SAP组各时相点可见不同程度的肺泡隔及毛细血管内炎症细胞附壁,肺泡扩张融合,红细胞和活性物质泄漏到肺泡腔,Ⅱ型肺泡上皮细胞线粒体肿胀,线粒体膜模糊不清,线粒体嵴消失；胞浆内板层小体数量减少及空泡变性,上述表现在12h及24h更加明显。不论是在mRNA还是蛋白水平,SAP组小鼠肺组织中Nrf2、HO-1及NQO1的表达在诱导SAP后3h和6h与CON组及NS组相比均略有上升,在12h和24h时均表现出下降的趋势,但所有差异均无统计学意义。
[结论]内源性抗氧化信号通路Nrf2/ARE在重症急性胰腺炎相关肺损伤中虽然可以被激活,但Nrf2及其下游抗氧化基因HO-1、NQO1的表达并没有明显增加,也没有维持足够的时长。
[目的]探讨脂氧素受体激动剂BML-111对小鼠重症急性胰腺炎相关肺损伤的影响与可能的分子机制。
[方法]128只健康雄性Babl/c小鼠,SPF级,随机分为4组,即①生理盐水对照组(NS组),②BML-111对照组(BML组)；③重症急性胰腺炎组(SAP组)；④BML-111治疗组(SAP+BML组),每组又分为3h、6h、12h及24h共4个亚组,每组8只小鼠；各组小鼠禁食24h,不禁水。NS组及BML组小鼠经腹腔内注射生理盐水10mL/kg/次,间隔1h一次,共七次,最后一次生理盐水加倍。SAP组通过腹腔内注射蛙皮素50μg/kg/次(5mg/L,10mL/kg),间隔1h一次,共七次,最后一次同时注射脂多糖10mg/kg (0.1g/L,10mL/kg); SAP+BML组于诱导SAP之前1h经腹腔注射BML-111(1mg/kg即10mL/kg),BML组于第一次注射生理盐水前1h经腹腔注射BML-111(1mg/kg即10mL/kg), NS组及SAP组于第一次注射生理盐水或蛙皮素之前1h经腹腔注射BML-111的溶媒(0.4%DMSO溶液,10mL/kg)。分别于最后一次注射后3h、6h、12h、24h处死小鼠采集标本,采用对-硝基苯麦芽七糖苷法检测血清AMY水平；双抗体夹心ELISA法检测血清IL-10、TNF-α、IL-β含量；比色法检测肺脏组织SOD、 MPO、MDA含量；胰腺及肺组织行苏木素-伊红染色(H-E染色)并行病理学评分；透射电镜观察肺脏超微结构；测量肺组织水含量并计算肺脏组织湿干重比率(W/D)；采用real-time PCR法检测肺脏组织Nrf2、HO-1、 NQO1mRNA水平；Western blot法检测肺脏Nrf2、HO-1、NQO1蛋白。
[结果]与NS组及BML组各对应时相点比较,SAP组小鼠血清淀粉酶、TNF-α、IL-1β及肺组织MPO、MDA水平、肺组织湿干重比率均显著增加(P<0.05)；血清IL-10及肺组织SOD水平均下降(P<0.05)；胰腺及肺脏H-E染色均符合上述SAP及相关肺损伤的表现；胰腺和肺组织的病理学损伤评分亦均显著增高(P<0.05)；肺脏透射电镜检查亦符合肺损伤的病理诊断。与SAP组各对应时相点比较,SAP+BML组小鼠血清淀粉酶、TNF-α、IL-1β及肺组织MPO、MDA、肺组织湿干重比率、胰腺及肺的病理学损伤评分均明显降低(P<0.05)；血清IL-10及肺组织SOD水平则增高(P<0.05)；肺组织中Nrf2、 HO-1及NQO1的表达均显着增加(P<0.05)；胰腺及肺组织病理学改变亦较SAP组有所改善。
[结论]BML-111预处理对蛙皮素诱导的胰腺炎相关肺损伤具有一定的保护作用,这种作用除归因于BML-111通过激活Nrf2/ARE信号转导通路,诱导下游抗氧化酶HO-1及NQO1的表达所发挥的抗氧化作用外,还可能与BML-111对促炎因子TNF-α、IL-1β及抗炎因子IL-10的调节有关。
Objective:To investigate the role of endogenous antioxidant signaling pathway Nrf2/ARE in acute pancreatitis associated lung injury (APALI) induced by cerulein with subsequent LPS administration in mice.
Methods:Ninety-six Babl/c mice were randomly allocated to three experimental groups:the normal control group (CON group), the normal saline group (NS group) and the severe acute pancreatitis group (SAP group). Each group was randomly divided into4time units (3,6,12,24h) with8mice in each time unit. Twenty-four hours before the start of the experiment, the mice were deprived of food but allowed access to water. The CON group mice received no treatment. In the NS group, mice were injected intraperitoneally (i. p.)10mL/kg BW normal saline repeatedly every1h (7injections in total) and the injection dosage were doubled at the last time. In the SAP group, mice were injected intraperitoneally50μg/kg BW cerulein (10mL/kg of BW) repeatedly every1h (7injections in total) and10mg/kg of BW LPS (10mL/kg of BW, i. p.) after the last dose of cerulein immediately. Eight mice of each group were anesthetized with sodium pentobarbital (90mg/kg BW, i.m.), then were executed at3,6,12and24h after the last injection. Serum amylase was assayed by P-nitrophenyl malt seven glycoside method, C-reactive protein (CRP) were measured by enzyme linked immunosorbent assay (Elisa), histological score of the pancreas and lung and the wet-to-dry weight ratio of lung were evaluated. The severity of lesions was evaluated by pancreatic and lung histology. Expression of Nrf2, HO-1, and NQO1in lung tissue was evaluated by real-time PCR and western blot analysis, respectively.
Results:Compared with CON and NS group, the serum amylase, CRP, histological score of the pancreas and lung and the wet-to-dry weight ratio of lung increased significantly in SAP group(P<0.05). In SAP group mice, the pathology of pancreas showed interstitial edema, minor inflammatory cells infiltration both around vessels and in the pancreatic mesenchyme at3h while lobules of it were still clear to observe. All the changes above were more obvious at6h. The organizational structure of the pancreas was more disturbed at12h and24h as there was no discernable normal lobular architecture, and massive acinar cell necrosis, hemorrhage, vascular necrosis, elastic fiber disintegration, thrombosis, together with microabscess could be seen in the necrotic pancreas; The pathology of lung showed edema, congestion, widened alveolar septa at3h and6h. Besides, RBC exudation, severe inflammatory cell infiltration, severe hemorrhage and alveolar collapse were observed at12h and24h. Ultrastructure of lung tissue showed complete mitochondrial outer membrane and distinct mitochondrial cristae in type II alveolar epithelial cells, and there was no evacuation phenomenon in laminated bodies in the control and NS group. In the SAP group, mitochondria in type II alveolar epithelial cells swelled with membranes indiscernible and most of mitochondrial cristae disappeared at3h and6h; At12h and24h, alveoli were clearly dilated and merged, a large number of red blood cells and active substance leaked into the alveolar space, vacuolar degeneration could be seen in lamellar bodies in type II alveolar epithelial cells. In SAP group mice, mRNA expression of Nrf2, HO-1and NQO1was slightly increased at3and6h compared with it of the CON group mice at the corresponding time point, however, it decreased somewhat at12and24h, but there were all no statistical significance. The expression of protein in the SAP group mice had a similar trend as its mRNA.
Conclusion:The endogenous antioxidant signaling pathway Nrf2/ARE can be activated in SAP, but expression of Nrf2and its downstream antioxidant gene HO-1and NQO1were not increased significantly and cannot maintain adequate time.
Objective:To investigate the effects of BML-111on acute pancreatitis associated lung injury (APALI) induced by cerulein with subsequent LPS administration in mice and its possible mechanisms.
Methods:One hundred twenty-eight mice were randomly allocated to four experimental groups:the SAP group (SAP group), the BML-111pretreatment group (SAP+BML group), the BM-111control group (BML group) and the normal saline group (NS group). Each group was randomly divided into4time units (3,6,12,24h) with8mice in each time unit. Twenty-four hours before the start of the experiment, the mice were deprived of food but allowed access to water. In the NS and BML group, mice were injected intraperitoneally (i. p.)10mL/kg BW normal saline repeatedly every1h (7injections in total) and the injection dosage were doubled at the last time. In the SAP group, mice were injected intraperitoneally50μg/kg BW cerulein (10mL/kg of BW) repeatedly every1h (7injections in total) and10mg/kg of BW LPS (10mL/kg of BW, i. p.) after the last dose of cerulein immediately, and one hour before the first injection of cerulein, the mice received intraperitoneal injections of0.4%DMSO (the menstruum for BML-111,10mL/kg BW). In the BML-111pretreatment group, the mice were administered BML-111(dissolved in0.4%DMSO solution,1mg/kg,10mL/kg BW) one hour before the first cerulein administration instead of0.4%DMSO, and the other was same as the SAP group. In the BML-111control group, identical to the BML-111pretreatment group were performed, except that the normal saline was administered instead of cerulein and LPS. In the NS group, identical to the SAP group except that the normal saline was administered instead of cerulein and LPS. Eight mice of each group were anesthetized with sodium pentobarbital (90mg/kg BW, i.m.), then were executed at3,6,12and24h after the last injection. Serum levels of amylase was assayed by P-nitrophenyl malt seven glycoside method, and TNF-a, IL-1β and IL-10were measured by enzyme linked immunosorbent assay (Elisa). Histological score of the pancreas and lung and the wet-to-dry weight ratio of lung were evaluated. Myeloperoxidase (MPO), malondialdehyde (MDA) and superoxide dismutase (SOD) of lung tissue were assayed by colorimetric analysis. Expression of Nrf2, HO-1and NQOl in lung tissue was evaluated by real-time PCR and western blot analysis, respectively.
Results:The findings revealed that injury of pancreas and lung was typically induced by cerulein. BML-11pretreatment significantly reduced the levels of serum amylase, TNF-a, IL-1β, lung MPO and MDA, the wet-to-dry weight ratio and the pathology injury scores of the lung, which increased in the SAP group. The expressions of Nrf2, HO-1, NQ01and activity of SOD in lung tissue increased in the SAP+BML group compared with those in the SAP group, and the serum levels of IL-10were markedly increased.
Conclusion:BML-111may play a critical protective role on APALI induced by cerulein. The underlying mechanisms of protective role may be attributable to its antioxidant and anti-inflammatory effects through activation of Nrf2/ARE pathway. BML-111pretreatment protected APALI induced by cerulein and these effects may attribute to the antioxidant effect of the antioxidant enzymes that were induced by activation of Nrf2/ARE signaling pathways. In addition, anti-inflammatory effect of BML-111may also be one of the reasons for these protective effects on APALI.
引文
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