地昔帕明对小鼠内毒素急性肺损伤的影响
摘要
急性呼吸窘迫综合征(ARDS)是临床常见危重疾病,发病机制尚未完全阐明,急性肺损伤(ALI)是ARDS的早期阶段,脂多糖(LPS)引起的脓毒症是引起ALI/ARDS的重要原因之一。药物治疗是ALI治疗的重要手段之一,但当前临床用于治疗ALI的药物均存在疗效不满意和／或不良反应严重等问题,因此,寻找新的ALI治疗药物是急需解决的难题。
地昔帕明(DP)是一种选择性去甲肾上腺素重摄取抑制剂,是经典的三环类抗抑郁药,已被广泛用于治疗抑郁、慢性疼痛及其它神经精神疾病。有研究报道,DP可降低LPS休克的病死率,对LPS休克具有保护作用。但是目前DP对LPS急性肺损伤有何影响未见报道。
目的：本研究旨在探讨地昔帕明对LPS引起的急性肺损伤的作用,并初步探讨其作用机制。
方法：(1)建立小鼠LPS肺损伤模型,设NS组、LPS组、DP处理组和DP对照组四组。6h后处死收取标本；(2)测量肺湿重和干重的比值(W／D)并观察肺组织病理变化,以反映肺组织的损伤程度；(3)测定支气管肺泡灌洗液中蛋白和白细胞(WBC)含量,以反映支气管肺泡毛细血管通透性变化；(4)生化测定肺组织髓过氧化物酶(MPO)活性和丙二醛(MDA)水平分别反映肺组织中性粒细胞的水平和氧化损伤的程度；(5)ELASA测定肺肿瘤坏死因子-α(TNF-α)含量反映细胞因子TNF-α的变化；(6)免疫组织化学染色法测定肺NF-κB p65的表达和分布反映NF-κB在肺中含量的变化。
结果：(1)肺组织湿重／干重比值：与NS组比较,LPS组明显升高(p<0.01),与LPS组比较,DP处理组的肺湿干重比降低(p<0.05)。(2)与NS组比较,LPS组肺泡灌洗液的蛋白含量和WBC总数均明显增高(p<0.01)；DP处理组可降低LPS所引起的上述指标的升高(p<0.05)。DP组各指标则与NS组比较无显著性差异。(3)LPS组小鼠肺组织匀浆中MPO活性、MDA含量和TNF-α水平同NS组比较升高(p<0.01),DP处理后小鼠肺匀浆内MPO活性、MDA含量和TNF-α水平均较LPS组降低(p<0.05),DP对照组各指标与NS组比较无显著性差异。(4)病理变化：光镜下可见LPS组病理切片显示肺泡和间隙水肿明显,大量中性粒细胞浸润,肺间隔增厚,充血明显,DP处理后使肺损伤病理改变不同程度减轻,病理评分均显著低于LPS组(p<0.01),但仍高于NS组(p<0.01)。DP对照组和NS组相比无显著性差异。(5)NF-κB p65在NS组仅见少量散在的NF-κB p65阳性细胞,LPS组气道黏膜及肺组织中可见大量NF-κB p65表达呈强阳性的细胞,阳性细胞免疫反应产物的比例较DP处理组对比明显升高(p<0.05)。与NS组相比,LPS组和DP处理组NF-κB p65蛋白表达强度明显增强(p<0.05),DP处理组NF-κB p65蛋白表达强度较LPS组明显减轻(p<0.05)。
结论：DP能降低LPS诱导小鼠ALI模型的肺组织TNF-α水平的升高,抑制NF-κB信号转导通路的活化,减轻肺组织中性粒细胞浸润程度,抑制毛细血管通透性的增高,减少蛋白渗出及肺水含量,从而减轻LPS急性肺损伤的程度。
BACKGROUD
Acute respiratory distress syndrome (ARDS) is a common clinical syndrome.The exact pathogenesis of ARDS.however,is not well characterized. Acute lung injury (ALI) is the early stage of ARDS, lipopolysaccharide (LPS) induced sepsis is one of the most common risk factor for ALI/ARDS.Drug therapy has been reported as an important treatment for ALI, but current clinical drugs for the treatment of ALI exist in efficacy and are not satisfied and/or adverse reactions and serious problems.Therefore, to find new ALI therapies become urgent and necessary.
Desipramine (DP), a selective norepinephrine reuptake inhibitor, is the classic tricyclic antidepressants, it has been widely used to treat depression, chronic pain and other neurological mental illness. Studies have reported that DP can reduce the mortality of LPS-induced septic shock, and has a protective effect against LPS-induced septic shock. But at present,the effect of DP for LPS-induced acute lung injury have not been reported.
OBJECTIVE
To investigate the potential role of desipramine on LPS-induced ALI and the underlying mechanism.
METHODS
LPS(10 mg/kg) was injected via intraperitoneal to create acute lung injury model in mice.Random selected mice were divided into four groups:normal saline(NS) control group, LPS injured group, DP treatment group and DP control group.The mice were sacrificed at 6 hour after establishment of LPS inducing model and the lungs were obtained for determination of the following indicators:(1)Lung wet-to-dry weight ratio (W/D) and histopathological examination were used to evaluate the severity of pulmonary edema. (2) Total neutrophil count and total protein concentration in bronchoalveolar lavage fluid (BALF) were examined to reflect the changes in alveolar-capillary permeability. (3) The myeloperoxidase (MPO) activity and malondialdehyde (MDA) level were investigated to reflect respectively neutrophil recruitment and the oxidative injury in ALL(4) The TNF-a in lung tissue were detected by ELISA.(5) The expression and distribution of nuclear factor kappa B(NF-κB) p65 in lung tissue were observed by immunohistochemistry methods.
RESULTS
(1)Compared with NS group, the lung W/D ratio in LPS group was significantly higher (p<0.01);While the lung W/D ratio in DP treatment group was much lower (p<0.05) than in LPS group.(2) Compared with NS group, the total protein and the neutrophil count in BALF were significantly increased in LPS group (p<0.01),while they were much lower in DP treatment group than in LPS group (p<0.05);however, there was no significant difference between DP group and NS group.(3) Compared with NS group, the MPO activity,the levels of MDA and TNF-a in the LPS group were significantly increased (p<0.01);While the LPS induced increase of MPO activity,MDA and TNF-a levels were significantly attenuated (p<0.05) by the treatment with DP; however, there was no significant difference between DP control group and NS group.(4) Pathological changes:Light microscopy revealed an obvious alveolar and interalveolar edema, a large mount of neutrophil recruitment and the thickened interalveolar septum with significantly hyperemia in lung tissue of the LPS group.In DP treatment group, the according pathological changes were slighter and the pathological score was significantly decreased (p<0.05).However, the pathological score of the DP treatment group was still higher than that of NS group (p<0.01). (5) In NS group, a few NF-Bp65 positive immunologic reactive products were detected in lung tissue.But, in the LPS group, the increasing a large mount of NF-Bp65 positive immunologic reactive products appeared in the airway mucosa and lung tissue.Compared with the DP treated group, the positive immune reactive products were significantly higher in the LPS group (p<0.05).Compared with NS group, the NF-κB P65 protein expression intensity was markedly enhanced in both LPS group and DP treatment group (p<0.05),however, it was significantly reduced in DP treatment group compared with LPS group (p<0.05).
CONCLUSIONS
DP decreased the level of TNF-a and reduced NF-κB signal transduction pathway activation in LPS-induced mice, DP also reduced neutrophil recruitment in lung tissue and inhibitd the increased pulmonary capillary permeability, reduced protein leakage and pulmonary edema fluid, then in turn reduced the extent of acute lung injury induced by LPS.
地昔帕明(DP)是一种选择性去甲肾上腺素重摄取抑制剂,是经典的三环类抗抑郁药,已被广泛用于治疗抑郁、慢性疼痛及其它神经精神疾病。有研究报道,DP可降低LPS休克的病死率,对LPS休克具有保护作用。但是目前DP对LPS急性肺损伤有何影响未见报道。
目的：本研究旨在探讨地昔帕明对LPS引起的急性肺损伤的作用,并初步探讨其作用机制。
方法：(1)建立小鼠LPS肺损伤模型,设NS组、LPS组、DP处理组和DP对照组四组。6h后处死收取标本；(2)测量肺湿重和干重的比值(W／D)并观察肺组织病理变化,以反映肺组织的损伤程度；(3)测定支气管肺泡灌洗液中蛋白和白细胞(WBC)含量,以反映支气管肺泡毛细血管通透性变化；(4)生化测定肺组织髓过氧化物酶(MPO)活性和丙二醛(MDA)水平分别反映肺组织中性粒细胞的水平和氧化损伤的程度；(5)ELASA测定肺肿瘤坏死因子-α(TNF-α)含量反映细胞因子TNF-α的变化；(6)免疫组织化学染色法测定肺NF-κB p65的表达和分布反映NF-κB在肺中含量的变化。
结果：(1)肺组织湿重／干重比值：与NS组比较,LPS组明显升高(p<0.01),与LPS组比较,DP处理组的肺湿干重比降低(p<0.05)。(2)与NS组比较,LPS组肺泡灌洗液的蛋白含量和WBC总数均明显增高(p<0.01)；DP处理组可降低LPS所引起的上述指标的升高(p<0.05)。DP组各指标则与NS组比较无显著性差异。(3)LPS组小鼠肺组织匀浆中MPO活性、MDA含量和TNF-α水平同NS组比较升高(p<0.01),DP处理后小鼠肺匀浆内MPO活性、MDA含量和TNF-α水平均较LPS组降低(p<0.05),DP对照组各指标与NS组比较无显著性差异。(4)病理变化：光镜下可见LPS组病理切片显示肺泡和间隙水肿明显,大量中性粒细胞浸润,肺间隔增厚,充血明显,DP处理后使肺损伤病理改变不同程度减轻,病理评分均显著低于LPS组(p<0.01),但仍高于NS组(p<0.01)。DP对照组和NS组相比无显著性差异。(5)NF-κB p65在NS组仅见少量散在的NF-κB p65阳性细胞,LPS组气道黏膜及肺组织中可见大量NF-κB p65表达呈强阳性的细胞,阳性细胞免疫反应产物的比例较DP处理组对比明显升高(p<0.05)。与NS组相比,LPS组和DP处理组NF-κB p65蛋白表达强度明显增强(p<0.05),DP处理组NF-κB p65蛋白表达强度较LPS组明显减轻(p<0.05)。
结论：DP能降低LPS诱导小鼠ALI模型的肺组织TNF-α水平的升高,抑制NF-κB信号转导通路的活化,减轻肺组织中性粒细胞浸润程度,抑制毛细血管通透性的增高,减少蛋白渗出及肺水含量,从而减轻LPS急性肺损伤的程度。
BACKGROUD
Acute respiratory distress syndrome (ARDS) is a common clinical syndrome.The exact pathogenesis of ARDS.however,is not well characterized. Acute lung injury (ALI) is the early stage of ARDS, lipopolysaccharide (LPS) induced sepsis is one of the most common risk factor for ALI/ARDS.Drug therapy has been reported as an important treatment for ALI, but current clinical drugs for the treatment of ALI exist in efficacy and are not satisfied and/or adverse reactions and serious problems.Therefore, to find new ALI therapies become urgent and necessary.
Desipramine (DP), a selective norepinephrine reuptake inhibitor, is the classic tricyclic antidepressants, it has been widely used to treat depression, chronic pain and other neurological mental illness. Studies have reported that DP can reduce the mortality of LPS-induced septic shock, and has a protective effect against LPS-induced septic shock. But at present,the effect of DP for LPS-induced acute lung injury have not been reported.
OBJECTIVE
To investigate the potential role of desipramine on LPS-induced ALI and the underlying mechanism.
METHODS
LPS(10 mg/kg) was injected via intraperitoneal to create acute lung injury model in mice.Random selected mice were divided into four groups:normal saline(NS) control group, LPS injured group, DP treatment group and DP control group.The mice were sacrificed at 6 hour after establishment of LPS inducing model and the lungs were obtained for determination of the following indicators:(1)Lung wet-to-dry weight ratio (W/D) and histopathological examination were used to evaluate the severity of pulmonary edema. (2) Total neutrophil count and total protein concentration in bronchoalveolar lavage fluid (BALF) were examined to reflect the changes in alveolar-capillary permeability. (3) The myeloperoxidase (MPO) activity and malondialdehyde (MDA) level were investigated to reflect respectively neutrophil recruitment and the oxidative injury in ALL(4) The TNF-a in lung tissue were detected by ELISA.(5) The expression and distribution of nuclear factor kappa B(NF-κB) p65 in lung tissue were observed by immunohistochemistry methods.
RESULTS
(1)Compared with NS group, the lung W/D ratio in LPS group was significantly higher (p<0.01);While the lung W/D ratio in DP treatment group was much lower (p<0.05) than in LPS group.(2) Compared with NS group, the total protein and the neutrophil count in BALF were significantly increased in LPS group (p<0.01),while they were much lower in DP treatment group than in LPS group (p<0.05);however, there was no significant difference between DP group and NS group.(3) Compared with NS group, the MPO activity,the levels of MDA and TNF-a in the LPS group were significantly increased (p<0.01);While the LPS induced increase of MPO activity,MDA and TNF-a levels were significantly attenuated (p<0.05) by the treatment with DP; however, there was no significant difference between DP control group and NS group.(4) Pathological changes:Light microscopy revealed an obvious alveolar and interalveolar edema, a large mount of neutrophil recruitment and the thickened interalveolar septum with significantly hyperemia in lung tissue of the LPS group.In DP treatment group, the according pathological changes were slighter and the pathological score was significantly decreased (p<0.05).However, the pathological score of the DP treatment group was still higher than that of NS group (p<0.01). (5) In NS group, a few NF-Bp65 positive immunologic reactive products were detected in lung tissue.But, in the LPS group, the increasing a large mount of NF-Bp65 positive immunologic reactive products appeared in the airway mucosa and lung tissue.Compared with the DP treated group, the positive immune reactive products were significantly higher in the LPS group (p<0.05).Compared with NS group, the NF-κB P65 protein expression intensity was markedly enhanced in both LPS group and DP treatment group (p<0.05),however, it was significantly reduced in DP treatment group compared with LPS group (p<0.05).
CONCLUSIONS
DP decreased the level of TNF-a and reduced NF-κB signal transduction pathway activation in LPS-induced mice, DP also reduced neutrophil recruitment in lung tissue and inhibitd the increased pulmonary capillary permeability, reduced protein leakage and pulmonary edema fluid, then in turn reduced the extent of acute lung injury induced by LPS.
引文
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