Endogenous surfactant therapy for the developing lung

描述（由申请人提供）：每年，全世界有9.6%的婴儿，即1300万婴儿出生时体重不足，死亡率比正常婴儿高20倍。大多数早产儿以及一些足月儿有异常或没有肺表面活性物质，肺泡II型上皮细胞（AEII）分泌的脂质-蛋白质混合物。当表面活性剂功能异常时，肺部分塌陷，阻碍气体交换，严重的情况可能导致死亡。患有表面活性剂缺乏症的患者总是需要机械通气。在过去的十年中，可变通气（VV）出现，并证明是上级优于常规通气（CV）。在VV中，潮气量（VT）在每次呼吸的基础上发生变化，以便从优化的分布中提取VT，以实现最佳肺泡复张。之前，我们发现在正常豚鼠中，VV增加了空气-液体界面处的表面活性剂浓度，这是由于增加了表面活性剂释放，我们通过使用可变拉伸模式拉伸培养中的原代AEII细胞直接证明了这一点。由于机械拉伸可能是AEII细胞释放表面活性剂的最有效刺激物，因此应用于体内AEII细胞的拉伸模式可能在婴儿通气的结果中具有至关重要的意义。因此，我们假设在表面活性物质缺乏的情况下，与CV相比，VV的应用将导致表面活性物质的产生和分泌增加，肺功能和气体交换改善。为了验证这一假设，我们设立了3个目标：1）研究不同牵张诱导的表面活性物质代谢的信号通路，包括从健康幼兔和表面活性物质缺乏的早产兔分离的AEII细胞培养物中的基因调控和释放。2)确定VV增强健康幼兔和表面活性物质缺乏早产兔和羔羊中AEII细胞表面活性物质基因上调和释放的最佳条件。3)在幼兔和羔羊中测试一种新型机械试验的有效性，该试验可无创监测表面活性剂系统的器官水平功能。研究将在细胞、组织和器官水平上进行，以揭示VV如何通过调节特定的融合孔蛋白来增强表面活性剂分泌。如果结果证实了我们的假设，其意义是真正重要的新生儿护理的显着影响。例如，我们将揭示可变拉伸诱导的表面活性剂产生和释放的细胞机制。该治疗不需要外源性表面活性剂治疗。相反，使用简单的机械扰动（VT的调谐可变性），我们将刺激体内AEII细胞产生更多的表面活性剂，我们称之为内源性表面活性剂治疗。该方法本质上是安全的，因为没有辐射，化学治疗或任何其他与中度变化的VT相关的伤害。因此，我们希望在奖励期结束时开始将该技术转化为临床实践。总之，这种简单的机械干预可以通过适当地引导身体的内源性反应来降低婴儿和儿童中与表面活性剂缺乏相关的发病率和死亡率。

DESCRIPTION (provided by applicant): Each year, 9.6% of infants, 13 million worldwide, are born with low birth weight with a mortality rate 20 times higher than in normal babies. Most of these preterm infants as well as some term babies have abnormal or no pulmonary surfactant, a lipid-protein mixture secreted by alveolar type II epithelial (AEII) cells. When surfactant functio is abnormal, the lung partially collapses hindering gas exchange, a severe condition that can lead to death. Patients suffering from surfactant deficiency invariably require mechanical ventilation. During the last decade, variable ventilation (VV) emerged and proved to be superior to conventional ventilation (CV). In VV, tidal volumes (VT) are varied on a breath-by-breath basis such that VT is drawn from a distribution optimized to achieve best alveolar recruitment. Previously, we found that in normal guinea pigs, VV increased surfactant concentration at the air-liquid interface due to increased surfactant release that we directly proved by stretching primary AEII cells in culture using a variable stretch pattern. Since mechanical stretch is perhaps the most potent stimulant for surfactant release by AEII cells, the stretch pattern applied to AEII cells in vivo might have a crucial importance in the outcome of ventilation of infants. Hence, we hypothesize that during conditions of surfactant deficiency, the application of VV will lead to enhanced surfactant production and secretion with improved lung function and gas exchange compared to CV. To test this hypothesis, we set up 3 aims: 1) To study the signaling pathways of variable stretch-induced surfactant metabolism including gene regulation and release by AEII cells in culture isolated from healthy baby rabbits and surfactant deficient preterm rabbits. 2) To determine the optimal conditions under which VV enhances surfactant gene upregulation and release by AEII cells in healthy baby rabbits and surfactant deficient preterm rabbits and lambs. 3) To test in baby rabbits and lambs the effectiveness of a novel mechanical assay which non-invasively monitors the organ level functionality of the surfactant system. Studies will be carried out at the cell, tissue and organ level to reveal how VV enhances surfactant secretion through regulating specific fusion pore proteins. If the results confirm our hypothesis, the implications are truly important with significant impact on neonatal care. For example, we will uncover the cellular mechanism of variable stretch-induced surfactant production and release. The treatment will not require exogenous surfactant therapy. Rather, using a simple mechanical perturbation (tuned variability in VT), we will stimulate AEII cells in vivo to generate more surfactant, a procedure we call endogenous surfactant therapy. The method is inherently safe as there is no radiation, chemical treatment or any other harm associated with moderately varying VT. Thus, we expect to start translating the technology to clinical practice toward the end of the award period. In conclusion, this simple mechanical intervention may reduce the morbidity and mortality associated with surfactant deficiency in infants and children by appropriately steering the body's endogenous response.