Platelet factors attenuate alveolar injury during severe pneumonia

血小板因子减轻重症肺炎期间的肺泡损伤

• 批准号: 9890459
• 负责人: William G Bain
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9890459
• 关键词: AGTR2 gene; Acids; Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Alveolar; Antibodies; Apoptosis; Apoptotic; Area; Attenuated; Bacterial Pneumonia; Blood Platelets; Blood capillaries; CASP3 gene; Cause of Death; Cell Death; Cell Death Inhibition; Cells; Clinical; Critical Illness; Cytoprotection; Development; Diffuse; Elements; Epithelial; Epithelial Cells; Epithelium; Exposure to; Gases; Genetic Transcription; Goals; Gram-Positive Bacteria; Human; Immune response; In Vitro; Infection; Injury; Lead; Lower Respiratory Tract Infection; Lung; Lung infections; MPL gene; Mediating; Mitochondria; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Physicians; Platelet Count measurement; Pneumonia; Predisposition; Proteins; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pseudomonas aeruginosa pneumonia; Pulmonology; Reporter; Research; Risk Factors; Role; Scientist; Site; Staphylococcus aureus; Surveys; Therapeutic; Thrombocytopenia; Toxin; Transfusion; Veterans; acute infection; alveolar epithelium; attenuation; base; career; clinical center; combat; cytotoxicity; health administration; improved; in vivo; lung injury; mortality; mortality risk; mouse model; novel; novel therapeutics; pathogen; prevent; protective effect; reconstitution; release factor; repaired; response

Lower respiratory tract infections are a leading cause of death worldwide and can be complicated by the acute respiratory distress syndrome (ARDS), which is a major cause of morbidity and mortality in critically ill patients. Veterans are at increased risk of mortality from pneumonia so identifying novel mechanisms of protection may help improve veteran outcomes. Platelet deficiency, or thrombocytopenia, has consistently been associated with increased mortality in patients with severe pneumonia and ARDS. However, the mechanisms by which platelets may protect the host are poorly understood. We have recently shown a role for platelets in limiting alveolar- capillary barrier disruption and lung injury during acute Pseudomonas aeruginosa (PA) pneumonia in mice. We further showed that PA cell-free supernatant was sufficient to induce lung epithelial cell death with features of apoptosis as well as severe lung injury. Finally, we showed that released platelet factors can limit apoptotic cell death in lung epithelial cells in vitro as well as limit cell death and lung injury during acute PA infection in thrombocytopenic mice. However, it remains unclear the mechanisms by which platelet factors contribute to lung epithelial cyto-protection during PA infection. The main objective of this proposal is to investigate the mechanisms and implications of infection-triggered lung epithelial cell death as well as the mechanisms by which platelets and their factors provide lung epithelial cyto-protection during PA pneumonia and lung injury. Three aims will be studied. Aim 1 will investigate whether PA supernatant induces lung epithelial mitochondrial damage that leads to initiation of cell death pathways, whether the intrinsic pathway of apoptosis that classically follows mitochondrial damage contributes to PA-triggered lung epithelial cell death in vivo, and whether inhibition of lung cell death limits disruption of the alveolar-capillary barrier during PA infection in both wildtype and platelet deficient mice. Aim 2 will investigate whether platelet factors modulate post-translational anti-apoptotic pathways, examine the transcriptional profile of lung epithelial cells after PA-mediated injury in the presence or absence of platelet releasate, and survey the role of candidate platelet proteins in providing lung epithelial cyto- protection. Aim 3 will utilize development of a novel thrombocytopenic type 2 lung epithelial reporter mouse to quantify the survival and proliferation of alveolar epithelial cells to determine whether platelets are required for optimal lung epithelial repair after injury. We will also expand the generalizability of our findings by investigating the role of platelets in protecting the lung during Staphylococcus aureus pneumonia, which is similar to PA in its ability to mediate lung epithelial damage with secreted toxins. By improving understanding of the mechanisms by which platelets may provide protection during severe pneumonia, this project may help to provide rational therapeutic strategies to improve morbidity and mortality of veterans and other critically ill patients. Furthermore, this project will provide the applicant the opportunity to develop a scientific toolkit and academic portfolio to support the transition to independence as a physician-scientist focused on veteran-centered clinical and scientific research issues with the long-term career goal to become a leader in the Veterans Health Administration and academic pulmonary medicine. The applicant’s research goal is to improve understanding of how the lung interacts with and employs cellular and humoral elements of innate immunity to combat pathogens and manage injury with the potential for translational applications in treatment of severe pneumonia and acute lung injury for veterans and other patients.

下呼吸道感染是全世界死亡的主要原因，并且可并发急性呼吸道感染。 呼吸窘迫综合征（ARDS）是危重患者发病和死亡的主要原因。 退伍军人因肺炎死亡的风险增加，因此确定新的保护机制可能 帮助改善退伍军人的结果。血小板缺乏症或血小板减少症一直与 严重肺炎和ARDS患者的死亡率增加。然而，血小板的机制 可能保护宿主的机制知之甚少。我们最近发现血小板在限制肺泡- 小鼠急性铜绿假单胞菌（PA）肺炎期间毛细血管屏障破坏和肺损伤。我们 进一步表明PA无细胞上清液足以诱导肺上皮细胞死亡， 细胞凋亡以及严重的肺损伤。最后，我们发现释放的血小板因子可以限制凋亡细胞， 在体外肺上皮细胞的死亡以及急性PA感染期间的有限细胞死亡和肺损伤， 血小板减少的小鼠。然而，血小板因子促进肺损伤的机制仍不清楚。 PA感染期间的上皮细胞保护。本提案的主要目的是调查 感染引发的肺上皮细胞死亡的机制和意义，以及 血小板及其因子在PA肺炎和肺损伤期间提供肺上皮细胞保护。三 将研究目标。目的1探讨PA上清是否诱导肺上皮细胞线粒体损伤 导致细胞死亡途径的启动，无论是经典的细胞凋亡的内在途径， 线粒体损伤有助于体内PA触发的肺上皮细胞死亡，以及是否抑制肺上皮细胞死亡， 在野生型和血小板中，细胞死亡限制了PA感染期间肺泡-毛细血管屏障的破坏 缺陷小鼠目的2研究血小板因子是否调节翻译后抗凋亡蛋白的表达。 途径，检查肺上皮细胞的转录谱后PA介导的损伤，在存在或 缺乏血小板释放，并调查候选血小板蛋白在提供肺上皮细胞增殖中的作用。 保护目的3将利用一种新的血小板减少2型肺上皮报告小鼠的发展， 定量肺泡上皮细胞的存活和增殖，以确定血小板是否是 损伤后最佳的肺上皮修复。我们还将扩大我们的调查结果的普遍性， 血小板在金黄色葡萄球菌肺炎中保护肺的作用，与PA相似， 分泌毒素介导肺上皮损伤的能力。通过提高对这些机制的理解， 血小板可以在严重肺炎期间提供保护，该项目可能有助于提供合理的 治疗策略，以改善退伍军人和其他危重病人的发病率和死亡率。此外，委员会认为， 该项目将为申请人提供开发科学工具包和学术组合的机会， 支持过渡到独立作为一个医生，科学家专注于退伍军人为中心的临床和科学 研究问题的长期职业目标，成为退伍军人健康管理局的领导者， 学术肺医学。申请人的研究目标是提高对肺如何 与先天免疫的细胞和体液成分相互作用并利用它们来对抗病原体并管理 在治疗重症肺炎和急性肺损伤方面具有潜在的转化应用， 退伍军人和其他病人。