Role of CD40 in Sepsis-Induced Lung Injury

描述（由申请人提供）： 急性肺损伤（acute lung injury，ALI）是一种以液体渗出进入肺泡和释放促炎细胞因子为特征的主要健康问题。 它通常是全身炎症过程的结果，包括败血症、创伤、出血和胰腺炎。 我们使用盲肠结扎穿孔（CLP）脓毒症模型来研究细胞表面分子CD 40在小鼠ALI发生中的重要性。 我们现在报告CLP在18小时时产生肺毛细血管渗漏、炎性细胞间质浸润和30%的死亡率。 缺失CD 40的匹配小鼠在18小时时肺部炎症明显减轻，死亡率为0%。 CD 40突变还显著减弱CLP后血清和支气管肺泡灌洗液（BAL）中抗炎性IL-10和促炎性IL-6和IL-12的产生。 CD 40敲除（KO）小鼠在CLP后肺和肝中的促炎性NfkB和抗炎性C/EBPB和STAT 3转录因子也减少。 虽然能够减弱pro和pro信号，但在CD 40缺陷的小鼠中炎症的减弱占主导地位。 仅在巨噬细胞和NK细胞中具有STAT 3条件性突变的小鼠（STAT 3 KO）在基线时肺泡巨噬细胞（AM）上的细胞表面CD 40表达显著增加，但淋巴细胞没有。 这些小鼠在亚致死CLP后具有更严重的ALI，如组织学外观所证明的。 这与血清和BAL中IL-6、IL-10和IL-12产生的显著增加有关。 相反，STAT 3野生型小鼠在CLP诱导的脓毒症后肺组织学或细胞因子水平均无变化。这些数据提高了AM CD 40表达是脓毒症期间肺损伤的中心调节因子的可能性。 我们推测ALI的发展依赖于促炎和抗炎转录因子之间的平衡。 通过控制这些转录因子的诱导，CD 40的AM表达是脓毒症期间完全发展ALI所必需的。 我们建议确定CD 40调节CLP诱导的脓毒症后巨噬细胞中促炎和抗炎转录因子（分别为STAT 1和STAT 3）诱导的能力，更好地定义STAT 1和STAT 3在CD 40表达反馈调节中的作用，并定义CD 40阻断剂治疗脓毒症诱导的ALI的效用。

DESCRIPTION (provided by applicant): Acute lung injury (ALI) is a major health problem that is characterized by exudation of fluid into the alveoli and release of proinflammatory cytokines. It is frequently the result of a systemic inflammatory process including sepsis, trauma, hemorrhage and pancreatitis. We have used the cecal ligation and puncture (CLP) model of sepsis to study the importance of the cell surface molecule CD40 in development of ALI in mice. We now report that CLP produces lung capillary leak, interstitial infiltration of inflammatory cells and 30 percent morality at 18 hours. Matched mice with deletion of CD40 have marked attenuation of lung inflammation and 0 percent mortality at 18 hours. CD40 mutation also markedly attenuates production of anti-inflammatory IL-10 and proinflammatory IL-6 and IL-12 in both serum and broncho-alveolar lavage (BAL) after CLP. CD40 knockout (KO) mice also have a reduction of pro-inflammatory NfkB and anti-inflammatory C/EBPB and STAT3 transcription factors after CLP in both the lung and liver. Although capable of attenuating both pro and antiinflammatory signals, attenuation of inflammation predominates in mice deficient in CD40. Mice with a conditional mutation of STAT3 only in macrophages and NK cells (STAT3 KO) have a marked increase in cell surface CD40 expression on alveolar macrophages (AM) but not lymphocytes at baseline. These mice have a more severe ALI after sublethal CLP as evidenced by histologic appearance. This is associated with a marked increase in IL-6, IL-10 and IL-12 production in serum and BAL. Conversely, STAT3 wild type mice had no alterations in either lung histology or cytokine levels after CLP induced sepsis. These data raise the possibility that AM CD40 expression is a central regulator of lung injury during sepsis. We hypothesize that development of ALI depends upon the balance between pro and anti-inflammatory transcription factors. By controlling induction of these transcription factors, AM expression of CD40 is necessary to fully develop ALI during sepsis. We propose to determine the ability of CD40 to modulate pro and anti-inflammatory transcription factor induction in macrophages (STATI and STAT3 respectively) after CLP induced sepsis, better define the role of STAT1 and STAT3 in feedback regulation of CD40 expression and define the utility of CD40 blocking agents for the treatment of sepsis induced ALI.