Co-Inhibitory Molecules and the Pathology of Indirect-Acute Lung Injury

共抑制分子和间接急性肺损伤的病理学

• 批准号: 8558564
• 负责人: Alfred Ayala
• 金额: $ 30.21万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8558564
• 关键词: Acute Lung Injury; Adult Respiratory Distress Syndrome; Apoptosis; Back; Belief; Blood; Cell Lineage; Cell physiology; Cell surface; Cells; Clinical; Critical Illness; Data; Dendritic Cells; Development; Diagnosis; Endothelial Cells; Epithelial Cells; Event; Experimental Models; Family; Functional disorder; Genes; Hemorrhage; Hemorrhagic Shock; Immune; Inflammation; Inflammation Mediators; Intensive Care Units; Intervention; Leukocytes; Ligands; Ligation; Lung; Lymphocyte; Mediating; Medical; Mind; Modeling; Molecular; Mus; Operative Surgical Procedures; Organ; Outcome; Pathologic Processes; Pathology; Patients; Phagocytes; Pharmaceutical Preparations; Play; Population; Process; Reporting; Role; Shock; Small Interfering RNA; Stimulus; Structure of parenchyma of lung; Supportive care; Surgical Intensive Care; Survivors; Testing; Therapeutic; Time; Tissues; Trauma; attenuation; base; design; improved; indexing; inflammatory marker; inhibitor/antagonist; injured; macrophage; neutralizing antibody; neutrophil; novel; public health relevance; receptor; response; septic

DESCRIPTION (provided by applicant): While through efforts of ARDSnet and others, supportive therapies have improved survival; it remains that in the face of the many failed anti-pro-inflammatory mediator trials, from a medicinal/ molecular therapeutic perspective, the morbid condition of indirect/extra-pulmonary acute lung injury (iALI)(& it's more severe form; acute respiratory distress syndrome [ARDS]) have remained enigmatic. Thus, the need persists to clarify the pathological processes by which such insult(s) cause iALI, using salient models that more closely approximate the clinical scenario encountered in the critically injured/shocked and/or septic patient. In this respect, utilizing our dual insult model of iALI, resulting from hemorrhagic shock (Hem; a 'priming' insult) followed by polymicrobial septic challenge (CLP; 'triggering' event) (stimuli which [as produced here] do not induce ALI alone), we have recently uncovered a novel role for a cell surface co-inhibitory receptor molecule, known as Programmed cell death receptor (PD)-1, in the developing pathology of iALI. Using PD-1 -/- mice in this model of iALI, we have made some initial observations that point to the proximal significance of this family of molecules: 1) following Hem alone as well as Hem/CLP, there are significant changes in blood/ pulmonary phagocyte, lymphocyte, as well as lung endothelial and epithelial cell expression of PD-1 and/or it's ligand PD- L1; 2) PD-1 gene deficiency suppresses indices of lung cell apoptosis (Ao), reduces aspects of lung tissue inflammation and markers of neutrophil (PMN) activation; 3) PD-1 -/- mice have a marked survival advantage over the wild-type control mice subjected to Hem/CLP; and 4) higher %PD-1+ blood leukocytes were detected in ICU patients with ALI that eventually succumbed vs. survivors. With this in mind, we propose the following hypothesis: that the classic co-inhibitory receptor, PD-1 and/or its ligands (PD-L1 or PD-L2), play a novel role(s) in regulating the development of iALI via induction of local pulmonary cell Ao and/or local tissue inflammation. The 2 Aims below test this hypothesis: AIM 1: Since neither Hem nor CLP alone are sufficient to produce marked indices of iALI, we will determine the degree to which the expression of PD-1, as well as its ligands, on lung cells is altered in response to Hem alone vs. the combined insult of Hem/ CLP (which produces fulminate iALI). Subsequently, we will establish the pathological role of not only PD-1, but also its ligands in the development of iALI. Finally, we will determine the extent to which these changes also occur in SICU/TICU patients. AIM 2: By utilizing selective cell depletion, chimeric construction, and/or cell lineage add-back, we will establish the extent to which the expression of PD-1 or PD-L1 or PD-L2 on a given effecter cell and/or target cell population is critical to the development of iALI. Concomitantly, we will begin to elucidate what the ligation of PD-1 and/or PD-L does to various leukocyte and/or endothelial/ epithelial cell functions and what mechanisms control the expression of these co-inhibitor/ ligands.

描述（由申请人提供）：虽然通过 ARDSnet 和其他人的努力，支持疗法已经改善了生存；面对许多失败的抗炎介质试验，从医学/分子治疗的角度来看，间接/肺外急性肺损伤（iALI）（及其更严重的形式；急性呼吸道疾病）的病态仍然存在。窘迫综合征[ARDS]）仍然是个谜。因此，仍然需要使用更接近严重受伤/休克和/或脓毒症患者所遇到的临床情况的显着模型来阐明此类损伤导致 iALI 的病理过程。在这方面，利用我们的 iALI 双重损伤模型，由失血性休克（Hem；“引发”损伤）引起，随后是多种微生物败血症挑战（CLP；“触发”事件）（[此处产生的]刺激不会诱发 ALI）单独），我们最近发现了细胞表面共抑制受体分子（称为程序性细胞死亡受体（PD）-1）在 iALI 病理发展中的新作用。在这个 iALI 模型中使用 PD-1 -/- 小鼠，我们进行了一些初步观察，这些观察指出了该分子家族的近端意义：1) 单独使用 Hem 以及 Hem/CLP 后，血液中出现显着变化/肺吞噬细胞、淋巴细胞以及肺内皮和上皮细胞PD-1和/或其配体PD-L1的表达； 2）PD-1基因缺陷抑制肺细胞凋亡（Ao）指数，减少肺组织炎症和中性粒细胞（PMN）激活标志物； 3) PD-1 -/- 小鼠比接受 Hem/CLP 的野生型对照小鼠具有明显的生存优势； 4) 与幸存者相比，最终死亡的 ICU 急性肺损伤患者检测到更高的 %PD-1+ 血液白细胞。考虑到这一点，我们提出以下假设：经典的共抑制受体 PD-1 和/或其配体（PD-L1 或 PD-L2）在调节 iALI 的发展中发挥新作用通过诱导局部肺细胞 Ao 和/或局部组织炎症。下面的 2 个目标检验了这一假设： 目标 1：由于单独使用 Hem 或 CLP 都不足以产生明显的 iALI 指数，因此我们将确定肺细胞上 PD-1 及其配体的表达程度单独的 Hem 与 Hem/CLP 的联合损伤（产生暴发性 iALI）的反应发生变化。随后，我们将确定 PD-1 及其配体在 iALI 发展中的病理作用。最后，我们将确定 SICU/TICU 患者中这些变化发生的程度。目标 2：通过利用选择性细胞耗竭、嵌合构建和/或细胞谱系添加，我们将确定给定效应细胞和/或细胞上 PD-1 或​​ PD-L1 或 PD-L2 的表达程度靶细胞群对于 iALI 的发展。与此同时，我们将开始阐明 PD-1 和/或 PD-L 连接对各种白细胞和/或内皮/上皮细胞功能的作用，以及控制这些共抑制剂/配体表达的机制。