Recombinant CC10 for treatment of meconium aspiration

描述(申请人提供)：重组人CC 10是一种新的治疗药物，目前正在临床开发中，用于预防早产儿的支气管肺发育不良(BPD)。CC10也被称为Clara细胞分泌蛋白(CCSP)或子宫红蛋白，主要由气管和支气管上皮产生。该蛋白似乎具有强大的抗炎特性，其中之一是抑制分泌型磷脂酶-2(SPLA2)。对CC10缺陷小鼠的几项研究表明，CC10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，因此RHCC10目前被用作替代药物，类似于早产儿呼吸窘迫综合征(RDS)的外源性表面活性物质。将重组人CC10引入肺内也可改善其他肺组织病理改变。在足月儿中，胎粪吸入呼吸道(无论是在宫内还是在出生后立即)会导致急性肺损伤，其特征是表面活性物质失活、肺不张和肺部炎症。sPLA2存在于胎粪中，被认为在损伤过程的发病机制中发挥重要作用。虽然表面活性物质替代疗法已用于胎粪吸入综合征(MAS)的治疗，但由于肺部炎症反应非常剧烈，这种疗法对急性肺损伤(可能是由于外源性表面活性物质失活所致)无效。由于RHCC10是一种已知有能力抑制sPLA2的抗炎药，我们建议(在体外)验证RHCC10抑制胎粪中sPLA2活性的能力，并在新生仔猪MAS动物模型(体内)中测试其疗效。

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).