Endogenous surfactant therapy for the developing lung

描述(申请人提供)：每年有9.6%的婴儿，即全球1300万婴儿出生时就有低出生体重，死亡率是正常婴儿的20倍。这些早产儿中的大多数以及一些足月儿都有异常或没有肺表面活性物质，这是一种由肺泡II型上皮(AEII)细胞分泌的脂-蛋白混合物。当肺表面活性物质功能异常时，肺部分塌陷，阻碍气体交换，这是一种可能导致死亡的严重情况。肺表面活性物质缺乏的患者总是需要机械通气。在过去的十年中，可变通风(VV)应运而生，并被证明优于传统通风(CV)。在VV中，潮气量(VT)是在逐个呼吸的基础上变化的，因此VT是从优化的分布中提取的，以实现最佳的肺泡充盈。此前，我们发现，在正常豚鼠中，VV由于表面活性物质释放增加而增加了气液界面上的表面活性物质浓度，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细胞释放表面活性物质最有效的刺激剂，体内应用于AEII细胞的拉伸模式可能对婴儿的呼吸机结局具有至关重要的作用。因此，我们推测，在表面活性物质缺乏的情况下，应用VV将导致表面活性物质的产生和分泌增加，与CV相比，肺功能和气体交换得到改善。为了验证这一假说，我们设立了3个目标：1)从健康的幼兔和肺表面活性物质缺乏的早产兔分离的培养中，研究可变牵张诱导的肺表面活性物质代谢的信号通路，包括基因调控和AEII细胞的释放。2)确定VV促进AEII细胞上调和释放肺表面活性物质基因的最佳条件。3)在幼兔和羔羊身上测试一种新的机械测试的有效性，该测试非侵入性地监测表面活性物质系统的器官水平功能。将在细胞、组织和器官水平上进行研究，以揭示VV如何通过调节特定的融合孔蛋白来促进表面活性物质的分泌。如果研究结果证实了我们的假设，那么研究结果将对新生儿护理产生重大影响。例如，我们将揭示可变拉伸诱导表面活性物质产生和释放的细胞机制。这种治疗将不需要外源性表面活性物质治疗。相反，使用简单的机械扰动(VT中的可调性)，我们将刺激体内的AEII细胞产生更多的表面活性物质，这一过程我们称为内源性表面活性物质治疗。该方法本质上是安全的，因为没有放射、化学治疗或任何其他与适度变化的VT相关的伤害。因此，我们希望在授权期结束时开始将这项技术转化为临床实践。总而言之，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与婴儿和儿童表面活性物质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.