Recombinant CC10 for treatment of meconium aspiration

描述（由申请人提供）：重组人CC 10是一种新型治疗药物，目前正在临床开发中，用于预防早产儿支气管肺发育不良（BPD）。CC 10也称为克拉拉细胞分泌蛋白（CCSP）或子宫珠蛋白，主要由气管和支气管上皮细胞产生。该蛋白似乎具有有效的抗炎特性，其中之一是抑制分泌型磷脂酶-2（sPLA 2）。在CC 10缺陷小鼠中的几项研究表明，CC 10在发育和维持正常肺功能方面非常重要。内源性CC 10在早产儿的肺中缺乏，使得rhCC 10目前被作为替代物施用，类似于患有呼吸窘迫综合征（RDS）的早产儿中的外源性表面活性剂。其他肺病理学也可以通过将rhCC 10引入肺中来改善。在足月婴儿中，胎粪吸入气道（在子宫内或出生后立即）引起急性肺损伤，其特征在于表面活性剂失活、肺不张和肺部炎症。sPLA 2存在于胎粪中，并且被认为在损伤过程的发病机制中起重要作用。虽然表面活性物质替代疗法已被用于治疗胎粪吸入综合征（MAS），但通常肺部炎症反应是如此剧烈，以至于这种疗法在治疗急性肺损伤时无效（可能是由于外源性表面活性物质失活）。由于rhCC 10是一种抗炎剂，具有已知的抑制sPLA 2的能力，我们建议验证rhCC 10抑制胎粪中sPLA 2活性的能力（体外），并在新生仔猪的MAS动物模型中测试其功效（体内）。

DESCRIPTION (provided by applicant): Recombinant human CC 10 is a novel therapeutic agent that is currently in clinical development for prevention of bronchopulmonary dysplasia (BPD) in preterm infants. CC10 is also known as clara cell secretory protein (CCSP) or uteroglobin and is produced primarily by tracheal and bronchial epithelia. The protein appears to have potent anti-inflammatory properties, one of which is inhibition of secretory phospholipase-2 (sPLA2). Several studies in CC10-deficient mice indicate that CC10 is very important in developing and maintaining normal lung function. Endogenous CC 10 is deficient in the lungs of preterm infants such that rhCC 10 is currently being administered as a replacement, analogous to exogenous surfactant in premature infants with respiratory distress syndrome (RDS). Other lung pathology may also be ameliorated by the introduction of rhCC10 into the lung. In term infants, the aspiration of meconium into the airway (either in utero or immediately after birth) causes acute lung injury, characterized by surfactant inactivation, atelectasis and pulmonary inflammation, sPLA2 is present in meconium and is thought to play a significant role in the pathogenesis of the injury process. While surfactant replacement therapy has been used in the treatment of meconium aspiration syndrome (MAS), often the pulmonary inflammatory response is so fulminant that this therapy is ineffective in treating the acute lung injury (possibly due to inactivation of the exogenous surfactant). Since rhCC 10 is an anti-inflammatory agent with known ability to inhibit sPLA2, we propose to verify the ability of rhCC 10 to inhibit sPLA2 activity in meconium (in vitro) and to test its efficacy in an animal model of MAS in newborn piglets (in vivo).