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）：通过Ardsnet和其他人的努力，支持疗法提高了生存；仍然是，从药物/分子治疗的角度来看，面对许多失败的抗Pro炎症介质试验，间接/肺外急性急性肺损伤（＆它更为严重的形式；急性呼吸窘迫综合征[ARDS]）的病态状况仍然存在。因此，使用突出的模型，持续的需求阐明了这种侮辱引起IALI的病理过程，这些模型更近似于严重受伤/震惊/震惊和/或化粪池患者中遇到的临床情况。 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,在IALI的发展病理中。在这种IALI模型中使用PD-1 - / - 小鼠，我们进行了一些初始观察，以表明该分子家族的近端重要性：1）单独下摆以及下摆/CLP，血液/肺吞噬细胞，淋巴细胞，淋巴细胞和肺部内皮和上皮细胞的表达有显着变化。 2）PD-1基因缺乏抑制肺细胞凋亡（AO）的指标，减少了肺组织炎症的各个方面和中性粒细胞（PMN）激活的标志。 3）PD-1 - / - 小鼠比受到下摆/CLP的野生型对照小鼠具有明显的生存优势； 4）在ICU ALI患者中检测到较高的％PD-1+血清细胞，该患者最终屈服于幸存者。考虑到这一点，我们提出了以下假设：经典的共抑制受体PD-1和/或其配体（PD-L1或PD-L2），在通过诱导局部肺部肺细胞AO和/或局部组织炎症的诱导来调节IALI的发展中起着新作用。这两个目的在以下检验以下假设：目标1：由于单独的下摆和CLP都不足以产生IALI的明显指数，因此我们将确定PD-1的表达及其配体在肺细胞上的表达程度，响应于HEM的肺部细胞上的响应而改变，而单独的HEM响应于Hem/ Clp的组合（产生fulminate filminate filminate filminate ialii）。随后，我们将不仅建立PD-1的病理作用，而且还将建立其在IALI发展中的配体。最后，我们将确定SICU/TICU患者发生这些变化的程度。 AIM 2：通过利用选择性细胞耗竭，嵌合构建和/或细胞谱系添加后背，我们将确定在给定效应元素和/或目标细胞中PD-1或PD-1或PD-L1或PD-L2的表达的程度对 iali的发展。同时，我们将开始阐明PD-1和/或PD-L的连接与各种白细胞和/或内皮/上皮细胞功能以及哪些机制控制这些共抑制剂/配体的表达。