Hyperthermia-augmented epithelial apoptosis and acute lung injury

热疗增强上皮细胞凋亡和急性肺损伤

基本信息

批准号：
8974334
负责人：
JEFFREY D HASDAY
金额：
--
依托单位：
BALTIMORE VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8974334
关键词：
Acceleration Acute Acute Lung Injury Adult Respiratory Distress Syndrome Apoptosis Apoptotic BCL2L11 gene Biological Body Temperature CASP2 gene CASP3 gene CASP9 gene Caspase Cell Death Cell Line Cell Survival Cells Cessation of life Chronic Clinical Complex Critical Illness Data Dissociation Epithelial Epithelial Cells Epithelium Exposure to Feline Panleukopenia Fever Future Gases Goals Health Heat Stroke Heat shock proteins Heat-Shock Response Heating Human Hyperthermia Immunologics In Vitro Induced Hyperthermia Inflammation Injury Knowledge Lead Lipopolysaccharides Lung MAPK8 gene Maintenance Membrane Potentials Mitogen-Activated Protein Kinase Kinases Modeling Mus N-terminal Organ failure Paper Pathway interactions Patients Pharmaceutical Preparations Phosphotransferases Predisposition Process Protocols documentation Publishing Recovery Respiratory physiology Signal Pathway Signal Transduction Strenuous Exercise Syndrome TNF gene TNFRSF1A gene Temperature Testing Therapeutic Intervention Time Translating Tumor Necrosis Factor Receptor Work Yoga activating transcription factor airway obstruction base clinically relevant cytochrome c effective therapy endothelial dysfunction heat-shock factor 1 human disease hyperthermia treatment in vivo lung injury malignant muscle neoplasm mitochondrial membrane mortality neutrophil pre-clinical prevent pro-apoptotic protein protective effect receptor research study secondary infection surfactant

项目摘要

DESCRIPTION (provided by applicant): Lung epithelium is critical to normal gas exchange and maintenance of a physical and immu- nologic barrier against environmental dangers. Acute loss of epithelium can have devastating consequences, including loss of gas exchange, surfactant synthesis, airway obstruction, and increased susceptibility to secondary infections. The processes that regulate epithelial cell sur- vival are critical to how lung epithelium responds to acute and chronic environmental challenges with important consequences for lung function and host survival. We have identified new path- ways by which hyperthermia, such as occurs in fever, clinical hyperthermia syndromes and en- vironmental exposures, accelerate apoptosis in lung epithelium and worsen lung injury. The overall objective of this application is to elucidate the mechanisms by which hyperthermia within the febrile range modifies lung epithelial injury and recovery. Our central hypothesis is that ex- posure to hyperthermia concurrent with activation of death receptors (e.g. TNF Receptor- 1/TNFR1 or fas) accelerates assembly of the death inducing signaling complexes, augments downstream pro-apoptotic pathways, and inhibits anti-apoptotic factors. The rationale for our hypothesis is based on our recent studies demonstrating that (1) co-exposure to hyperthermia in the HS (42C) or febrile (39.5C) range greatly increases and accelerates caspase-3 activation and apoptosis in mouse MLE15 lung epithelial cells after TNF treatment or fas activation and is independent of NFB and the major heat activated transcription factor, HSF-1, and (2) there is a limited time window following TNF treatment but not fas activation after which cells are pro- tected from HS-augmented apoptosis (discussed in the Preliminary Data section). We will utilize MLE-15 mouse lung epithelial cells, BEAS2B human lung epithelial cells, and primary cultured human small airway epithelial cells (SAECs), and an in vivo intratracheal LPS-induced mouse ALI model to pursue the following specific aims: (1) determine how hyperthermia alters TNF- and fas-activated death-inducing signaling complexes, their composition, and function and the consequences for cell survival vs. death; (2) delineate the effect of hyperthermia on JNK MAP kinase signaling and the consequences for cells survival vs. death in cells TNF-treated cells; (3) analyze the mechanisms of hyperthermia-enhanced apoptosis in human lung epithelial cells, and (4) analyze the contribution of accelerated epithelial apoptosis to LPS-induced lung injury. We expect that the results of the proposed studies will identify new pathophysiologic pathways that contribute to lung injury under clinically relevant conditions. The pharmacologic studies in aim 4 will provide new preclinical data that may lead to future therapies in patients with ALI.

描述（由申请人提供）：肺上皮对于正常气体交换和维持应对环境危险的物理和免疫性障碍至关重要。上皮的急性损失可能会带来毁灭性的后果，包括气体交换，表面活性剂合成，气道阻塞以及对继发感染的易感性增加。调节上皮细胞表面的过程对于肺上皮如何应对急性和慢性环境挑战至关重要，对肺功能和宿主存活产生了重要影响。我们已经确定了高温（例如发烧，临床高温综合征和环境暴露），肺上皮凋亡加速并加速肺损伤的新路径。该应用的总体目的是阐明高热范围内的高温修饰肺上皮损伤和恢复的机制。我们的中心假设是，与激活死亡受体（例如TNF受体1/TNFR1或FAS）同时发生的高温可加速死亡诱导信号传导复合物的组装，增强下游促凋亡途径，并抑制抗吞噬因素。我们的假设的理由是基于我们最近的研究，表明（1）HS（42C）或高温（39.5C）在HS（42C）或高温（39.5C）中的共同曝光范围很大，caspase-3的激活和凋亡加速了小鼠MLE15小鼠MLE15肺上皮细胞在TNF治疗或FAS激活和NFB的肺上皮细胞中，并具有独立的NFB和IS nfb的主要因素，并且是主要的HEFB，并且是主要的HEFB，并且是主要的HEFB和IS a ISTRACTION HEFB，主要是HEFB，并且是IS nfb的主要因素，并且是主要的HEFB和INFB的主要因素。（2）TNF处理后有一个有限的时间窗口，但没有FAS激活，然后从HS-EAGENT的细胞凋亡中调查细胞（在初步数据部分中进行了讨论）。 We will utilize MLE-15 mouse lung epithelial cells, BEAS2B human lung epithelial cells, and primary cultured human small airway epithelial cells (SAECs), and an in vivo intratracheal LPS-induced mouse ALI model to pursue the following specific aims: (1) determine how hyperthermia alters TNF- and fas-activated death-inducing signaling complexes, their composition, and function and细胞生存与死亡的后果；（2）描述高温对JNK MAP激酶信号传导的影响以及细胞与细胞中TNF处理的细胞中生存的后果；（3）分析人肺上皮细胞中高温增强细胞凋亡的机制，（4）分析加速上皮凋亡对LPS诱导的肺损伤的贡献。我们预计拟议的研究的结果将确定在临床相关条件下导致肺损伤的新的病理生理途径。 AIM 4中的药理学研究将提供新的临床前数据，这些数据可能会导致ALI患者的未来疗法。