整合素αVβ3在机械通气性肺损伤中的作用及机制
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摘要
目的机械通气是呼吸衰竭患者不可缺少的生命支持手段,也是手术患者常用的呼吸管理方法,而机械通气性肺损伤(ventilator induced lung injury, VILI)是机械通气的常见并发症,影响机械通气的治疗效果。尽管肺保护通气策略(小潮气量机械通气)能减少VILI的发生,但为了保证足够的气体交换潮气量的减少常常受到限制,因此寻求VILI有效的药物预防仍有重要意义。VILI的主要病理基础是肺泡炎症及肺泡毛细血管通透性增加,但具体机制还不清楚。因此,本研究拟观察SD大鼠VILI过程中肺泡炎症反应、整合素αVβ3、核转录因子(nuclear factor kappa B, NF-κB)的活性,以及人工合成RGDS肽(非特异性整合素受体阻断剂)对机械通气导致的αVβ3、NF-κB活性变化的影响,以期阐明整合素αVβ3介导的NF-κB通路在肺泡炎症中的作用。同时,建立人肺微血管内皮细胞(human pulmonary microvascular,HPMVEC)的机械牵拉模型,观察机械牵拉对HPMVEC单层通透性及整合素αVβ3活性的影响,并分析两者的关系,以期阐明整合素αVβ3在肺泡毛细血管通透性中的作用。从而最终明确整合素αVβ3在VILI中的作用及相关机制,为VILI的防治寻求新的靶点。
方法
动物实验:21只雄性SD(Sprague Dawley)成年大鼠随机分为3组(n=7):对照组(Control组),大潮气量机械通气组(H_(VT)组);RGDS肽预处理组(H_(VT)+RGDS组)。各组大鼠麻醉后气管切开插管,Control组大鼠自主呼吸4 h;H_(VT)组大鼠行机械通气,潮气量35 ml/kg,呼吸频率50次/min;H_(VT)+RGDS组在机械通气前30 min给予整合素受体阻断剂RGDS肽5 mg/kg腹腔注射,机械通气参数设定同H_(VT)组。机械通气4 h后放血处死大鼠,收集支气管肺泡灌洗液(bronchoalveolar lavage ?uid,BALF)和肺组织。BALF经离心分别收集上清和沉淀,用酶联免疫吸附实验(enzyme-linked immunosorbent assays, ELISA)检测上清中肿瘤坏死因子α(tumor necrosis factor alpha, TNF-α)、白细胞介素-6(interleukin-6, IL-6)的浓度,用BAC( bicinchoninic acid)蛋白检测试剂盒检测上清中总蛋白的浓度;BALF沉淀用于有核细胞计数,并通过细胞涂片的瑞氏染色对有核细胞进行分类。左肺组织行苏木精-伊红(hematoxylin-eosin, HE)染色观察肺组织病理变化;右肺组织提取总蛋白并用蛋白质免疫印迹(Western Blot)方法测定整合素αVβ3、NF-κB抑制蛋白(I-κB)的表达以及其磷酸化水平。
细胞实验:购买HPMVEC细胞株进行培养传代,4～8代细胞用于实验。实验分为3组:对照组(Control组);机械牵拉组(Stretch组);ML9预处理组(Stretch+ML9组)。Control组细胞静态培养在培养箱内,不给予机械牵拉;Stretch组细胞给予机械牵拉刺激2 h;Stretch+ML9组细胞于机械牵拉前给予肌球蛋白轻链激酶抑制剂ML9预处理(50μM,2 h)。用磁扭力刺激(magnetic twisting stimulation, MTS)对单层内皮细胞实施机械牵拉。用Transwell模型及异硫氰酸荧光素标记的右旋糖苷(fluorescrin isothiocyanate marked dextran, FITC-dextran)溶液检测单层细胞通透性,右旋糖苷通过单层内皮细胞的多少代表单层细胞通透性,用光密度(optical density, OD)表示;用磁扭力细胞仪(magnetic twisting cytometry, MTC)检测细胞间拉力;用免疫荧光染色检测整合素αVβ3和肌动蛋白的分布;用Western Blot方法检测整合素αVβ3的表达。
计量资料用均数±标准差表示。采用SPSS12.0统计软件进行方差分析(ANOVA),P值小于0.05为差异有显著性。
结果
动物实验:(1)Control组大鼠无明显的病理改变,而H_(VT)组肺组织病理变化明显,包括炎症细胞浸润、肺泡水肿以及肺泡结构破坏,而H_(VT)+RGDS组的肺组织病理变化较H_(VT)组明显减轻;(2)与Control组比较,H_(VT)组支气管肺泡灌洗液中多核细胞、单核细胞数量和总蛋白浓度明显增高;与H_(VT)组比较,H_(VT)+RGDS组支气管肺泡灌洗液中多核细胞、单核细胞及总蛋白明显减少(P<0.05);(3)与Control组比较,H_(VT)组支气管肺泡灌洗液中IL-6,TNF-α浓度明显增加;与H_(VT)组比较,H_(VT)+RGDS组支气管肺泡灌洗液中IL-6,TNF-α浓度明显减少(P<0.05);(4)与Control组比较,H_(VT)组肺组织整合素αVβ3、I-κB磷酸化明显增加;与H_(VT)组比较,H_(VT)+RGDS组肺组织整合素αVβ3、I-κB磷酸化明显减少(P<0.05)。
细胞实验:(1)与Control组比较,Stretch组的通透性明显增加(P<0.05),而Stretch+ML9组通透性无明显变化;(2)Control组细胞肌动蛋白主要分布在细胞周边,而Stretch组细胞浆内可见明显的应力纤维形成,Stretch+ML9组肌动蛋白的分布与Control组相似(;3)Control组细胞整合素αVβ3均匀分布在细胞表面;而Stretch组细胞的整合素αVβ3明显簇积;Stretch+ML9组细胞整合素αVβ3的分布与Control组相似;(4)与Control组比较,Stretch组细胞间拉力明显增加(P<0.05),而Stretch+ML9组无明显改变。
结论(1)整合素αVβ3活化参与VILI的炎症反应及毛细血管通透性增加;(2)整合素αVβ3介导的NF-κB活化是VILI炎症反应的机制之一;(3)整合素αVβ3簇积及应力纤维形成导致的细胞间拉力增加是VILI毛细血管通透性增加的可能机制; (4)抑制整合素活性可望成为VILI新的防治手段。
Objective Mechanical ventilation (MV) is a necessary supportive method for patients with respiratory failure without alternatives, it is also a common way to manage respiration during anesthesia and operations. However, ventilator induced lung injury (VILI) is a common complication of MV and aggravates previous lung injury. Although lung protective MV with low tidal volume (VT) can attenuate lung injury degree of VILI, it is still needed to find effective adjuvant pharmacological therapy for prevention from VILI in addition to lung protective ventilation because the necessity to guarantee sufficient gas exchange frequently limits a further substantial reduction of tidal volumes. The main pathology of VILI is alveolar inflammation response and hyperpermeability of pulmonary capillary, but the mechanism is not clear yet. Therefore, model of rats exposed to mechanical ventilation with high VT was constructed to investigate alveolar inflammation and activation of integrinαVβ3 and nuclear factor kappa B (NF-κB), and effect of synthesized RGDS peptide (non-specific blocker of integrins) on activation of integrinαVβ3 and inhibitor of NF-κB (I-κB), and then to evaluate the role of integrinαVβ3 mediated NF-κB activation in alveolar inflammation of VILI in rats. In addition, model of human pulmonary microvascular endothelial cells (HPMVEC) exposed to mechanical stretch was constructed to investigate the effect of mechanical stretch on monolayer permeability and integrinαVβ3 activity, and to analyze the relationship between integrinαVβ3 activity and monolayer permeability, and then to assess the effect of integrinαVβ3 in endothelium permeability. Taken all together, this study is aimed to discover the role of integrinαVβ3 in the development of VILI and its underlying mechanism, and to find a new target of prevention from VILI.
Methods
Animal experiment: Anesthetized and intratracheal intubation male Sprague Dawley (SD) rats were randomly divided into 3 groups: control group (Control), mechanical ventilating with high tidal volume (H_(VT)) group, RGDS pretreatment group (H_(VT) +RGDS). Each group had 7 rats. Rats kept spontaneous respiration in Control group; rats in H_(VT) group were mechanical ventilated with high tidal volme of 35 ml/kg and frequency of 50 per minutes; rats in H_(VT) +RGDS group were pretreated with RGDS peptide 5 mg/kg, i.p. 30 min before mechanical ventilation, and the parameters of mechanical ventilation were as same as H_(VT) group. Rats were killed after 4 h mechanical ventilation, and bronchoalveolar lavaged fluid (BALF) and lung tissues were collected. BALF was centrifuged to get supernant and deposit. Cytokines of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) in supernant were detected with enzyme linked immunoabsorbance assay (ELISA); total protein in supernant was detected with bicinchoninic acid (BCA) protein assay kit. Cell counts and classification were examined with deposit slides and Wright’s staining. Pathological changes of lung tissue were detected with hematoxylin and eosin (HE) staining; expression of integrinαVβ3, I-κB and their phosphataion were detected with Western Blot.
Cellular experiment: Primary HPMVEC were purchased and passaged, and the passages 4 to 8 were used in this study. Cells were randomly divided into 3 groups: control group (group Control), mechanical stretching group (group Streth), and ML9 pretreatment group (group Stretch+ML9). Cells in group Control were cultured in static condition without mechanical stretch; cells in group Stretch were exposed to mechanical stretch for 2 h; cells in group Stretch+ML9 were pretreated with 50μM ML9 2 h before mechanical stretch. Mechanical stretch was produced with magnetic twisting stimulation (MTS); monolayer permeability was examined with fluorescein isothiocyanate marked dextran (FITC-dextran) in Transwell model, permeability was evaluated by the quantity of dextran through monolayer HPMVEC and expressed as optical density (OD); distribution of integrinαVβ3 and actin was investigated by immunofluorescence staining; expression of integrinαVβ3 was detected with Western Blot; intracellular tension was measured with magnetic twisting cytometry (MTC).
All data were expressed as mean±S.D. (standard deviation), difference was tested by ANOVA with SPSS software,P values less than or equal to 0.05 was considered significant.
Results
Animal experiment: (1) There was no pathological changes in lung tissues of Control group; in, significant pathological changes in lung tissue was observed including leukocyte recruitment, alveolar edema and structure damage of alveolar; the pathological changes in lung tissue of H_(VT)+RGDS group was less than H_(VT) group. (2) Compared with Control group, polynuclear cells, mononuclear cells and total protein in BALF increased significantly in H_(VT) group; compared with H_(VT) group, they decreased significantly in H_(VT)+RGDS group (P<0.05). (3) Compared with Control group, IL-6 and TNF-αin BALF increased significantly in H_(VT) group; compared with H_(VT) group, they decreased significantly in H_(VT)+RGDS group (P<0.05). (4) Compared with Control group, phosphorylation of integrinαVβ3 and NF-κB in lung tissues increased significantly in H_(VT) group; compared with H_(VT) group, they decreased significantly in H_(VT)+RGDS group (P<0.05).
Cellular experiment: (1) Compared with Control group, permeability of monolayer HPMVEC increased significantly in Stretch group (P<0.05), while no significant change was observed in Stretch+ML9 group. (2) Actin was distributed at the border of HPMVEC in control group; in Stretch group, actin polymerized into stress fiber in plasma; in Stretch+ML9 group, actin distributed similarly with Control group. (3) IntegrinαVβ3 distributed evenly on the HPMVEC surface in Control group, while integrinαVβ3 clustered significantly in Stretch group, and its clustering decreased in Stretch+ML9 group. (4) Compared with Control group, intracellular tension increased significantly in Stretch group (P<0.05), while no significant change was observed in Stretch+ML9 group.
Conclusions (1) IntegrinαVβ3 activation takes part in pulmonary inflammation response and hyperpermeability of capillary in VILI. (2) IntegrinαVβ3 mediated NF-κB activation is one of the mechanisms of pulmonary inflammation in VILI. (3) Stress fiber formation and integrinαVβ3 clustering may be the mechanism of mechanical stretch induced monolayer hyperpermeability in HPMVEC. (4) It is a promising method to inhibit integrin activity for prevention of VILI.
方法
动物实验:21只雄性SD(Sprague Dawley)成年大鼠随机分为3组(n=7):对照组(Control组),大潮气量机械通气组(H_(VT)组);RGDS肽预处理组(H_(VT)+RGDS组)。各组大鼠麻醉后气管切开插管,Control组大鼠自主呼吸4 h;H_(VT)组大鼠行机械通气,潮气量35 ml/kg,呼吸频率50次/min;H_(VT)+RGDS组在机械通气前30 min给予整合素受体阻断剂RGDS肽5 mg/kg腹腔注射,机械通气参数设定同H_(VT)组。机械通气4 h后放血处死大鼠,收集支气管肺泡灌洗液(bronchoalveolar lavage ?uid,BALF)和肺组织。BALF经离心分别收集上清和沉淀,用酶联免疫吸附实验(enzyme-linked immunosorbent assays, ELISA)检测上清中肿瘤坏死因子α(tumor necrosis factor alpha, TNF-α)、白细胞介素-6(interleukin-6, IL-6)的浓度,用BAC( bicinchoninic acid)蛋白检测试剂盒检测上清中总蛋白的浓度;BALF沉淀用于有核细胞计数,并通过细胞涂片的瑞氏染色对有核细胞进行分类。左肺组织行苏木精-伊红(hematoxylin-eosin, HE)染色观察肺组织病理变化;右肺组织提取总蛋白并用蛋白质免疫印迹(Western Blot)方法测定整合素αVβ3、NF-κB抑制蛋白(I-κB)的表达以及其磷酸化水平。
细胞实验:购买HPMVEC细胞株进行培养传代,4～8代细胞用于实验。实验分为3组:对照组(Control组);机械牵拉组(Stretch组);ML9预处理组(Stretch+ML9组)。Control组细胞静态培养在培养箱内,不给予机械牵拉;Stretch组细胞给予机械牵拉刺激2 h;Stretch+ML9组细胞于机械牵拉前给予肌球蛋白轻链激酶抑制剂ML9预处理(50μM,2 h)。用磁扭力刺激(magnetic twisting stimulation, MTS)对单层内皮细胞实施机械牵拉。用Transwell模型及异硫氰酸荧光素标记的右旋糖苷(fluorescrin isothiocyanate marked dextran, FITC-dextran)溶液检测单层细胞通透性,右旋糖苷通过单层内皮细胞的多少代表单层细胞通透性,用光密度(optical density, OD)表示;用磁扭力细胞仪(magnetic twisting cytometry, MTC)检测细胞间拉力;用免疫荧光染色检测整合素αVβ3和肌动蛋白的分布;用Western Blot方法检测整合素αVβ3的表达。
计量资料用均数±标准差表示。采用SPSS12.0统计软件进行方差分析(ANOVA),P值小于0.05为差异有显著性。
结果
动物实验:(1)Control组大鼠无明显的病理改变,而H_(VT)组肺组织病理变化明显,包括炎症细胞浸润、肺泡水肿以及肺泡结构破坏,而H_(VT)+RGDS组的肺组织病理变化较H_(VT)组明显减轻;(2)与Control组比较,H_(VT)组支气管肺泡灌洗液中多核细胞、单核细胞数量和总蛋白浓度明显增高;与H_(VT)组比较,H_(VT)+RGDS组支气管肺泡灌洗液中多核细胞、单核细胞及总蛋白明显减少(P<0.05);(3)与Control组比较,H_(VT)组支气管肺泡灌洗液中IL-6,TNF-α浓度明显增加;与H_(VT)组比较,H_(VT)+RGDS组支气管肺泡灌洗液中IL-6,TNF-α浓度明显减少(P<0.05);(4)与Control组比较,H_(VT)组肺组织整合素αVβ3、I-κB磷酸化明显增加;与H_(VT)组比较,H_(VT)+RGDS组肺组织整合素αVβ3、I-κB磷酸化明显减少(P<0.05)。
细胞实验:(1)与Control组比较,Stretch组的通透性明显增加(P<0.05),而Stretch+ML9组通透性无明显变化;(2)Control组细胞肌动蛋白主要分布在细胞周边,而Stretch组细胞浆内可见明显的应力纤维形成,Stretch+ML9组肌动蛋白的分布与Control组相似(;3)Control组细胞整合素αVβ3均匀分布在细胞表面;而Stretch组细胞的整合素αVβ3明显簇积;Stretch+ML9组细胞整合素αVβ3的分布与Control组相似;(4)与Control组比较,Stretch组细胞间拉力明显增加(P<0.05),而Stretch+ML9组无明显改变。
结论(1)整合素αVβ3活化参与VILI的炎症反应及毛细血管通透性增加;(2)整合素αVβ3介导的NF-κB活化是VILI炎症反应的机制之一;(3)整合素αVβ3簇积及应力纤维形成导致的细胞间拉力增加是VILI毛细血管通透性增加的可能机制; (4)抑制整合素活性可望成为VILI新的防治手段。
Objective Mechanical ventilation (MV) is a necessary supportive method for patients with respiratory failure without alternatives, it is also a common way to manage respiration during anesthesia and operations. However, ventilator induced lung injury (VILI) is a common complication of MV and aggravates previous lung injury. Although lung protective MV with low tidal volume (VT) can attenuate lung injury degree of VILI, it is still needed to find effective adjuvant pharmacological therapy for prevention from VILI in addition to lung protective ventilation because the necessity to guarantee sufficient gas exchange frequently limits a further substantial reduction of tidal volumes. The main pathology of VILI is alveolar inflammation response and hyperpermeability of pulmonary capillary, but the mechanism is not clear yet. Therefore, model of rats exposed to mechanical ventilation with high VT was constructed to investigate alveolar inflammation and activation of integrinαVβ3 and nuclear factor kappa B (NF-κB), and effect of synthesized RGDS peptide (non-specific blocker of integrins) on activation of integrinαVβ3 and inhibitor of NF-κB (I-κB), and then to evaluate the role of integrinαVβ3 mediated NF-κB activation in alveolar inflammation of VILI in rats. In addition, model of human pulmonary microvascular endothelial cells (HPMVEC) exposed to mechanical stretch was constructed to investigate the effect of mechanical stretch on monolayer permeability and integrinαVβ3 activity, and to analyze the relationship between integrinαVβ3 activity and monolayer permeability, and then to assess the effect of integrinαVβ3 in endothelium permeability. Taken all together, this study is aimed to discover the role of integrinαVβ3 in the development of VILI and its underlying mechanism, and to find a new target of prevention from VILI.
Methods
Animal experiment: Anesthetized and intratracheal intubation male Sprague Dawley (SD) rats were randomly divided into 3 groups: control group (Control), mechanical ventilating with high tidal volume (H_(VT)) group, RGDS pretreatment group (H_(VT) +RGDS). Each group had 7 rats. Rats kept spontaneous respiration in Control group; rats in H_(VT) group were mechanical ventilated with high tidal volme of 35 ml/kg and frequency of 50 per minutes; rats in H_(VT) +RGDS group were pretreated with RGDS peptide 5 mg/kg, i.p. 30 min before mechanical ventilation, and the parameters of mechanical ventilation were as same as H_(VT) group. Rats were killed after 4 h mechanical ventilation, and bronchoalveolar lavaged fluid (BALF) and lung tissues were collected. BALF was centrifuged to get supernant and deposit. Cytokines of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) in supernant were detected with enzyme linked immunoabsorbance assay (ELISA); total protein in supernant was detected with bicinchoninic acid (BCA) protein assay kit. Cell counts and classification were examined with deposit slides and Wright’s staining. Pathological changes of lung tissue were detected with hematoxylin and eosin (HE) staining; expression of integrinαVβ3, I-κB and their phosphataion were detected with Western Blot.
Cellular experiment: Primary HPMVEC were purchased and passaged, and the passages 4 to 8 were used in this study. Cells were randomly divided into 3 groups: control group (group Control), mechanical stretching group (group Streth), and ML9 pretreatment group (group Stretch+ML9). Cells in group Control were cultured in static condition without mechanical stretch; cells in group Stretch were exposed to mechanical stretch for 2 h; cells in group Stretch+ML9 were pretreated with 50μM ML9 2 h before mechanical stretch. Mechanical stretch was produced with magnetic twisting stimulation (MTS); monolayer permeability was examined with fluorescein isothiocyanate marked dextran (FITC-dextran) in Transwell model, permeability was evaluated by the quantity of dextran through monolayer HPMVEC and expressed as optical density (OD); distribution of integrinαVβ3 and actin was investigated by immunofluorescence staining; expression of integrinαVβ3 was detected with Western Blot; intracellular tension was measured with magnetic twisting cytometry (MTC).
All data were expressed as mean±S.D. (standard deviation), difference was tested by ANOVA with SPSS software,P values less than or equal to 0.05 was considered significant.
Results
Animal experiment: (1) There was no pathological changes in lung tissues of Control group; in, significant pathological changes in lung tissue was observed including leukocyte recruitment, alveolar edema and structure damage of alveolar; the pathological changes in lung tissue of H_(VT)+RGDS group was less than H_(VT) group. (2) Compared with Control group, polynuclear cells, mononuclear cells and total protein in BALF increased significantly in H_(VT) group; compared with H_(VT) group, they decreased significantly in H_(VT)+RGDS group (P<0.05). (3) Compared with Control group, IL-6 and TNF-αin BALF increased significantly in H_(VT) group; compared with H_(VT) group, they decreased significantly in H_(VT)+RGDS group (P<0.05). (4) Compared with Control group, phosphorylation of integrinαVβ3 and NF-κB in lung tissues increased significantly in H_(VT) group; compared with H_(VT) group, they decreased significantly in H_(VT)+RGDS group (P<0.05).
Cellular experiment: (1) Compared with Control group, permeability of monolayer HPMVEC increased significantly in Stretch group (P<0.05), while no significant change was observed in Stretch+ML9 group. (2) Actin was distributed at the border of HPMVEC in control group; in Stretch group, actin polymerized into stress fiber in plasma; in Stretch+ML9 group, actin distributed similarly with Control group. (3) IntegrinαVβ3 distributed evenly on the HPMVEC surface in Control group, while integrinαVβ3 clustered significantly in Stretch group, and its clustering decreased in Stretch+ML9 group. (4) Compared with Control group, intracellular tension increased significantly in Stretch group (P<0.05), while no significant change was observed in Stretch+ML9 group.
Conclusions (1) IntegrinαVβ3 activation takes part in pulmonary inflammation response and hyperpermeability of capillary in VILI. (2) IntegrinαVβ3 mediated NF-κB activation is one of the mechanisms of pulmonary inflammation in VILI. (3) Stress fiber formation and integrinαVβ3 clustering may be the mechanism of mechanical stretch induced monolayer hyperpermeability in HPMVEC. (4) It is a promising method to inhibit integrin activity for prevention of VILI.
引文
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