Fibroblast Cell Signaling in Utero Nicotine-Induced Lung Injury

子宫内尼古丁引起的肺损伤中的成纤维细胞信号传导

• 批准号: 7528242
• 负责人: VIRENDER K REHAN
• 金额: $ 28.38万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7528242
• 关键词: Acinus organ component; Agonist; Alveolar; Arts; Chronic lung disease; Complex; Development; Disruption; Down-Regulation; Epithelial; Exposure to; Fetus; Fibroblasts; Homeostasis; Immunohistochemistry; In Vitro; Injury; Life; Lung; Mesenchymal; Mesenchyme; Modeling; Molecular; Molecular Target; Myofibroblast; Newborn Infant; Nicotine; PPAR gamma; Paracrine Communication; Pathway interactions; Perinatal; Perinatal Exposure; Peroxisome Proliferator-Activated Receptors; Peroxisome Proliferators; Phenotype; Polymerase Chain Reaction; Pregnancy; Preventive; Pulmonary function tests; Range; Risk; Signal Pathway; Signal Transduction; Smoke; Structure; Technology; Testing; Therapeutic; Time; Transcriptional Activation; Translating; Up-Regulation; Work; alveolar homeostasis; base; concept; functional genomics; in utero; in vivo; in vivo Model; injury and repair; innovation; interstitial; laser capture microdissection; lung development; lung injury; maternal cigarette smoking; medical complication; metabolomics; novel; parathyroid hormone-related protein; prevent; receptor; respiratory; transdifferentiation

DESCRIPTION (provided by applicant): Maternal smoking during pregnancy causes a broad range of effects on the developing lung of the fetus that greatly impairs its long-term function and capacity. The molecular mechanisms underlying these effects are not known. Since both normal lung development and injury/repair utilize common alveolar epithelial-mesenchymal signaling pathways to maintain homeostasis, we propose that in utero nicotine exposure disrupts the critical homeostatic epithelial-mesenchymal paracrine signaling pathways, resulting in the transdifferentiation of alveolar intersitial fibroblasts (AIFs) to myofibroblasts (MYFs). This AIF-to-MYF transdifferentiation is characterized by down regulation of the Peroxisome Proliferator Activated Receptor gamma (PPAR() signaling pathway and up regulation of the Wingless/Int (Wnt) signaling pathway. Although the effects of in utero nicotine exposure on PPAR( signaling have recently been described, there is no information on its effect on the Wnt signaling in the developing lung. We hypothesize that in utero nicotine exposure up-regulates AIF Wnt signaling and that by specific molecular targeting to down regulate the Wnt signaling and/or up regulate the PPAR( signaling, in utero nicotine-induced lung injury can be prevented or even reversed. Using well established in vitro and in vivo models of in utero nicotine-induced lung injury, through real-time RT- PCR, Western analysis, immunohistochemistry, laser capture microdissection, metabolomics, antisense and over expression studies, and in vivo pulmonary function tests, we will determine (1) how in utero nicotine exposure alters lung development, resulting in altered structure and function, and (2) if PPAR( agonists and/or Wnt antagonists, either alone or in combination, can prevent and/or reverse perinatal nicotine exposure-induced alterations in PPAR( and Wnt signaling in lung mesenchyme, and hence lung structure and function. Since the paradigm and models used by us are based on a universal developmental model for the formation, establishment, and homeostasis of the alveolar acinus, the information generated will not be limited only to in utero nicotine-induced injury but is likely to have a much larger applicability to lung development and injury/repair in general. Therefore, by utilizing functional genomics, the studies proposed herein are likely to translate into novel and innovative molecular preventive and therapeutic approaches for all chronic lung diseases in general. PROJECT NARRATIVE: Maternal smoking during pregnancy poses significant risks not only during gestation and immediate newborn period, but may also results in life long medical complications including devastating respiratory problems. The mechanisms underlying the harmful effects of maternal smoking on the lung are complex and incompletely understood. Using novel and innovative concepts, and the state-of-the-art technology, the proposed studies will unravel mechanisms that underlie not only the in utero smoke exposure-induced lung injury, but also almost all other forms of chronic lung diseases.

描述（由申请人提供）：怀孕期间的孕产妇吸烟会对胎儿发育中的肺产生广泛的影响，从而极大地损害了其长期功能和能力。这些作用背后的分子机制尚不清楚。 Since both normal lung development and injury/repair utilize common alveolar epithelial-mesenchymal signaling pathways to maintain homeostasis, we propose that in utero nicotine exposure disrupts the critical homeostatic epithelial-mesenchymal paracrine signaling pathways, resulting in the transdifferentiation of alveolar intersitial fibroblasts (AIFs) to myofibroblasts (MYFs). This AIF-to-MYF transdifferentiation is characterized by down regulation of the Peroxisome Proliferator Activated Receptor gamma (PPAR() signaling pathway and up regulation of the Wingless/Int (Wnt) signaling pathway. Although the effects of in utero nicotine exposure on PPAR( signaling have recently been described, there is no information on its effect on the Wnt signaling in the developing lung. We hypothesize that in utero nicotine exposure up-regulates AIF Wnt signaling and that by specific molecular targeting to down regulate the Wnt signaling and/or up regulate the PPAR( signaling, in utero nicotine-induced lung injury can be prevented or even reversed. Using well established in vitro and in vivo models of in utero nicotine-induced lung injury, through real-time RT- PCR, Western analysis, immunohistochemistry,激光捕获显微解剖，代谢组学，反义和过度表达研究以及体内肺功能测试，我们将确定（1）在子宫内尼古丁暴露中如何改变肺的发育，导致结构和功能改变，以及（2）如果PPAR（单独或/或Wnt ppar），则可以预防和/或ppar conteration-by-parrys-nic compartion-nic comparion-nic nic nic nic ander-inter-inter-nic to nic，nication-nic anderation-nict in nication-nic anderation-nic ander-nication-nication-nic anderation-nict in nic anderation-nication-nication-nical nic，肺间隙中的Wnt信号传导，因此肺结构和功能。由于我们使用的范式和模型是基于肺泡抗衰素的形成，建立和稳态的通用发展模型，因此所产生的信息不仅限于子宫尼古丁诱导的损伤，但总体上可能具有更大的适用性。因此，通过利用功能性基因组学，本文提出的研究可能会转化为所有慢性肺部疾病的新型和创新的预防和治疗方法。项目叙述：怀孕期间的孕产妇不仅在妊娠和直接新生儿时期构成了重大风险，而且还可能导致寿命长期的医疗并发症，包括毁灭性呼吸系统问题。孕产妇吸烟对肺部的有害作用的基础机制是复杂的，尚不完全理解。拟议的研究使用新颖和创新的概念以及最先进的技术，将揭示不仅是子宫烟雾暴露引起的肺损伤的机制，而且几乎所有其他形式的慢性肺疾病。