In vivo evidence for the role of GM-CSF as a mediator in acute pancreatitis-associated lung injury
In vivo evidence for the role of GM-CSF as a mediator in acute pancreatitis-associated lung injury
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DOI：
10.1152/ajplung.00413.2001
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发表时间：
2002-09-01
影响因子：
4.9
通讯作者：
Steer, ML
中科院分区：
文献类型：
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作者：
Frossard, JL;Saluja, AK;Steer, ML
重症胰腺炎经常与急性肺损伤（ALI）和呼吸窘迫综合征相关。使用 GMCSF 敲除小鼠 (GM-CSF -/-) 评估了粒细胞巨噬细胞集落刺激因子 (GMCSF) 在介导与促分泌素诱导的实验性胰腺炎相关的 ALI 中的作用。每小时（12x）腹膜内注射超最大刺激剂量的胆囊收缩素类似物雨蛙素诱导胰腺炎。 GM-CSF 充足 (GM-CSF +/+) 对照动物和 GM-CSF -/- 小鼠中产生的胰腺炎相似。通过测量肺髓过氧化物酶活性（中性粒细胞隔离的指标）、肺泡毛细血管通透性和肺泡膜厚度来定量，GM-CSF -/- 小鼠的肺损伤比 GM-CSF +/+ 小鼠的肺损伤轻。在 GM-CSF +/+ 小鼠中，胰腺炎期间，胰腺、肺和血清 GM-CSF 水平增加。胰腺炎期间，肺中巨噬细胞炎症蛋白 (MIP)-2 的水平也会升高，但在这种情况下，GM-CSF -/- 小鼠的升高程度不如 GM-CSF +/+ 对照小鼠明显。研究发现，施用抗 MIP-2 抗体可以减轻胰腺炎相关 ALI 的严重程度。我们的研究结果表明，GM-CSF 在胰腺炎与 ALI 的耦合中发挥着关键作用，并表明 GM-CSF 可能通过调节其他促炎因子（包括 MIP-2）的释放来间接发挥作用。
Severe pancreatitis is frequently associated with acute lung injury (ALI) and the respiratory distress syndrome. The role of granulocyte-macrophage colony-stimulating factor (GMCSF) in mediating the ALI associated with secretagogue-induced experimental pancreatitis was evaluated with GMCSF knockout mice (GM-CSF -/-). Pancreatitis was induced by hourly (12x) intraperitoneal injection of a supramaximally stimulating dose of the cholecystokinin analog caerulein. The resulting pancreatitis was similar in GM-CSF-sufficient (GM-CSF +/+) control animals and GM-CSF -/- mice. Lung injury, quantitated by measuring lung myeloperoxidase activity (an indicator of neutrophil sequestration), alveolar-capillary permeability, and alveolar membrane thickness was less severe in GM-CSF -/- than in GM-CSF +/+ mice. In GM-CSF +/+ mice, pancreas, lung and serum GM-CSF levels increase during pancreatitis. Lung levels of macrophage inflammatory protein (MIP)-2 are also increased during pancreatitis, but, in this case, the rise is less profound in GM-CSF -/- mice than in GM-CSF +/+ controls. Administration of anti-MIP-2 antibodies was found to reduce the severity of pancreatitis-associated ALI. Our findings indicate that GM-CSF plays a critical role in coupling pancreatitis to ALI and suggest that GM-CSF may act indirectly by regulating the release of other proinflammatory factors including MIP-2.