Endogenous surfactant therapy for the developing lung

针对发育中肺的内源性表面活性剂疗法

• 批准号: 8370730
• 负责人: BELA SUKI
• 金额: $ 48.58万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8370730
• 关键词: Air; Alveolar; Award; Basic Science; Biological; Biological Assay; Caring; Cavia; Cells; Cessation of life; Chemicals; Child; Clinical; Clinical Research; Data; Developing Countries; Effectiveness; Environmental air flow; Epithelial; Epithelial Cells; Frequencies; Future; Gases; Gene Expression Regulation; Genes; Infant; Infant Mortality; Intervention; Lead; Lipids; Liquid substance; Low Birth Weight Infant; Lung; Mechanical ventilation; Mechanics; Metabolism; Methods; Monitor; Morbidity - disease rate; Neonatal; Organ; Oryctolagus cuniculus; Outcome; Oxygen; Patients; Pattern; Pore Proteins; Premature Infant; Probability; Procedures; Production; Proteins; Pulmonary Surfactants; Radiation; Recruitment Activity; Respiratory physiology; Signal Pathway; Signal Transduction; Stretching; System; Technology; Testing; Tidal Volume; Time; Tissues; Translating; Type II Epithelial Receptor Cell; Up-Regulation; Ventilator; World Health Organization; base; clinical practice; follow-up; improved; in vivo; lung injury; mortality; novel; premature; prospective; respiratory; response; surfactant; surfactant deficiency; surfactant deficiency in infants; therapy development

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. PUBLIC HEALTH RELEVANCE: Each year, millions of infants worldwide are born with low birth weight that results in abnormal lung function and high mortality rate. Using a simple mechanical perturbation during mechanical ventilation that is inherently safe, we aim to test a novel method that has the potential to reduce the morbidity and mortality of these infants by appropriately steering the body's own biological response.

描述（由申请人提供）：全球每年有9.6%的婴儿（1300万）出生时体重过轻，死亡率比正常婴儿高20倍。大多数早产儿和一些足月婴儿有异常或没有肺表面活性剂，这是一种由肺泡II型上皮细胞分泌的脂质-蛋白混合物。当表面活性剂功能异常时，肺部部分塌陷阻碍气体交换，严重时可导致死亡。表面活性剂缺乏的病人总是需要机械通气。在过去的十年中，可变通气（VV）出现并被证明优于常规通气（CV）。在VV中，潮汐量（VT）是在每次呼吸的基础上变化的，因此VT是从优化的分布中提取的，以实现最佳的肺泡补充。之前，我们发现在正常豚鼠中，VV增加了气液界面表面活性剂的浓度，这是由于表面活性剂释放增加，我们直接通过使用可变拉伸模式拉伸培养的原代AEII细胞来证明。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AEII细胞体内的拉伸模式可能对婴儿通气的结果具有至关重要的意义。因此，我们假设在表面活性剂缺乏的情况下，与CV相比，VV的应用将导致表面活性剂的产生和分泌增加，并改善肺功能和气体交换。为了验证这一假设，我们设定了3个目标：1)研究健康家兔和表面活性剂缺乏早产儿AEII细胞在可变拉伸诱导表面活性剂代谢的信号通路，包括基因调控和释放。2)确定VV促进健康家兔、表面活性剂缺乏的早产儿家兔和羔羊AEII细胞表面活性剂基因上调和释放的最佳条件。3)在小兔子和羔羊身上测试一种新型机械试验的有效性，该试验可以无创地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如何通过调节特异性融合孔蛋白来促进表面活性剂的分泌。如果结果证实了我们的假设，那么对新生儿护理的影响是真正重要的。例如，我们将揭示可变拉伸诱导表面活性剂生产和释放的细胞机制。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（调整VT的可变性），我们将刺激AEII细胞在体内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。该方法本身是安全的，因为没有辐射、化学处理或任何其他与适度变化的VT相关的危害。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表面活性剂缺乏相关的发病率和死亡率。