缺血后处理对大鼠肺缺血再灌注损伤的保护作用
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摘要
目的:肺缺血-再灌注损伤( Lung Ischemia Reperfusion Injury, LIRI)在很多临床情况下都可能发生,例如体外循环手术、肺移植、肺切除术后、肺动脉血栓摘除术后等,迄今为止,肺缺血-再灌注损伤仍然是胸心外科医生面临的严峻挑战,特别是在肺移植手术后最为多见。缺血-再灌注导致的肺损伤的特点是非特异性的肺泡损伤、肺水肿和低氧血症。尽管通过改进肺保存方法、提高手术技术以及加强围手术期的监护使肺移植的成功率有所提高,但是缺血-再灌注导致的肺损伤在肺移植手术后仍有较高的发病率和致死率,所以更好的了解肺缺血-再灌注损伤的机理,研究更有效的方法来减轻肺缺血-再灌注损伤具有非常重要的临床意义。缺血后处理(Ischemic Postconditioning, I PostC )是一种在再灌注初期间断预灌注的新方法,在心肌和肝脏中已经证明可以减轻缺血-再灌注损伤。本实验建立大鼠在体肺缺血-再灌注模型,应用后处理干预,验证后处理对肺缺血-再灌注损伤的保护作用,并通过检测肺组织中炎性细胞因子TNF-α及IL-1β的水平初步探讨其保护作用的机制,为临床应用提供理论基础。
材料和方法:取健康雄性SD大鼠80只,戊巴比妥钠(30mg/kg)腹腔内注射麻醉,气管切开后气管插管连接小动物呼吸机控制呼吸,呼吸频率60次/min,吸呼比为1:1.5,工作压力(即潮气量):0.02MPa。经左胸第五肋间进入胸腔,游离左侧肺门,过阻断带,末端套橡皮胶管形成活结备阻断用。手术操作前经阴茎背静脉注射肝素钠100U/kg以维持肝素化,在再灌注期间,每隔1h由皮下注射生理盐水0.5ml以补充水分的丢失。
将实验动物随机分成5组(n=8):①假手术组(C组,单纯开胸60min,不阻断肺门);②缺血-再灌注30min组(RI30组,肺门阻断30min后再灌注30min);③缺血-再灌注120min组(RI120组,肺门阻断30min后再灌注120min);④后处理30min组(P30组,在缺血30min后,短暂再灌注30s,缺血30s,反复5次,然后全面恢复灌注30min);⑤后处理120min组(P120组,在缺血30min后,短暂再灌注30s,缺血30s,反复5次,然后全面恢复再灌注120min)。
实验结束后放血处死大鼠,取新鲜左肺组织用4%多聚甲醛固定,用免疫组化法测定肺组织中TNF-α及IL-1β的表达水平;光镜下HE染色观察病理形态学改变。另将40只健康雄性SD大鼠按上述方法随机分成5组,测定125I标记牛血清白蛋白(BSA)漏出量,以此来反映肺毛细血管通透性。
结果:
(1) 125I标记牛血清白蛋白(BSA)漏出量变化:IR组与C组相比较,肺组织经过缺血再灌注后肺125I标记牛血清白蛋白(BSA)漏出量明显升高(p<0.05),P组与IR组比较,经后处理后肺125I标记牛血清白蛋白(BSA)漏出量较相应时段的再灌注组明显减轻(p<0.01)。
(2)肺TNF-α表达水平的变化:以胞浆出现棕黄色为阳性染色,肺组织经缺血再灌注后,IR组与C组相比,TNF-α的表达水平明显升高(P<0.01),且随着时间的推移有上升趋势;P组与相应时段的IR组相比,表达水平明显降低(P<0.01)。
(3)肺IL-1β表达水平的变化:以胞浆出现棕黄色为阳性染色,肺组织经/。缺血再灌注后,IR组与C组相比,IL-1β的表达水平明显升高(P<0.01),且随着时间的推移有上升趋势;P组与相应时段的IR组相比,表达水平明显降低(P<0.01)。
(4)肺组织病理变化:C组:肺组织肺泡壁薄,结构清晰,近似正常肺组织; IR组:肺泡间隔炎症细胞浸润、水肿,肺泡腔内炎性细胞及液体渗出,肺泡结构模糊,以上改变随时间延长而加重;P组较之相应时段的IR组,上述变化均明显减轻。
结论:(1) I postC可以抑制再灌注肺组织中致炎因子TNF-α及IL-1β的表达;(2) I postC能减轻LIRI导致的肺毛细血管通透性增高,可以减少再灌注后炎性细胞及炎性介质在肺内聚集;(3) I postC可以使肺组织血清白蛋白(BSA)漏出量减少。通过以上机制减轻炎性介质引起的肺损伤,从而起到减轻大鼠LIRI损伤的作用。
Objective
Ischemia reperfusion injury of the lung (LIRI) is still a challenge for the thoracic and cardiovascular surgeon, which occurs in many clinical conditions, such as cardiopulmonary bypass, lung transplantation, lung embolism, shock, ans so on, especially during lung transplantation. The characteristics of ischemia reperfusion injury in lung transplantation are nonspecific alveoli pulmonum injury, lung edema and hypoxemia. The morbidity and mortality of lung ischemia reperfusion injury are still higher which takes place in lung transplantation, though the achievement ratio increases to some extent by improving lung conservation method, upgrading surgical technic and strengthening guardianship in perioperation. Ischemic postconditioning(I postC), a new method which is practiced by interrupted pre-irritating in the initial stage of reperfusion, has been certificated to decrease the reperfusion injury of myocardium and liver. This experiment was carried out, establishing an in situ hilar occlusion, in vivo rat lung ischemia reperfusion injury model. The 125I-BSA leakage, the expression level of TNF-αand IL-1βof the lung tissue were measured. The histopathological changes of the lung tissue were observed to explore the effects of ischemic post-conditioning on ischemia reperfusion injury of rat lung in vivo.
Materials and Methods
Eighty male Sprague-Dawley rats were anesthetized with an intraperitoneal injection of sodium pentobarbital (30mg/kg). The animals were shaved, endotracheal intubated with a 14 gauge tube, and ventilated with a rodent respirator ventilator at a respiratory rate of 60 breaths/min, a 1:1.5 of I/E ratio and a mean peak pressure of 0.02 MPa. All animals received 0.04 mg/kg of intramuscular atropine after being anesthetized. The chest was opened via a left thoracotomy through the fifth intercostal space. After the left pulmonary hilum including neural, vascular, lymphatic, and connective tissue was stripped, a ligature was placed through, and the ends of the tie were threaded through a small plastic tube to form a snare for reversible left pulmonary hilar occlusion. Heparinization was maintained during the experimental period with a bolus injection of 100U/kg sodium heparin via the dorsal penile vein.
All animals were randomized into five gro ups with 8 animals in each group:①sham operation group (C group) ;②IR 30mins group( IR30 ) ;③IR 120mins group(IR120) ;④postconditioning 30mins group(P30).⑤postconditioning 120mins group(P120). IR injury consisted of 30 minutes of lung cross-clamping followed by 30/120mins of reperfusion, sham operation animals had a thoracotomy only. postconditioning was given by 30s reperfusion/30s ischemia for 5 circle before the persistent reperfusion.
At the end of the experiment, all operated rats were killed by blood letting through carotid artery. The left lung tissue were retrieved, and then saved in 4% Polyoxymethylene for determining. The expression level of TNF-αand IL-1βof lung tissue were detected by immunohistochemical stain technically. The pathological changes of the lung tissue were observed under microscopy. Another forty male Sprague-Dawley rats were randomized into five groups with 8 animals in each group to determine the 125I-BSA leakage in lung tissue to detecte permeability of pulmonary capillary.
Results
(1) The 125I-BSA leakage in lung tissue After reperfusion 30mins/120mins, the 125I-BSA leakage increased markedly in IR group and had significantly change compared with group C (p <0.05). Treatment with postconditioning alleviated the 125I-BSA leakage. Moreover, the 125I-BSA leakage in P group were lower than IR group (p <0.01).
(2) The level of TNF-αin lung tissue Immunohistochemical stain analysis of lung TNF-α: The cell which express TNF-αshowed brown immunostaining in cytoplasm. In contrast, significant increase of TNF-αexpression was found in IR group (p <0.01). In the rats treated with postconditioning, the positive cell ratio is lower compared with IR group (p <0.01).
(3) The level of IL-1βin lung tissue Using immunohistochemical stain analysis, expression of IL-1βin the cell of lung tissue showed brown immunostaining in cytoplasm. In contrast, significant increase of IL-1βexpression was found in IR group (p <0.01). In the rats treated with postconditioning, the positive cell ratio is lower compared with IR group (p <0.01).
(4) Histological evaluation In the process of ischemia-reperfusion, the lung injury was aggravating progressively in the IR group. Marked pulmonary capillary congestion, edema in pulmonary stroma, neutrophils infiltration, inflammatory exudation, thickening of alveolar wall and intra-alveolar hemorrhage could be observed. These changes in morphology were less pronounced in rats that had been pretreated with postconditioning.
Conclusions
(1) Ischemic Postconditioning can restrain the expression of TNF-αand IL-1βon the lung;
(2) Ischemic Postconditioning can attenuate pulmonary capillary permeability and inhibit the exudation of inflammatory factors and cells; (3) Ischemic Postconditioning can attenuate the BSA leakage in lung. In a word, ischemic Postconditioning can attenuate the lung ischemia reperfusion injury in rats through restraining the inflammation by the mechanisms above .
材料和方法:取健康雄性SD大鼠80只,戊巴比妥钠(30mg/kg)腹腔内注射麻醉,气管切开后气管插管连接小动物呼吸机控制呼吸,呼吸频率60次/min,吸呼比为1:1.5,工作压力(即潮气量):0.02MPa。经左胸第五肋间进入胸腔,游离左侧肺门,过阻断带,末端套橡皮胶管形成活结备阻断用。手术操作前经阴茎背静脉注射肝素钠100U/kg以维持肝素化,在再灌注期间,每隔1h由皮下注射生理盐水0.5ml以补充水分的丢失。
将实验动物随机分成5组(n=8):①假手术组(C组,单纯开胸60min,不阻断肺门);②缺血-再灌注30min组(RI30组,肺门阻断30min后再灌注30min);③缺血-再灌注120min组(RI120组,肺门阻断30min后再灌注120min);④后处理30min组(P30组,在缺血30min后,短暂再灌注30s,缺血30s,反复5次,然后全面恢复灌注30min);⑤后处理120min组(P120组,在缺血30min后,短暂再灌注30s,缺血30s,反复5次,然后全面恢复再灌注120min)。
实验结束后放血处死大鼠,取新鲜左肺组织用4%多聚甲醛固定,用免疫组化法测定肺组织中TNF-α及IL-1β的表达水平;光镜下HE染色观察病理形态学改变。另将40只健康雄性SD大鼠按上述方法随机分成5组,测定125I标记牛血清白蛋白(BSA)漏出量,以此来反映肺毛细血管通透性。
结果:
(1) 125I标记牛血清白蛋白(BSA)漏出量变化:IR组与C组相比较,肺组织经过缺血再灌注后肺125I标记牛血清白蛋白(BSA)漏出量明显升高(p<0.05),P组与IR组比较,经后处理后肺125I标记牛血清白蛋白(BSA)漏出量较相应时段的再灌注组明显减轻(p<0.01)。
(2)肺TNF-α表达水平的变化:以胞浆出现棕黄色为阳性染色,肺组织经缺血再灌注后,IR组与C组相比,TNF-α的表达水平明显升高(P<0.01),且随着时间的推移有上升趋势;P组与相应时段的IR组相比,表达水平明显降低(P<0.01)。
(3)肺IL-1β表达水平的变化:以胞浆出现棕黄色为阳性染色,肺组织经/。缺血再灌注后,IR组与C组相比,IL-1β的表达水平明显升高(P<0.01),且随着时间的推移有上升趋势;P组与相应时段的IR组相比,表达水平明显降低(P<0.01)。
(4)肺组织病理变化:C组:肺组织肺泡壁薄,结构清晰,近似正常肺组织; IR组:肺泡间隔炎症细胞浸润、水肿,肺泡腔内炎性细胞及液体渗出,肺泡结构模糊,以上改变随时间延长而加重;P组较之相应时段的IR组,上述变化均明显减轻。
结论:(1) I postC可以抑制再灌注肺组织中致炎因子TNF-α及IL-1β的表达;(2) I postC能减轻LIRI导致的肺毛细血管通透性增高,可以减少再灌注后炎性细胞及炎性介质在肺内聚集;(3) I postC可以使肺组织血清白蛋白(BSA)漏出量减少。通过以上机制减轻炎性介质引起的肺损伤,从而起到减轻大鼠LIRI损伤的作用。
Objective
Ischemia reperfusion injury of the lung (LIRI) is still a challenge for the thoracic and cardiovascular surgeon, which occurs in many clinical conditions, such as cardiopulmonary bypass, lung transplantation, lung embolism, shock, ans so on, especially during lung transplantation. The characteristics of ischemia reperfusion injury in lung transplantation are nonspecific alveoli pulmonum injury, lung edema and hypoxemia. The morbidity and mortality of lung ischemia reperfusion injury are still higher which takes place in lung transplantation, though the achievement ratio increases to some extent by improving lung conservation method, upgrading surgical technic and strengthening guardianship in perioperation. Ischemic postconditioning(I postC), a new method which is practiced by interrupted pre-irritating in the initial stage of reperfusion, has been certificated to decrease the reperfusion injury of myocardium and liver. This experiment was carried out, establishing an in situ hilar occlusion, in vivo rat lung ischemia reperfusion injury model. The 125I-BSA leakage, the expression level of TNF-αand IL-1βof the lung tissue were measured. The histopathological changes of the lung tissue were observed to explore the effects of ischemic post-conditioning on ischemia reperfusion injury of rat lung in vivo.
Materials and Methods
Eighty male Sprague-Dawley rats were anesthetized with an intraperitoneal injection of sodium pentobarbital (30mg/kg). The animals were shaved, endotracheal intubated with a 14 gauge tube, and ventilated with a rodent respirator ventilator at a respiratory rate of 60 breaths/min, a 1:1.5 of I/E ratio and a mean peak pressure of 0.02 MPa. All animals received 0.04 mg/kg of intramuscular atropine after being anesthetized. The chest was opened via a left thoracotomy through the fifth intercostal space. After the left pulmonary hilum including neural, vascular, lymphatic, and connective tissue was stripped, a ligature was placed through, and the ends of the tie were threaded through a small plastic tube to form a snare for reversible left pulmonary hilar occlusion. Heparinization was maintained during the experimental period with a bolus injection of 100U/kg sodium heparin via the dorsal penile vein.
All animals were randomized into five gro ups with 8 animals in each group:①sham operation group (C group) ;②IR 30mins group( IR30 ) ;③IR 120mins group(IR120) ;④postconditioning 30mins group(P30).⑤postconditioning 120mins group(P120). IR injury consisted of 30 minutes of lung cross-clamping followed by 30/120mins of reperfusion, sham operation animals had a thoracotomy only. postconditioning was given by 30s reperfusion/30s ischemia for 5 circle before the persistent reperfusion.
At the end of the experiment, all operated rats were killed by blood letting through carotid artery. The left lung tissue were retrieved, and then saved in 4% Polyoxymethylene for determining. The expression level of TNF-αand IL-1βof lung tissue were detected by immunohistochemical stain technically. The pathological changes of the lung tissue were observed under microscopy. Another forty male Sprague-Dawley rats were randomized into five groups with 8 animals in each group to determine the 125I-BSA leakage in lung tissue to detecte permeability of pulmonary capillary.
Results
(1) The 125I-BSA leakage in lung tissue After reperfusion 30mins/120mins, the 125I-BSA leakage increased markedly in IR group and had significantly change compared with group C (p <0.05). Treatment with postconditioning alleviated the 125I-BSA leakage. Moreover, the 125I-BSA leakage in P group were lower than IR group (p <0.01).
(2) The level of TNF-αin lung tissue Immunohistochemical stain analysis of lung TNF-α: The cell which express TNF-αshowed brown immunostaining in cytoplasm. In contrast, significant increase of TNF-αexpression was found in IR group (p <0.01). In the rats treated with postconditioning, the positive cell ratio is lower compared with IR group (p <0.01).
(3) The level of IL-1βin lung tissue Using immunohistochemical stain analysis, expression of IL-1βin the cell of lung tissue showed brown immunostaining in cytoplasm. In contrast, significant increase of IL-1βexpression was found in IR group (p <0.01). In the rats treated with postconditioning, the positive cell ratio is lower compared with IR group (p <0.01).
(4) Histological evaluation In the process of ischemia-reperfusion, the lung injury was aggravating progressively in the IR group. Marked pulmonary capillary congestion, edema in pulmonary stroma, neutrophils infiltration, inflammatory exudation, thickening of alveolar wall and intra-alveolar hemorrhage could be observed. These changes in morphology were less pronounced in rats that had been pretreated with postconditioning.
Conclusions
(1) Ischemic Postconditioning can restrain the expression of TNF-αand IL-1βon the lung;
(2) Ischemic Postconditioning can attenuate pulmonary capillary permeability and inhibit the exudation of inflammatory factors and cells; (3) Ischemic Postconditioning can attenuate the BSA leakage in lung. In a word, ischemic Postconditioning can attenuate the lung ischemia reperfusion injury in rats through restraining the inflammation by the mechanisms above .
引文
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