Coimbra Raul, Melbostad Heidi, Loomis William, Porcides Rafael D, Wolf Paul, Tobar Maria, Hoyt David B
Division of Trauma and Surgical Critical Care, Department of Surgery, University of California San Diego School of Medicine, 200 W. Arbor Drive, San Diego, CA 92103-8896, USA.
J Trauma. 2006 Jan;60(1):115-25. doi: 10.1097/01.ta.0000200075.12489.74.
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.
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 IL-8 (ELISA), BAL MMP-2, plasma MMP-9, and BAL MMP-9 (Zymography) were measured. Lung histology (H&E), in addition to lung MPO, ICAM-1, and NF-kappaB expression evaluated by immunohistochemistry were analyzed. Lung NF-kappaB DNA binding was evaluated by electrophoretic mobility shift assay.
PTX treatment decreased BAL IL-8 levels, BAL MMP-2, and plasma MMP-9 activity. Lung neutrophil infiltration (MPO), ICAM-1 expression and NF-kappaB activation were decreased by PTX. In addition, PTX treatment caused a marked attenuation of LPS-induced lung injury.
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-kappaB DNA binding and activation.
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，已被证明可降低肿瘤坏死因子-α水平并下调中性粒细胞活化，这可能是由于细胞内环磷酸腺苷增加所致。其对脂多糖（LPS）诱导的肺损伤的影响，更具体地说是对组织中性粒细胞浸润和脱颗粒、黏附分子表达以及转录因子激活的影响，尚未得到充分研究。我们推测，急性内毒素血症时PTX治疗可下调炎症反应并可能减轻肺损伤。
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组（静脉注射5 mg/kg）和PTX+LPS组（分别静脉注射25 mg/kg和5 mg/kg；同时注射）。4小时后，采集支气管肺泡灌洗液（BAL）、血浆和肺组织样本。检测BAL白细胞介素-8（ELISA法）、BAL基质金属蛋白酶-2、血浆基质金属蛋白酶-9以及BAL基质金属蛋白酶-9（酶谱法）。分析肺组织学（苏木精-伊红染色），以及通过免疫组织化学评估的肺髓过氧化物酶（MPO）、细胞间黏附分子-1（ICAM-1）和核因子-κB（NF-κB）表达。通过电泳迁移率变动分析评估肺NF-κB DNA结合情况。
PTX治疗降低了BAL白细胞介素-8水平、BAL基质金属蛋白酶-2和血浆基质金属蛋白酶-9活性。PTX降低了肺中性粒细胞浸润（MPO）、ICAM-1表达和NF-κB激活。此外，PTX治疗显著减轻了LPS诱导的肺损伤。
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，这可能是由于NF-κB DNA结合和激活显著减轻所致。
