七氟醚抗单肺通气致急性肺损伤保护作用机制
摘要
[研究背景和目的]
单肺通气(one-lungventilation,OLV)作为临床常用的机械通气模式,可引起急性肺损伤(acute lung injury,ALI)。因此,研究OLV发病机制,寻找和阐明抗OLV致肺损伤的药物及其作用机制是临床实际工作中亟待解决和研究的重点之一
研究证实,花生四烯酸(arachidonic acid.AA)及其代谢产物在肺损伤的发生发展中起着重要作用。但是,它们在OLV致AL1中的作用并不十分清楚。
七氟醚(Sevoflurane)为临床常用挥发性麻醉药,被发现具有抗OLV致肺损伤保护作用,但其抗OLV致肺损伤作用机制是否与影响AA及其代谢产物的生成有关,未见报道。
因而,本研究旨在从AA生成和代谢关键酶途径研究OLV致ALI和七氟醚抗OLV致ALI保护作用机制,为临床防治单肺通气致肺损伤寻找药物作用的新干预途径提供一定的实验依据。
[研究方法]
1.实验分组
1.1单肺通气致急性肺损伤动物模型的建立
采用右主支气管内插管+胸骨旁开窗术,建立单肺通气致急性肺损伤动物模型。24只日本大耳白兔随机分组(n=6)为：①假手术组(S组)；②双肺通气组(T组)；③双肺通气+胸骨旁开窗术组(TF组)和④单肺通气组(O组)。
1.2Clara细胞剥除动物模型的建立
采用萘气吸入法建立Clara细胞剥除动物模型。随机将12只日本大耳白兔分组(n=6)为：①对照组(C组)和②萘气吸入组(NA组),连续吸入萘气(100mg/L)12h。
1.3七氟醚抗单肺通气致肺损伤作用机制研究方法
实验动物随机分组：①假手术组(S组)；②单肺通气组(O组)；③单肺通气+七氟醚组(OS组),OS组又按所给七氟醚浓度的不同分为1vo1%、2vo1%、3vol%和4vo1%浓度亚组：④Clara细胞剥除假手术组(NA组)；⑤Clara细胞剥除+单肺通气组(NAO组)和⑥Clara细胞剥除+单肺通气+七氟醚组(NAOS组)：每组n=6。
2.各项观察指标
(1)显微镜观察肺组织形态学改变,同时进行肺组织病理学评分；
(2)电镜观察肺细支气管Clara细胞形态学变化并计数；
(3)测定肺湿／干(wet/dry,W/D)比值；
(4) ELISA测定肺组织髓过氧化物酶(myeloperoxidase, MPO)活性,肺组织花生四烯酸(AA)、前列环素(prostacyclin,Prostaglandin i2, PGI2)、血栓素A2(thromboxane A2. TXA2)及白三烯B4(leukotrienes B4. LTB4)含量；
(5)计数支气管肺泡灌洗液(bronchoalveolar lavage fluid, BALF)中多形核白细胞(polymorphonuclear leukocyte, PMN)数量：
(6) Western-blot和定量RT-PCR分别检测肺组织Clara细胞分泌蛋白(clara cell secretory protein, CCSP)、胞质型磷脂酶A2(cytosolic phospholipase A2.C-PLA2)、环氧化酶-2(cyclooxygenase-2, COX2)和5-脂氧化酶(5-lipoxygenase,5-LOX)蛋白及其各自mRNA表达水平。
[结果]
第一部分动物模型的建立
1.1单肺通气致急性肺损伤动物模型的建立
与S组相比,O组、T组和TF组动物BALF中PMN计数,肺组织AA含量、MPO活性,肺W/D比值和肺组织病理学评分均明显增高(P<0.05)；TF组和T组动物的上述各项指标无显著性差异,但均显著低于O组(P<0.05)；光镜观察：S组动物肺组织未见明显病理学改变；T组和TF组动物肺组织可见散在充血、出血灶,肺泡腔少量红细胞和炎细胞浸润,肺泡壁略增厚；0组动物肺组织大面积充血、出血,肺泡腔内有较多红细胞和炎细胞浸润,肺泡壁广泛充血、增厚和渗出。
1.2Clara细胞剥除动物模型的建立
与C组相比,NA组动物肺组织CCSP mRNA和蛋白表达水平及细支气管Clara细胞计数显著降低(P<0.05),但两组间肺W/D比值和肺组织病理学评分无显著性差异。光镜观察：两组实验动物肺组织除部分区域见毛细血管扩张充血外,均未见明显病理改变。电镜观察：C组动物细支气管Clara细胞内含有较多分泌颗粒,而NA组动物细支气管内clara细胞数量明显减少且呈空泡样变性,其内未见明显分泌颗粒。
第二部分七氟醚抗单肺通气致肺损伤作用机制
2.1从花生四烯酸的胞质型磷脂酶A2(C-PLA2)生成途径研究
2.1.1七氟醚对单肺通气致急性肺损伤兔肺组织CCSP及C-PLA2表达的影响
与S组相比,O组和OS组兔肺组织CCSP mRNA和蛋白表达水平明显降低(P<0.05),肺组织C-PLA2mRNA和蛋白表达水平、AA含量、肺W/D比值及肺组织病理学评分均明显升高(P<0.05)；与O组相比,OS组动物肺组织CCSP mRNA和蛋白表达水平明显增高(P<0.05),而肺组织C-PLA2mRNA和蛋白表达水平、肺组织AA含量及病理学评分显著下降(P<0.05)；OS组不同浓度七氟醚兔肺组织CCSP mRNA和蛋白表达水平均无显著性差异,但随着七氟醚浓度的增加OS组肺组织C-PLA2mRNA和蛋白表达水平、肺组织AA含量、肺W/D比值及肺组织病理学评分逐渐降低(P<0.05)。光镜观察：S组动物肺组织除部分区域见毛细血管扩张外,无明显病理改变；O组动物肺组织可见大量出血、充血灶,肺泡腔内较多红细胞和炎症细胞浸润,肺泡壁明显充血、增厚和渗出；随七氟醚浓度增加,OS组动物肺组织上述病理形态学改变逐渐减轻。
2.1.2CCSP在七氟醚抗单肺通气致急性肺损伤中的作用
与S组相比,其它各组动物肺组织CCSP mRNA和蛋白表达水平均明显降低(P<0.05),肺组织C-PLA2mRNA和蛋白表达水平、AA含量、肺W/D比值和肺组织病理学评分除在NA组无显著差异外,其余各组均明显升高(P<0.05)；与NA组相比,NAO组和NAOS组肺组织CCSP mRNA和蛋白表达水平无显著差异(P>0.05),而O组和OS组明显增高(P<0.05)；与O组相比,肺组织CCSP mRNA和蛋白表达水平在OS组明显增高(P<0.05),在NAO和NAOS组明显降低(P<0.05),但肺组织C-PLA2mRNA和蛋白表达水平、肺组织AA含量、肺W/D比值及肺组织病理学评分在OS组和NAOS组中均明显降低(P<0.05),在NAO组明显增高(P<0.05)：与OS组相比,NAO组和NAOS组动物肺组织CCSP mRNA和蛋白表达水平明显降低(P<0.05),但其余各指标均明显升高(P<0.05)。与NAO组相比,NAOS组动物肺组织CCSP mRNA和蛋白表达水平无明显差异,其余各指标均明显降低(P<0.05)。光镜观察：S组和NA组动物肺组织未见明显病理形态学改变：O组动物肺组织可见大量出血、充血灶,肺泡腔内较多红细胞和炎症细胞浸润,肺泡壁明显充血、增厚和渗出；NAO组动物肺组织上述病理形态学改变进一步加重；OS组肺组织散在小范围充血、出血灶,肺泡腔内散在红细胞和炎细胞浸润,肺泡壁明显增厚、渗出；NAOS组动物肺组织病理改变与OS组类似,但明显加重。
2.2从花生四烯酸的COX2和5-LOX代谢途径研究
与S组相比,O组和OS组动物肺组织COX2蛋白、COX2mRNA和5-LOX蛋白、5-LOX mRNA表达水平,肺组织PGI2、LTB4和TXA2含量,肺W/D比值及肺组织病理学评分均明显升高(P<0.05),肺组织PGI2/TXA2比值明显降低(P<0.05)。与O组相比,OS组动物肺组织PGI2/TXA2比值明显升高(P<0.05),而其余指标均明显降低(P<0.05)。S组动物肺组织除部分区域见毛细血管扩张充血外,未见明显病理改变。O组肺组织可见大量出血、充血灶,肺泡腔内较多红细胞和炎症细胞浸润,可见肺泡壁明显充血、增厚和渗出；OS组肺组织散在小范围充血、出血灶,肺泡腔内散在红细胞和炎细胞浸润,肺泡壁增厚。
结论
1.右主支气管内插管联合胸骨旁开窗术可用于构建兔单肺通气致急性肺损伤动物模型。
2.单肺通气可诱发急性肺损伤,其机制可能与下调肺组织CCSP mRNA和蛋白表达,从而削弱了其对C-PLA2的抑制作用,以及激活AA代谢COX2和5-LOX途径,使得AA及其代谢产物大量生成有关。
3.七氟醚抗单肺通气致急性肺损伤作用可能与通过或不通过促进肺组织CCSP的表达而抑制肺内AA生成的C-PLA2途径,减少肺组织AA的生成有关。
4.七氟醚可通过调控肺内AA的COX2和5-LOX代谢途径发挥抗单肺通气致ALI作用,其机制可能与下调COX2和5-LOX表达,减少AA代谢产物的生成和调控PGI2/TXA2比值有关。
5.肺内花生四烯酸生成和代谢途径可能是七氟醚抗单肺通气致急性肺损伤作用新的潜在干预途径。
Background and Objective
Studies have shown that, as a widely used mechanical ventilation mode, one-lung ventilation (OLV) can result in acute lung injury (ALI). Therefore, to investigate the mechanisms of ALI induced by OLV and to unravell the preventive and therapeutic effects of drugs on OLV-induced ALI are currently areas of intense investigation.
Sevoflurane, a commonly used clinical anesthetic, is considered to possess protective effects on OLV-induced ALI by inhibition of inflammatory response. However, its protective mechanisms are still unclear. Studies showed that arachidonic acid (AA) and its metabolites play an important role in the development of lung injury. Thus, the purpose of this study is to investigate the effects of sevoflurane on OLV-induced ALI from arachidonic acid metabolic pathways to present novel avenues for therapeutic intervention.
Methods
1. Animal grouping
(1) OLV-induced ALI animal model
OLV-induced ALI rabbit model was constructed by right mainstem bronchial intubation with parasternal fenestration. Totally24healthy Japanese white rabbits were randomly divided into4groups(n=6):①sham operated group(S group);②two-lung ventilation(TLV) group (T group);③TLV with parasternal fenestration group (TF group) and④OLV group (O group).
(2) Exfoliation of clara cell rabbit model
12healthy Japanese white rabbits were randomized into two groups (n=6): control group(C group),and naphthalene vapor (100mg/L,12h) inhaled group (NA group).
(3) The protective mechanisms of sevoflurane on OLV-induced ALI
Healthy Japanese white rabbits were randomized into groups as follows:①sham operated group (S group);②OLV group (O group);③OLV+sevoflurane group (OS group). The OS group was divided into4subgroups with different concentrations of sevoflurane(lvol%,2vol%,3vol%and4vol%respectively);④inhaled naphthalene vapor group (NA group);⑤inhaled naphthalene vapor before OLV group; and⑥inhaled naphthalene vapor before OLV+sevoflurane group (n=6).
2. Detection indcators and methods
(1) Histological scores and lung wet/dry weight (W/D) ratios were determined for lung injury assessment.
(2) Expressions of lung CCSP, C-PLA2, COX2and5-LOX proteins and their homologous mRNAs were detected by western-blotting and real time-PCR, respectively.
(3) PMN in the BALF were quantified by automated hematology analyzer.
(4) Lung myeloperoxidase (MPO) activity, levels of lung arachidonic acid (AA), prostaglandin I2(PGI2), thromboxane A2(TXA2) and leukotrienes B4(LTB4) were quantified by ELISA.
(5) Morphology and counts of clara cell were performed by electron microscope.
(6) Lung histological change was observed by light microscope.
Result
1. One-lung ventilation (OLV) induced ALI animal model
Compared with those in S group, MPO activity and AA contents in lung tissues, PMN counts in BALF, lung W/D ratio and histopathologic score were increased in O group,T group and TF group (P<0.05).No difference was observed between T group and TF group., but all the indicators mentioned above in the two groups were lower than those in O group (P<0.05). No significant histopathologic changes were observed in S group except for mild capillary dilatation in some areas of the lung tissues. Serious hyperemia and hemorrhage in the lung tissues, thickening and exudation of alveolar wall, marked red blood cell and inflammatory cell infiltration in the alveolar space were found in O group. In both T group and TF group, pulmonary histopathologic changes alleviated significantly as compared with those in O group
2. Exfoliation of clara cell rabbit model
Lung W/D ratio and lung histopathologic score in NA group were the same as those in N A group, but the counts of clara cell in bronchioles and the levels of lung CCSP mRNA and protein expressions were decreased dramatically in NA group as compared with those in C group (P<0.05). No significant histopathologic changes were observed in the two groups, but the counts of clara cell in bronchioles and the secretory granules in clara cell of NA group were lower than those of C group under electron microscope.
3. Effects of sevoflurane on cytosolic phospholipaseA2and clara cell secretory protein in OLV-induced injured rabbit lung tissues
In both O group and OS group, pulmonary CCSP mRNA and protein expressions were significantly lower, while C-PLA2mRNA and protein expressions, lung W/D ratios and lung histopathologic scores were higher than those in the S group (P<0.05). Compared with O group,the OS group showed significantly increased expressions of CCSP mRNA and protein and reduced C-PLA2mRNA and protein expressions. In the4OLV+sevoflurane groups, CCSP underwent no significant changes as sevoflurane concentration increased,but C-PLAt mRNA and protein expressions, lung W/D ratios and lung histopathologic scores all decreased gradually as the concentrations of sevoflurane increased (P<0.05).No significant pathological changes were observed in the S group except for mild capillary dilatation in some areas of lung tissues.In the0group,the lung tissues presented with severe hyperemia and hemorrhage, alveolar wall thickening and exudation, with markedly red blood cell and inflammatory cell infiltration in alveolar space. These pathological changes above mentioned in lung tissues were alleviated gradually as the concentration of sevoflurane increased.
4. The role of clara cell secretory protein in the protective effects of sevoflurane against OLV-induced ALI
Compared with those in the S group, lung CCSP mRNA and protein expressions were decreased in all the other groups(P<0.05), while lung C-PLA2mRNA and protein expressions,the contents of lung AA, lung W/D ratio and histopathologic score were increased (P<0.05), except that those in the NA group; Lung CCSP mRNA and protein expressions in NA group were the same as those in the NAO Group and NAOS group, but were significant lower than those in the O group and OS group (P<0.05), while the other indicators were significant higher than those in the latter four groups(P<0.05). Compared with those in the O group, lung CCSP mRNA and protein expressions decreased significantly in the NAO group and NAOS groups(P<0.05),but increased significantly in the OS group(P<0.05),while the rest indicators were increased significantly in the OS and NAOS groups(P<0.05),but decreased significantly in NAO group(P<0.05). Except for the lung CCSP mRNA and protein expressions were significant lower(P<0.05), the rest indicators were significant higher in the NAO group than those in the OS group and NAOS groups (P <0.05). The levels of lung CCSP mRNA and protein expressions increased significantly,but the other indicators decreased significantly in the OS group as compared with those in the NOS group(P<0.05). No apparent pathologic changes were found in both S group and NA group. A large area of hyperemia and hemorrhage in lung tissues, thickening and exudation in alveolar wall, marked red blood cell and inflammatory cell infiltration in alveolar space were found in O group and the pathologic changes above-mentioned were further deterioration in the NAO group. In the OS group, scattered regions of hyperemia and hemorrhage spots, mild red blood cell and inflammatory cell infiltration in alveolar space and apparent incrassation and exudation in alveolar wall were found. Pathologic changes in NAOS group were aggravated apparently as compared with those in the OS group.
5. The effects of sevoflurane on AA metabolism COX2and5-LOX pathways in OLV-induced ALI
COX2and5-LOX mRNA and protein expressions and the contents of LTB4, TXA2and PGI2in the lungs, lung wet/dry(W/D) ratio and histopathologic score were significantly higher, while PGI2/TXA2ratio was significantly lower in O group and OS group than those in S group (P<0.05). Compared with those in O group, all the indicators above-mentioned were decreased significantly but PGI2/TXA2ratio was elevated markedly in OS group(P<0.05). No significant histopathologic changes were observed in S group except for mild capillary dilatation in some areas of the lung tissues. Serious hyperemia and hemorrhage in the lung tissues, thickening and exudation of alveolar wall, marked red blood cell and inflammatory cell infiltration in the alveolar space were found in O group. These pulmonary histopathologic changes were alleviated significantly in OS group.
Conclusion
1. Combined the right mainstem bronchial intubation with parasternal fenestration can be used to construct rabbit model of OLV-induced ALI.
2. OLV induced ALI may be associated with the increased expressions of C-PLA2by downregulating the expression of CCSP, and the activations of COX2and5-LOX pathways to result in increased generation of arachidonic acid (AA) and its metabolities in injured rabbit lung tissues.
3. The protective effects of sevoflurane on OLV-induced ALI may be through the inhibition of C-PLA2expression by up-regulating the expression of CCSP or through other mechanisms to down-regulate the expression of C-PLA2.
4. Sevoflurane can produce protective effects against on OLV-induced ALI possibly by reducing AA metabolities and regulating PGI2/TXA2ratio via inhibition of COX2and5-LOX pathways.
5. Arachidonic acid generation and metabolism pathways in lung may be a novel avenues for therapeutic potential intervention of sevoflurane on OLV-induced ALI.
单肺通气(one-lungventilation,OLV)作为临床常用的机械通气模式,可引起急性肺损伤(acute lung injury,ALI)。因此,研究OLV发病机制,寻找和阐明抗OLV致肺损伤的药物及其作用机制是临床实际工作中亟待解决和研究的重点之一
研究证实,花生四烯酸(arachidonic acid.AA)及其代谢产物在肺损伤的发生发展中起着重要作用。但是,它们在OLV致AL1中的作用并不十分清楚。
七氟醚(Sevoflurane)为临床常用挥发性麻醉药,被发现具有抗OLV致肺损伤保护作用,但其抗OLV致肺损伤作用机制是否与影响AA及其代谢产物的生成有关,未见报道。
因而,本研究旨在从AA生成和代谢关键酶途径研究OLV致ALI和七氟醚抗OLV致ALI保护作用机制,为临床防治单肺通气致肺损伤寻找药物作用的新干预途径提供一定的实验依据。
[研究方法]
1.实验分组
1.1单肺通气致急性肺损伤动物模型的建立
采用右主支气管内插管+胸骨旁开窗术,建立单肺通气致急性肺损伤动物模型。24只日本大耳白兔随机分组(n=6)为：①假手术组(S组)；②双肺通气组(T组)；③双肺通气+胸骨旁开窗术组(TF组)和④单肺通气组(O组)。
1.2Clara细胞剥除动物模型的建立
采用萘气吸入法建立Clara细胞剥除动物模型。随机将12只日本大耳白兔分组(n=6)为：①对照组(C组)和②萘气吸入组(NA组),连续吸入萘气(100mg/L)12h。
1.3七氟醚抗单肺通气致肺损伤作用机制研究方法
实验动物随机分组：①假手术组(S组)；②单肺通气组(O组)；③单肺通气+七氟醚组(OS组),OS组又按所给七氟醚浓度的不同分为1vo1%、2vo1%、3vol%和4vo1%浓度亚组：④Clara细胞剥除假手术组(NA组)；⑤Clara细胞剥除+单肺通气组(NAO组)和⑥Clara细胞剥除+单肺通气+七氟醚组(NAOS组)：每组n=6。
2.各项观察指标
(1)显微镜观察肺组织形态学改变,同时进行肺组织病理学评分；
(2)电镜观察肺细支气管Clara细胞形态学变化并计数；
(3)测定肺湿／干(wet/dry,W/D)比值；
(4) ELISA测定肺组织髓过氧化物酶(myeloperoxidase, MPO)活性,肺组织花生四烯酸(AA)、前列环素(prostacyclin,Prostaglandin i2, PGI2)、血栓素A2(thromboxane A2. TXA2)及白三烯B4(leukotrienes B4. LTB4)含量；
(5)计数支气管肺泡灌洗液(bronchoalveolar lavage fluid, BALF)中多形核白细胞(polymorphonuclear leukocyte, PMN)数量：
(6) Western-blot和定量RT-PCR分别检测肺组织Clara细胞分泌蛋白(clara cell secretory protein, CCSP)、胞质型磷脂酶A2(cytosolic phospholipase A2.C-PLA2)、环氧化酶-2(cyclooxygenase-2, COX2)和5-脂氧化酶(5-lipoxygenase,5-LOX)蛋白及其各自mRNA表达水平。
[结果]
第一部分动物模型的建立
1.1单肺通气致急性肺损伤动物模型的建立
与S组相比,O组、T组和TF组动物BALF中PMN计数,肺组织AA含量、MPO活性,肺W/D比值和肺组织病理学评分均明显增高(P<0.05)；TF组和T组动物的上述各项指标无显著性差异,但均显著低于O组(P<0.05)；光镜观察：S组动物肺组织未见明显病理学改变；T组和TF组动物肺组织可见散在充血、出血灶,肺泡腔少量红细胞和炎细胞浸润,肺泡壁略增厚；0组动物肺组织大面积充血、出血,肺泡腔内有较多红细胞和炎细胞浸润,肺泡壁广泛充血、增厚和渗出。
1.2Clara细胞剥除动物模型的建立
与C组相比,NA组动物肺组织CCSP mRNA和蛋白表达水平及细支气管Clara细胞计数显著降低(P<0.05),但两组间肺W/D比值和肺组织病理学评分无显著性差异。光镜观察：两组实验动物肺组织除部分区域见毛细血管扩张充血外,均未见明显病理改变。电镜观察：C组动物细支气管Clara细胞内含有较多分泌颗粒,而NA组动物细支气管内clara细胞数量明显减少且呈空泡样变性,其内未见明显分泌颗粒。
第二部分七氟醚抗单肺通气致肺损伤作用机制
2.1从花生四烯酸的胞质型磷脂酶A2(C-PLA2)生成途径研究
2.1.1七氟醚对单肺通气致急性肺损伤兔肺组织CCSP及C-PLA2表达的影响
与S组相比,O组和OS组兔肺组织CCSP mRNA和蛋白表达水平明显降低(P<0.05),肺组织C-PLA2mRNA和蛋白表达水平、AA含量、肺W/D比值及肺组织病理学评分均明显升高(P<0.05)；与O组相比,OS组动物肺组织CCSP mRNA和蛋白表达水平明显增高(P<0.05),而肺组织C-PLA2mRNA和蛋白表达水平、肺组织AA含量及病理学评分显著下降(P<0.05)；OS组不同浓度七氟醚兔肺组织CCSP mRNA和蛋白表达水平均无显著性差异,但随着七氟醚浓度的增加OS组肺组织C-PLA2mRNA和蛋白表达水平、肺组织AA含量、肺W/D比值及肺组织病理学评分逐渐降低(P<0.05)。光镜观察：S组动物肺组织除部分区域见毛细血管扩张外,无明显病理改变；O组动物肺组织可见大量出血、充血灶,肺泡腔内较多红细胞和炎症细胞浸润,肺泡壁明显充血、增厚和渗出；随七氟醚浓度增加,OS组动物肺组织上述病理形态学改变逐渐减轻。
2.1.2CCSP在七氟醚抗单肺通气致急性肺损伤中的作用
与S组相比,其它各组动物肺组织CCSP mRNA和蛋白表达水平均明显降低(P<0.05),肺组织C-PLA2mRNA和蛋白表达水平、AA含量、肺W/D比值和肺组织病理学评分除在NA组无显著差异外,其余各组均明显升高(P<0.05)；与NA组相比,NAO组和NAOS组肺组织CCSP mRNA和蛋白表达水平无显著差异(P>0.05),而O组和OS组明显增高(P<0.05)；与O组相比,肺组织CCSP mRNA和蛋白表达水平在OS组明显增高(P<0.05),在NAO和NAOS组明显降低(P<0.05),但肺组织C-PLA2mRNA和蛋白表达水平、肺组织AA含量、肺W/D比值及肺组织病理学评分在OS组和NAOS组中均明显降低(P<0.05),在NAO组明显增高(P<0.05)：与OS组相比,NAO组和NAOS组动物肺组织CCSP mRNA和蛋白表达水平明显降低(P<0.05),但其余各指标均明显升高(P<0.05)。与NAO组相比,NAOS组动物肺组织CCSP mRNA和蛋白表达水平无明显差异,其余各指标均明显降低(P<0.05)。光镜观察：S组和NA组动物肺组织未见明显病理形态学改变：O组动物肺组织可见大量出血、充血灶,肺泡腔内较多红细胞和炎症细胞浸润,肺泡壁明显充血、增厚和渗出；NAO组动物肺组织上述病理形态学改变进一步加重；OS组肺组织散在小范围充血、出血灶,肺泡腔内散在红细胞和炎细胞浸润,肺泡壁明显增厚、渗出；NAOS组动物肺组织病理改变与OS组类似,但明显加重。
2.2从花生四烯酸的COX2和5-LOX代谢途径研究
与S组相比,O组和OS组动物肺组织COX2蛋白、COX2mRNA和5-LOX蛋白、5-LOX mRNA表达水平,肺组织PGI2、LTB4和TXA2含量,肺W/D比值及肺组织病理学评分均明显升高(P<0.05),肺组织PGI2/TXA2比值明显降低(P<0.05)。与O组相比,OS组动物肺组织PGI2/TXA2比值明显升高(P<0.05),而其余指标均明显降低(P<0.05)。S组动物肺组织除部分区域见毛细血管扩张充血外,未见明显病理改变。O组肺组织可见大量出血、充血灶,肺泡腔内较多红细胞和炎症细胞浸润,可见肺泡壁明显充血、增厚和渗出；OS组肺组织散在小范围充血、出血灶,肺泡腔内散在红细胞和炎细胞浸润,肺泡壁增厚。
结论
1.右主支气管内插管联合胸骨旁开窗术可用于构建兔单肺通气致急性肺损伤动物模型。
2.单肺通气可诱发急性肺损伤,其机制可能与下调肺组织CCSP mRNA和蛋白表达,从而削弱了其对C-PLA2的抑制作用,以及激活AA代谢COX2和5-LOX途径,使得AA及其代谢产物大量生成有关。
3.七氟醚抗单肺通气致急性肺损伤作用可能与通过或不通过促进肺组织CCSP的表达而抑制肺内AA生成的C-PLA2途径,减少肺组织AA的生成有关。
4.七氟醚可通过调控肺内AA的COX2和5-LOX代谢途径发挥抗单肺通气致ALI作用,其机制可能与下调COX2和5-LOX表达,减少AA代谢产物的生成和调控PGI2/TXA2比值有关。
5.肺内花生四烯酸生成和代谢途径可能是七氟醚抗单肺通气致急性肺损伤作用新的潜在干预途径。
Background and Objective
Studies have shown that, as a widely used mechanical ventilation mode, one-lung ventilation (OLV) can result in acute lung injury (ALI). Therefore, to investigate the mechanisms of ALI induced by OLV and to unravell the preventive and therapeutic effects of drugs on OLV-induced ALI are currently areas of intense investigation.
Sevoflurane, a commonly used clinical anesthetic, is considered to possess protective effects on OLV-induced ALI by inhibition of inflammatory response. However, its protective mechanisms are still unclear. Studies showed that arachidonic acid (AA) and its metabolites play an important role in the development of lung injury. Thus, the purpose of this study is to investigate the effects of sevoflurane on OLV-induced ALI from arachidonic acid metabolic pathways to present novel avenues for therapeutic intervention.
Methods
1. Animal grouping
(1) OLV-induced ALI animal model
OLV-induced ALI rabbit model was constructed by right mainstem bronchial intubation with parasternal fenestration. Totally24healthy Japanese white rabbits were randomly divided into4groups(n=6):①sham operated group(S group);②two-lung ventilation(TLV) group (T group);③TLV with parasternal fenestration group (TF group) and④OLV group (O group).
(2) Exfoliation of clara cell rabbit model
12healthy Japanese white rabbits were randomized into two groups (n=6): control group(C group),and naphthalene vapor (100mg/L,12h) inhaled group (NA group).
(3) The protective mechanisms of sevoflurane on OLV-induced ALI
Healthy Japanese white rabbits were randomized into groups as follows:①sham operated group (S group);②OLV group (O group);③OLV+sevoflurane group (OS group). The OS group was divided into4subgroups with different concentrations of sevoflurane(lvol%,2vol%,3vol%and4vol%respectively);④inhaled naphthalene vapor group (NA group);⑤inhaled naphthalene vapor before OLV group; and⑥inhaled naphthalene vapor before OLV+sevoflurane group (n=6).
2. Detection indcators and methods
(1) Histological scores and lung wet/dry weight (W/D) ratios were determined for lung injury assessment.
(2) Expressions of lung CCSP, C-PLA2, COX2and5-LOX proteins and their homologous mRNAs were detected by western-blotting and real time-PCR, respectively.
(3) PMN in the BALF were quantified by automated hematology analyzer.
(4) Lung myeloperoxidase (MPO) activity, levels of lung arachidonic acid (AA), prostaglandin I2(PGI2), thromboxane A2(TXA2) and leukotrienes B4(LTB4) were quantified by ELISA.
(5) Morphology and counts of clara cell were performed by electron microscope.
(6) Lung histological change was observed by light microscope.
Result
1. One-lung ventilation (OLV) induced ALI animal model
Compared with those in S group, MPO activity and AA contents in lung tissues, PMN counts in BALF, lung W/D ratio and histopathologic score were increased in O group,T group and TF group (P<0.05).No difference was observed between T group and TF group., but all the indicators mentioned above in the two groups were lower than those in O group (P<0.05). No significant histopathologic changes were observed in S group except for mild capillary dilatation in some areas of the lung tissues. Serious hyperemia and hemorrhage in the lung tissues, thickening and exudation of alveolar wall, marked red blood cell and inflammatory cell infiltration in the alveolar space were found in O group. In both T group and TF group, pulmonary histopathologic changes alleviated significantly as compared with those in O group
2. Exfoliation of clara cell rabbit model
Lung W/D ratio and lung histopathologic score in NA group were the same as those in N A group, but the counts of clara cell in bronchioles and the levels of lung CCSP mRNA and protein expressions were decreased dramatically in NA group as compared with those in C group (P<0.05). No significant histopathologic changes were observed in the two groups, but the counts of clara cell in bronchioles and the secretory granules in clara cell of NA group were lower than those of C group under electron microscope.
3. Effects of sevoflurane on cytosolic phospholipaseA2and clara cell secretory protein in OLV-induced injured rabbit lung tissues
In both O group and OS group, pulmonary CCSP mRNA and protein expressions were significantly lower, while C-PLA2mRNA and protein expressions, lung W/D ratios and lung histopathologic scores were higher than those in the S group (P<0.05). Compared with O group,the OS group showed significantly increased expressions of CCSP mRNA and protein and reduced C-PLA2mRNA and protein expressions. In the4OLV+sevoflurane groups, CCSP underwent no significant changes as sevoflurane concentration increased,but C-PLAt mRNA and protein expressions, lung W/D ratios and lung histopathologic scores all decreased gradually as the concentrations of sevoflurane increased (P<0.05).No significant pathological changes were observed in the S group except for mild capillary dilatation in some areas of lung tissues.In the0group,the lung tissues presented with severe hyperemia and hemorrhage, alveolar wall thickening and exudation, with markedly red blood cell and inflammatory cell infiltration in alveolar space. These pathological changes above mentioned in lung tissues were alleviated gradually as the concentration of sevoflurane increased.
4. The role of clara cell secretory protein in the protective effects of sevoflurane against OLV-induced ALI
Compared with those in the S group, lung CCSP mRNA and protein expressions were decreased in all the other groups(P<0.05), while lung C-PLA2mRNA and protein expressions,the contents of lung AA, lung W/D ratio and histopathologic score were increased (P<0.05), except that those in the NA group; Lung CCSP mRNA and protein expressions in NA group were the same as those in the NAO Group and NAOS group, but were significant lower than those in the O group and OS group (P<0.05), while the other indicators were significant higher than those in the latter four groups(P<0.05). Compared with those in the O group, lung CCSP mRNA and protein expressions decreased significantly in the NAO group and NAOS groups(P<0.05),but increased significantly in the OS group(P<0.05),while the rest indicators were increased significantly in the OS and NAOS groups(P<0.05),but decreased significantly in NAO group(P<0.05). Except for the lung CCSP mRNA and protein expressions were significant lower(P<0.05), the rest indicators were significant higher in the NAO group than those in the OS group and NAOS groups (P <0.05). The levels of lung CCSP mRNA and protein expressions increased significantly,but the other indicators decreased significantly in the OS group as compared with those in the NOS group(P<0.05). No apparent pathologic changes were found in both S group and NA group. A large area of hyperemia and hemorrhage in lung tissues, thickening and exudation in alveolar wall, marked red blood cell and inflammatory cell infiltration in alveolar space were found in O group and the pathologic changes above-mentioned were further deterioration in the NAO group. In the OS group, scattered regions of hyperemia and hemorrhage spots, mild red blood cell and inflammatory cell infiltration in alveolar space and apparent incrassation and exudation in alveolar wall were found. Pathologic changes in NAOS group were aggravated apparently as compared with those in the OS group.
5. The effects of sevoflurane on AA metabolism COX2and5-LOX pathways in OLV-induced ALI
COX2and5-LOX mRNA and protein expressions and the contents of LTB4, TXA2and PGI2in the lungs, lung wet/dry(W/D) ratio and histopathologic score were significantly higher, while PGI2/TXA2ratio was significantly lower in O group and OS group than those in S group (P<0.05). Compared with those in O group, all the indicators above-mentioned were decreased significantly but PGI2/TXA2ratio was elevated markedly in OS group(P<0.05). No significant histopathologic changes were observed in S group except for mild capillary dilatation in some areas of the lung tissues. Serious hyperemia and hemorrhage in the lung tissues, thickening and exudation of alveolar wall, marked red blood cell and inflammatory cell infiltration in the alveolar space were found in O group. These pulmonary histopathologic changes were alleviated significantly in OS group.
Conclusion
1. Combined the right mainstem bronchial intubation with parasternal fenestration can be used to construct rabbit model of OLV-induced ALI.
2. OLV induced ALI may be associated with the increased expressions of C-PLA2by downregulating the expression of CCSP, and the activations of COX2and5-LOX pathways to result in increased generation of arachidonic acid (AA) and its metabolities in injured rabbit lung tissues.
3. The protective effects of sevoflurane on OLV-induced ALI may be through the inhibition of C-PLA2expression by up-regulating the expression of CCSP or through other mechanisms to down-regulate the expression of C-PLA2.
4. Sevoflurane can produce protective effects against on OLV-induced ALI possibly by reducing AA metabolities and regulating PGI2/TXA2ratio via inhibition of COX2and5-LOX pathways.
5. Arachidonic acid generation and metabolism pathways in lung may be a novel avenues for therapeutic potential intervention of sevoflurane on OLV-induced ALI.
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