LPS-induced acute lung injury is attenuated by phosphodiesterase inhibition:: Effects on proinflammatory mediators, metalloproteinases, NF-κB, and ICAM-1 expression
LPS-induced acute lung injury is attenuated by phosphodiesterase inhibition:: Effects on proinflammatory mediators, metalloproteinases, NF-κB, and ICAM-1 expression
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DOI：
10.1097/01.ta.0000200075.12489.74
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发表时间：
2006-01-01
影响因子：
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通讯作者：
Hoyt, DB
中科院分区：
文献类型：
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作者：
Coimbra, R;Melbostad, H;Hoyt, DB
背景。急性内毒素血症的特征是炎症反应增强。己酮可可碱 (PTX) 是一种磷酸二酯酶抑制剂，已被证明可以降低 TNF-α 水平并下调中性粒细胞活化，可能是因为细胞内环 AMP 增加。其对脂多糖（LPS）诱导的肺损伤的影响，更具体地说对组织中性粒细胞浸润和脱颗粒、粘附分子表达和转录因子激活的影响尚未得到充分研究。我们假设 PTX 治疗急性内毒素血症可下调炎症反应并可能减少肺损伤。方法：将雄性 Sprague-Dawley 大鼠随机分为三组：假手术组（静脉注射生理盐水）、LPS（静脉注射 5 mg/kg）和 PTX + LPS（静脉注射分别 25 mg/kg 和 5 mg/kg；同时注射）。 4小时后，对支气管肺泡灌洗液（BAL）、血浆和肺进行取样。测量了 BAL 11-8 (ELISA)、BAL MMP-2、血浆 MW-9 和 BAL MMP-9 (酶谱)。除了通过免疫组织化学评估的肺 MPO、ICAM-1 和 NF-κ B 表达之外，还分析了肺组织学 (H&E)。通过电泳迁移率变动测定评估肺 NF-kappa B DNA 结合。结果：PTX 治疗降低了 BAL IL-8 水平、BAL MMP-2 和血浆 MMP-9 活性。 PTX 降低了肺中性粒细胞浸润 (MPO)、ICAM-1 表达和 NF-κ B 激活。此外，PTX 治疗可显着减轻 LPS 诱导的肺损伤。结论：PTX 抑制磷酸二酯酶可减轻 LPS 诱导的终末器官损伤。此外，促炎细胞因子的产生也下调，可能是因为 NF-κ B DNA 结合和激活显着减弱。
Background. Acute endotoxemia is characterized by an enhanced inflammatory response. Pentoxifylline (PTX), a phosphodiesterase inhibitor, has been shown to decrease TNF-alpha levels and to down-regulate neutrophil activation, likely because of increases in intracellular cyclic AMP. Its effects on lipopolysaccharide (LPS) induced lung injury, more specifically on tissue neutrophil infiltration and degranulation, adhesion molecule expression, and transcriptional factor activation, have not been fully investigated. We postulated that PTX treatment in acute endotoxemia downregulates the inflammatory response and may decrease lung injury.Methods: Male Sprague-Dawley rats were randomized into three groups: Sham (saline i.v.), LPS (5 mg/kg i.v.), and PTX + LPS (25 mg/kg and 5 mg/kg i.v., respectively; concomitant injection). After 4 hours, bronchoalveolar lavage fluid (BAL), plasma, and lungs were sampled. BAL 11-8 (ELISA), BAL MMP-2, plasma MW-9, and BAL MMP-9 (Zymography) were measured. Lung histology (H&E), in addition to lung MPO, ICAM-1, and NF-kappa B expression evaluated by immunohistochemistry were analyzed. Lung NF-kappa B DNA binding was evaluated by electrophoretic mobility shift assay.Results: PTX treatment decreased BAL IL-8 levels, BAL MMP-2, and plasma MMP-9 activity. Lung neutrophil infiltration (MPO), ICAM-1 expression and NF-kappa B activation were decreased by PTX. In addition, PTX treatment caused a marked attenuation of LPS-induced lung injury.Conclusions: Phosphodiesterase inhibition by PTX attenuates LPS-induced end-organ injury. In addition, proinflammatory cytokine production is also downregulated, likely because of the marked attenuation of NF-kappa B DNA binding and activation.