CXCR4 signaling in lung epithelial repair

CXCR4信号在肺上皮修复中的作用

• 批准号: 9232194
• 负责人: CHRISTOPHER M WATERS
• 金额: $ 27.13万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-18 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9232194
• 关键词: Acute Lung Injury; Admission activity; Adult Respiratory Distress Syndrome; Alveolar; Autopsy; Berlin; Biochemical; Biological Markers; Blood capillaries; Bronchoalveolar Lavage Fluid; CXCL12 gene; CXCR4 Receptors; CXCR4 gene; Cells; Clinical; Clinical Research; Communities; Complex; Cultured Cells; Data; Disease; Dissociation; Epithelial; Epithelial Cells; Exposure to; Focal Adhesion Kinase 1; Gases; Hyperoxia; Hypoxemia; Inflammation; Injury; Intensive Care Units; Investigation; Knockout Mice; Knowledge; Life; Lipopolysaccharides; Lung; Lung Compliance; MAP3K5 gene; MAPK8 gene; Measurement; Measures; Mechanical ventilation; Mechanics; Membrane; Modeling; Mus; Outcome; Oxygen; PP5 protein-serine-threonine phosphatase; Pathogenesis; Patients; Periodicity; Phosphoserine; Phosphothreonine; Phosphotransferases; Phosphotyrosine; Physiological; Plasma; Pneumonia; Process; Pulmonary Edema; Rattus; Reactive Oxygen Species; Recovery; Resolution; Respiratory Failure; Role; Sampling; Severity of illness; Signal Pathway; Signal Transduction; Signaling Molecule; Stretching; Supportive care; TXN gene; Testing; Therapeutic; Therapeutic Intervention; Tidal Volume; Ventilator; Ventilator-induced lung injury; Wound Healing; autocrine; base; capillary; chemokine; economic impact; in vitro Model; in vivo; injured; injury and repair; lung injury; lung repair; mechanical pressure; migration; mortality; mouse model; public health relevance; repaired; restoration; targeted treatment; tissue-factor-pathway inhibitor 2; wound

DESCRIPTION (provided by applicant): Community-acquired pneumonia (CAP) is the most common cause of acute respiratory distress syndrome (ARDS), a severe form of acute lung injury that is one of the most frequent causes of admission into the intensive care unit. Few therapeutic options are available, and mortality is high. Supportive therapy with supplemental oxygen and mechanical ventilation are essential, but additional injury can be caused by the ventilator, termed ventilator-induced lung injury (VILI). Epithelial repair is critical for disease resolution and survival, but we have limited knowledge of the underlying mechanisms of repair and how mechanical stretch impacts these mechanisms. The long term objective of this project is to increase our understanding of the mechanisms of epithelial repair and how overdistention of pulmonary epithelial cells contributes to VILI and maladaptive repair mechanisms. We previously identified an autocrine role for the chemokine CXCL12 in alveolar epithelial repair involving its receptor CXCR4. We now have preliminary data showing that patients with CAP-induced ARDS that had high levels of CXCL12 in their bronchoalveolar lavage fluid had shorter duration of mechanical ventilation and lower mortality. Based upon additional preliminary data, we propose that CXCR4 interacts with a complex of signaling molecules including focal adhesion kinase (FAK) and apoptosis signal-regulating kinase-1 (ASK1) that regulates epithelial repair. The central hypothesis of this application is that CXCL12 promotes epithelial repair, but mechanical stretch causes disruption of CXCR4-FAK-ASK1 signaling that inhibits cell spreading, migration, and repair. We will first examine whether CXCL12 is a biomarker for ARDS patients undergoing adaptive repair by measuring CXCL12 in banked samples of bronchoalveolar lavage fluid and plasma. In addition we will use autopsy samples from ARDS patients to evaluate expression of CXCR4 and phosphorylated (activated) ASK1. In the second aim we will investigate the interactions between CXCR4, FAK, and ASK1 during recovery from lung injury caused by LPS as a model of pneumonia. We will use mice with conditional deletion of CXCR4 in lung epithelial as well as ASK1 knockout mice. We will also examine the biochemical interactions of these signaling molecules in cultured alveolar epithelial cells in a scratch wound model. In the third aim we will investigate how high stretch mechanical ventilation or cyclic stretch of cultured cells disrupts these signaling pathways during repair in combined model of pneumonia (LPS) and mechanical ventilation. These studies will elucidate new signaling pathways involved in alveolar epithelial repair and how mechanical stretch disrupts the repair processes.

描述(申请人提供)：社区获得性肺炎(CAP)是急性呼吸窘迫综合征(ARDS)的最常见原因，ARDS是一种严重的急性肺损伤，是进入重症监护病房的最常见原因之一。可供选择的治疗方法很少，死亡率很高。补充氧气和机械通气的支持治疗是必要的，但呼吸机可能会造成额外的损伤，称为呼吸机诱导的肺损伤(VILI)。上皮修复对疾病至关重要 但我们对修复的潜在机制以及机械拉伸如何影响这些机制的了解有限。这个项目的长期目标是增加我们对上皮修复机制的了解，以及肺上皮细胞过度扩张是如何导致VILI和适应不良修复机制的。我们先前发现趋化因子CXCL12在涉及其受体CXCR4的肺泡上皮修复中具有自分泌作用。我们现在有初步数据表明，CAP诱导的ARDS患者的支气管肺泡灌洗液中CXCL12水平较高，机械通气时间较短，死亡率较低。基于更多的初步数据，我们认为CXCR4与调节上皮修复的信号分子复合体相互作用，包括粘着斑激酶(FAK)和凋亡信号调节激酶-1(ASK1)。这一应用的中心假设是CXCL12促进上皮修复，但机械拉伸导致CXCR4-FAK-ASK1信号中断，从而抑制细胞的扩散、迁移和修复。我们将首先通过检测储存的支气管肺泡灌洗液和血浆样本中的CXCL12来检验CXCL12是否是接受适应性修复的ARDS患者的生物标志物。此外，我们将使用ARDS患者的尸检样本来评估CXCR4和磷酸化(激活的)ASK1的表达。在第二个目的中，我们将研究CXCR4、FAK和ASK1在作为肺炎模型的内毒素引起的肺损伤恢复过程中的相互作用。我们将在肺上皮细胞中使用条件缺失CXCR4的小鼠，以及ASK1基因敲除小鼠。我们还将在划痕创伤模型中检测这些信号分子在培养的肺泡上皮细胞中的生化相互作用。在第三个目标中，我们将研究在肺炎(LPS)和机械通气联合模型中，高张机械通气或培养细胞的周期性拉伸是如何在修复过程中扰乱这些信号通路的。这些研究将阐明参与肺泡上皮修复的新的信号通路，以及机械拉伸如何扰乱修复过程。